5,7- Dimethoxycoumarin Enhances Insulin Release and Stimulates Extrapancreatic Secretion of Amylin.

5,7- Dimethoxycoumarin Enhances Insulin Release and Stimulates Extrapancreatic Secretion of Amylin. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 5,7- Dimethoxycoumarin Enhances Insulin Release and Stimulates Extrapancreatic Secretion of Amylin. Emeka Ofodire, Samuel Ghasi, Anthony Mbah, Edith U. Ugwu, Theophilus O. Mbah, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4751863/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Oxidative stress decreases the ability of β-cells to secrete insulin through glucolipotoxicity of the pancreatic islets. Flavonoids modulate insulin and amylin secretion through mainly antioxidant activities. Coumarins isomers of flavonoids have direct effects on the cardiovascular system, not linked to antioxidant activities. This study aimed to investigate the effects of 5,7-dimethoxycoumarin (Citropten) fractions present in grapefruit peel on insulin and amylin secretions in normal male Wistar rats. Methods Methanol extract of grapefruit peels was fractionated using vacuum assisted liquid chromatography with n-Hexane, Ethyl acetate and Methanol. Gas Chromatography Mass Spectrometry analysis reported ethyl acetate fraction with highest concentration (85.66%) of 5,7-dimethoxycoumarin. Intraperitoneal Glucose Tolerance Test was performed on 5 sets of 5 rats receiving intraperitoneally: 1) negative control, 1ml of sterile water 2) positive control, 0.2mg/kg glimepiride, 3) ethyl acetate fraction containing 10mg/kg, 20mg/kg 5,7-dimethoxycoumarin, 4) methanol fraction containing 10mg/kg, 20mg/kg 5,7-dimethoxycoumarin 5a)1ml H 2 O 2 (0.6%, 6%) plus 20mg/kg 5,7-dimethoxycoumarin, and 5b)1000mg/kg Vitamin C plus 20mg/kg 5,7-dimethoxycoumarin. Results Results showed ethyl acetate fractions containing 10mg/kg and 20mg/kg 5,7-dimethoxycoumarin had comparable plasma glucose control with glimepiride, with indirect insulin secretion effect unlike direct acting glimepiride; the methanol fraction was less effective. Both ethyl acetate and methanol fractions of 5,7- dimethoxycoumarin induced extrapancreatic amylin synthesis and secretion. Conclusion 5,7-dimethoxycoumarin will find special applications in the management of obesity, and diabetics with chronic complications. Since the overall plasma glucose regulation is achieved through amylin and insulin synergy, attention should be shifted from insulin-based to amylin-based therapy. There is need to focus on natural compounds that stimulate extrapancreatic amylin release. Drug Discovery, Design, & Development Coumarin Antidiabetic Insulin Extrapancreatic Amylin Secretion Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Grapefruits (Citrus paradisi) are known to have antidiabetic and cardiovascular effects ( 1 ) ( 2 ) with flavonoids as their main bioactive constituents ( 3 ). Natural plant antioxidants like phenolic compounds, polysaccharides and vitamin C equally have antidiabetic effects ( 4 ) ( 5 ) ( 6 ) ( 7 ). Citrus fruits also contain other secondary metabolites like alkaloids, coumarins, carotenoids, limonoids, essential oils ( 8 ) ( 9 ). Flavanones and furanocoumarins are the main components of grapefruits implicated in grapefruits - drugs interactions by inhibiting the cytochrome P – 450 metabolisms ( 3 ). Citrus plants biosynthesize both coumarins and furanocoumarins, with grapefruits contributing about 73% of furanocoumarins in western diet ( 3 ). The highest concentration of coumarins and furanocoumarins are found in the peel of citrus fruits, just like flavonoids ( 10 ). Most of the flavonoids in grapefruit occur as glycosides while Coumarins occur in free forms, as glycosides, esters, and sublimates ( 11 ). Coumarins and flavonoids are heterocyclic molecules and they are also isomers. Coumarins are used in the treatment of prostate cancer, renal cell carcinoma and leukemia ( 12 ) They have been reported to neutralize the side effects of radiotherapy ( 12 ) . Unlike the flavonoids whose effects are predominantly antioxidant in nature, coumarins have direct anticoagulation pharmacological activities on the cardiovascular systems, not linked to antioxidant effects( 13 ) by inhibiting the activation of Vitamin K and blocking the synthesis of coagulation factors. Coumarins also have direct antiplatelet effects by inhibiting ADP( 13 ) ( 14 ) and vasodilating activities by inhibition of calcium influx into the cell through calcium channel blockage ( 13 ) ( 15 ). Coumarins are known to be hepatotoxic and carcinogenic following chronic oral gavages in rats ( 16 ) ( 17 ).. Coumarin - linked toxicity are also known to be species-specific and metabolism - dependent ( 17 ). Coumarin – mediated toxicity in rat liver and mouse lung cancer are linked to the production of coumarin 3, 4- epoxide (CE) the preferential metabolite in rats. Several studies in 1989 and 1998 in animals treated with dihydrocoumarin (DHC), a structural analog of coumarin saturated at the 3, 4-position, impossible to form an epoxide, showed neither hepatotoxicity nor Lung cancer ( 17 ). There were no liver nor lung cancers in F344 rats in the National Toxicology Program oral gavage studies in 1993 ( 17 ). Also, CD – 1 mice exposed to dietary coumarin at 0, 27, 89 and 276mg/kg/day in utero, via lactation and weaning, and chronically for two years afterwards, reported no increased incidence in liver nor lung cancers ( 17 ) ( 18 ). Sprague – Dawley rats given up to 234mg/kg/day of coumarin in the diet for two years showed no tumors until they exceeded the maximum tolerated dose ( 17 ) ( 18 ). While a single Intraperitoneal injection of coumarin (25mg/kg, 50mg/kg) caused tissue – selective cytotoxicity in olfactory mucosa of Wistar rats and C57BL/6 mice, there were no reduction of P450 components in the liver of either rats nor mice at 50mg/kg, after 48 hours of injection ( 19 ). Intraperitoneal administration of 7-hydroxycoumarin or 3,4-dihydrocoumarin at 50mg/kg did not lead to reduction of olfactory nor liver P450. This shows that toxicity is not mediated by P450-catalyzed coumarin 7 – hydroxylation and greatly supports the theory that the production of coumarin 3, 4-epoxide is the cause of the toxicity ( 19 ). Coumarins oral LD50 is 290-680mg/kg in rats, 196-780mg/kg in mice. Intraperitoneal LD50 is 710mg/kg in mice. The no sign of oral acute toxicity level in rats is 125mg/kg ( 20 ) ( 21 ). The maximal allowed daily intake from diet is 3.5mg/day,( 22 ) while the maximal allowed coumarins levels in foods prepared with cinnamon flavor in EU are 50mg/kg in bakery products and 5mg/kg in desserts ( 20 ). Recommended clinical doses of coumarins varies from 8mg for treatment of venous constriction to 7000mg/day in chemotherapies ( 22 ). In type 1 diabetes (10% of Diabetes), there is deficient insulin and amylin production and secretion. This results in their low baseline serum concentrations and decreased or absence response of these hormones to caloric intake, leading to chronic hyperglycemia. Type 2 diabetes (90% of diabetes) is characterized by hyperglycemia, insulin resistance and abnormal beta cell function ( 23 ). 30% or more of type 2 diabetes patients will benefit from insulin therapy to control blood glucose ( 24 ). Coumarins have been reported to show antidiabetic effects through several mechanisms and pathways in vitro and in vivo ( 11 ) ( 25 ). Oxidative stress is implicated in type 2 diabetes pathogenesis through glucolipotoxicity of the pancreatic islets and non-islet tissues, leading to deterioration of islet function and insulin sensitivity, with alterations in insulin gene expression leading to severely reduced levels of transcription factors MafA and Pdx-1 ( 26 ). Glucolipotoxicity affects mitochondria function like impairment of electron transport chain activity, leading to reactive oxygen species generation, triggering inflammation in peripheral tissues and insulin secreting β-cells ( 27 ). Coumarins have shown ability to activate the Nrf2 pathway in various cells. The Keap/Nrf2/ARE system is a major defensive pathway against oxidative stress ( 28 ). Insulin production in β-cells of pancreas is initiated as preproinsulin, which is translated and translocated across the endoplasmic reticulum, oriented, folded and cleaved to form proinsulin ( 29 ). Folded proinsulin transit through the Golgi apparatus where they are packaged in secretory vesicles. The mature insulin will be exocytose in equimolar amounts with C – Peptide, from the cells into circulation upon activation by metabolic signals and vagal nerve stimulation. After each meal, the β – cells release insulin to enhance glucose uptake by cells. Insulin release is divided into 3 phases viz., cephalic, early and late enteric. ATP – sensitive K + channel activity couple β-cell metabolism to voltage - gated Ca 2+ channels. A study on the in vitro cell culture with a new prenylated coumarin diglycoside and five known flavonoid glycosides reported insulin release enhancing activities ( 30 ). Another study showed that coumarins extracted from Clutia lanceolate Forssk promoted glucose-triggered secretion of insulin from pancreatic islet ( 31 ). Coumarins are equally known to inhibit Dipeptidyl peptidase - IV enzyme in vitro ( 32 ). Amylin (islet amyloid polypeptide) is formed in pancreatic islet β-cells. it was originally discovered as the main component of pancreatic amyloid deposit ( 33 ). It is co-localized, co-packaged and co-secreted with insulin in response to caloric intake in the ratio 1:100 ( 34 ).But its immunoreactivity and mRNA are equally found in islet somatostatin - producing δ - cells; in the lungs, stomach, duodenum, jejunum, ileum, colon, and rectum; and all through the CNS ( 35 ). The secreted ratio of amylin: insulin in acute states is constant, but chronic hyperglycemia may enhance the induction of amylin synthesis and secretion over that of insulin. The degree of amylin deficiency correlates with the degree of insulin deficiency ( 36 ). Amylin plasma concentration is 4–8 pmol/L in fasting and 15–25 pmol/L in postprandial states and these levels correlate with those of insulin ( 35 ). The molecular weight of amylin is 1378.6g/mol. The tendency of human amylin to form amyloid aggregation has limited research on the development of pharmacological agents that can stimulate endogenous amylin secretion and has led to the development of synthetic amylin analogs like pramlintide, that is more resistant to fibril formation. Coumarins due to their aromatic structures, are known to potently inhibit cholinesterases (acetylcholinesterase, and butyrylcholinesterase) enzymes that promote and propagate β - amyloid aggregation ( 37 ), and also Monamine Oxidase (MAO) which induces β - amyloid deposition ( 38 ) ( 39 ). Various flavonoids inhibit human amylin amyloidosis through unknown mechanism ( 40 ). Amylin is a 37 - amino acid peptide member of the calcitonin gene family, with G- Protein - functionally linked receptors. Amylin gene is located on the p arm of human chromosome 12 ( 41 ). It functions in glycemic control by enhancing satiety, inhibiting postprandial glucagon release, slowing gastric emptying, inhibiting secretion of digestive enzymes ( 41 ), inhibition of bone resorption ( 35 ) and synergizes with leptin to cause weight loss ( 41 ). This study strives to be the first to focus on extrapancreatic stimulation of amylin release by natural compounds in the management of diabetes. Flavonoids are known to modulate insulin and amylin secretion through mainly their antioxidant activities, but the effects of coumarins on insulin and amylin secretion have not been thoroughly studied and elucidated. Coumarins with direct effects on the cardiovascular system will be of utmost benefit in the management of diabetics, since the chronic complications of diabetes are mainly vascular in nature. The aim of this study is to investigate in vivo the effects of 5,7-dimethoxycoumarin (Citropten) fractions present in grapefruit peel extract on insulin and amylin secretions in normal male Wistar rats. MATERIALS AND METHODS Study Area The research was carried out at the Department of Laboratory Animals, Enugu State University of Science and Technology, Enugu (ESUT). The draft proposal was reviewed and approved by the Department of Pharmacology and Therapeutics, College of Medicine University of Nigeria Enugu Campus. The study protocol was approved by the college of medicine research ethics committee. Study Animals 60 male Wistar rats approximately of same aged (12 -16week old) and weight (160 – 273g) (Supplementary Table 1 and Supplementary Table 2) were sourced from ESUT animal house. Only male rats were used for the study due to considerable gender differences in glucose regulation and insulin sensitivity (42) (43). They were kept in 12 cages (5 rats per cage), weighed and fed with standard laboratory diet, and had free access to water for 1 month. The rodent cages were temperature, humidity and light-controlled housing. The study was carried out in line with conventional laboratory principles on the use of animals based on the European Community Guidelines 1986. Study Plant Fresh grapefruit peels were obtained from one of the grapefruit trees in the garden of Ofodire Emeka (the principal investigator) for the study. The LD50 of grapefruit peel and seed extract is 5,000mg/kg (44). The No-observed-adverse-effect-level (NOAEL) for male rats is 600mg/kg/day (45) . Sample Preparation : Samples of grapefruit peels were first dried in air. The dried samples were coarse ground to particles less than 0.5mm to improve the extraction efficiency and weighed 1.187kg. Extraction of Coumarins from Grapefruit Peel was carried out in Department of Chemistry Laboratory, University of Nigeria, Nsukka. Cold maceration method of extraction was used as studies have shown it to be suitable and convenient method for coarse ground plant materials (46) and phenolic compounds (46) (47). Methanol was chosen as the solvent of extraction as studies reported it to have the highest extractability among other solvents for phenolic compounds (47) and coumarins (48). 90% methanol was added to the sample at menstruum: sample ratio 4:1. The mixture was constantly agitated and left for 72 hours. Filtration was carried out using number 1 Whatman filter paper. The micelle was concentrated using Rotary evaporator under vacuum to remove the menstruum from the extract, and water bath used for cooling. The crude extract was weighed and measured 212g, and the marc discarded. Separation of the Extract into Factions: was carried out using Vacuum Liquid Chromatography (VLC) in Department of Chemistry Laboratory, University of Nigeria, Nsukka. The crude extract was mixed with silica gel adsorbent (solid phase) of size 100 – 200 mesh to form homogeneous mixture. The mixture was allowed to dry and was further ground into fine powder using porcelain (ceramic) mortar. Then, it was gently and neatly packed into glass column of length 1m and diameter 4cm.The column was connected to a vacuum pump and the pump switched on. The fractionation took place based on choice solvent (mobile phase), N-Hexane, Ethyl Acetate and methanol in increasing order of polarity. The fractions were concentrated by exposing them to dry air. The weights of the concentrated fractions were as follows: n-Hexane (dry fraction) = 0.02g, Ethyl Acetate (dry fraction) = 1.01g, Methanol (oily, waxy, viscous fraction) = 78.20g. Gas Chromatography – Mass Spectrometry (GCMS): was carried out at Ebic Integrated Services Limited Laboratory Port Harcourt Nigeria (Supplementary figure 1). The analyzed results for the 3 fractions reported the most abundant constituents as follows: a) Ethyl Acetate Fraction: 2H-1-Benzopyran-2-one, 5,7-dimethoxy- (Citropten Coumarin C 11 H 10 O 4 ) 85.66%, Phytol (Diterpenes) 1.96%, 7H – Furo(3,2-g)(1) benzopyran – 7- one, 4-methoxy- (bergapten Furanocoumarin C 12 H 8 O 4 ) 1.05%, Carveol (Tarpenoid alcohols) 0.63%. b) Methanol Fraction: 2H-1-Benzopyran-2-one, 5,7-dimethoxy- (Citropten Coumarin) 70.60%, 7H – Furo(3,2-g)(1) benzopyran – 7- one, 4-methoxy- (bergapten Furanocoumarin) 4.70%, Diisooctyl phthalate (Phthalate esters) 1.16%, Phytol (Diterpenes) 0.64%. c) n-Hexane Fraction: Bis(2-ethylhexyl) phthalate (Phythalate esters) 51.03%, beta-Bisabolene (sesquiterpenes) 8.70%. Further purification of fractions was not possible due to unavailability of specified High Performance Liquid Chromatography and Nuclear Magnetic Resonance equipment in Nigeria at time of study. Study Design The study was Randomized Controlled Blinded and divided into experiments. Because we were dealing with homogenous rat population that were in cages (clusters), multistage cluster sampling method was used for selection. The mean values of obtained results sets were used. Heparinized sample bottles were used for blood samples collection. Plasma was used for assessing hormones due to their short lifespan in serum (49). 0.5% polysorbate 20 excipient (Tween 20) served as diluents and vehicle for the methanol and ethyl acetate fractions of 5,7 – dimethoxycoumarin and the controls (50). Intraperitoneal Glucose Tolerance Tests (IPGTT) was used in the study 1) to produce hyperglycemia, 2) for on-the-spot determination of glucose levels with Glucometer, 3) for simultaneous injection of glucose (50% dextrose 2g/kg), grapefruit peel fractions and drugs, 4) for determination of plasma parameters at 0min, 30min, 60min and 120min intervals of time, after overnight fast (12 hours), 5) as an alternative route of administering coumarins. About 3mls of blood was collected from retro-orbital plexus puncturing of each animal for the entire study. The samples were immediately centrifuged after collection and plasma separated from blood cells. The plasma was stored at – 20degrees Celsius and analysis started immediately. Primary Experiments on All Parameters: 1) 5 rats (Rats 1 – 5) were used as negative control on IPGTT. 1ml of sterile water was given simultaneously (in quick succession) with 2g/kg of glucose intraperitoneally over 30 seconds. 2) 5 rats (Rats 6 -10) as positive control on IPGTT. 0.2mg/kg of glimepiride (equivalent of 2mg daily dosing in humans) (51) given simultaneously with 2g/kg of glucose. Glimepiride was chosen as positive control drug because has better safety profile, does not interfere with insulin and glucagon homeostasis and is less prone to profound hypoglycemia compared to other sulfonylureas (52). Oral LD50 of glimepiride in rats is >10000mg/kg, intraperitoneal LD50 in rats is 3950mg/kg (53). 3) 5 rats (Rats 11 -15) test for direct insulin releasing effects of ethyl acetate fractions containing 5,7-dimethoxycoumarin on IPGTT. 2g/kg of glucose was given simultaneously with ethyl acetate fraction containing 20mg/kg of 5,7-dimethoxycoumarin. (1g of ethyl acetate fraction contains 856.6mg of 5,7-dimethoxycoumarin). 4) 5 rats (Rats 16 – 20) test for direct insulin releasing effects of methanol fractions containing 5,7-dimethoxycoumarin on IPGTT. 2g/kg of glucose was given simultaneously with methanol fraction containing 20mg/kg of 5,7-dimethoxycoumarin. 5) 5 rats (Rats 21 – 25) test for pro-oxidant actions of H 2 O 2 and high dose vitamin C on effects of ethyl acetate fractions containing 5,7-dimethoxycoumarin on IPGTT. H 2 O 2 is an oxidizing agent implicated in the pathogenesis of oxidative stress. The LD50 is 600 – 1617mg/kg (Y.Li, unpublished; Ito et al., 1976). It is generally safe at 3%. Household concentration varies from 3 – 9% (Nelson AL, et al., 2023). 2g/kg of glucose was given simultaneously with 1ml of 6% H 2 O 2 and 20mg/kg of 5,7-dimethoxycoumarin, intraperitoneally in Rat 23. Repeat with 0.6% H 2 O 2 for Rats 21 – 22. Vitamin C acts as antioxidant at low doses (30 – 100 mg/kg) and pro-oxidant at high doses (1000mg/kg) (54). The LD50 of vitamin C is 11,900mg/kg in rats (55). 2g/kg of glucose was given simultaneously with 1000mg/kg of vitamin C and 20mg/kg of 5,7-dimethoxycoumarin, in Rats 24 - 25. Secondary (Supplemental) Experiments on Plasma Glucose Effect Only: 6) 5 Rats (Rats 26 – 30) test for ethyl acetate fraction containing 10mg/kg 5,7-dimethoxycoumarin on IPGTT. 7) 5 Rats (Rats 31 – 35) test for methanol fraction containing 10mg/kg 5,7-dimethoxycoumarin on IPGTT. 8) 5 Rats (Rats 36 – 40) negative control on Oral Glucose Tolerance Test (OGTT). 9) 5 Rats (Rats 41 – 45) positive (glimepiride) control on OGTT. 10) 5 Rats (Rats 46 – 50) test for ethyl acetate fraction containing 20mg/kg 5,7-dimethoxycoumarin on OGTT. RESULTS AND ANALYSIS Test kits and Laboratory Analysis Rat ELISA Test Kits for insulin, amylin, c- peptide and proinsulin, were procured from Solarbio Life Sciences and Technology Co., Ltd Beijing China, and also total antioxidant status (TAS) and malondialdehyde sourced locally. Laboratory analysis was carried out at the Department of Chemical Pathology Laboratory and Molecular Virology Laboratory University of Nigeria Teaching Hospital, Enugu following the procedures outlined in the kits’ manual. Statistical Analysis Statistical analysis was carried out with IBM SPSS version 25. Data were summarized using mean and standard deviation and presented in graphs. Bars were used to represent different groups. Comparison between groups was done using one-way independent ANOVA with Fisher's Least Significant Difference (LSD) for the post-hoc multiple comparisons. Comparison within group was done using paired samples t-test. Differences were considered significant when p-value < 0.05. Plasma Glucose Analysis Table 1 Plasma Glucose Results (mmol/L) for the 2-hour IPGTT and OGTT for Rats 1–50. Rat 0 MIN 30 MIN 60 MIN 120 MIN Rat 0MIN 30MIN 60MIN 120MIN Rat 1 4.5 24.94 19.5 14.38 Rat 26 5.166 29.16 20.61 15.72 Rat 2 4.72 13.8 14.16 10.77 Rat 27 5.33 15.11 9.66 11.38 Rat 3 5.77 32.61 26.11 16.16 Rat 28 6.05 28.77 17.00 13.94 Rat 4 7.83 13.66 21.94 16.77 Rat 29 5.66 25.72 21.33 22.66 Rat 5 4.61 12.88 12.22 7.94 Rat 30 7.00 29.50 17.27 12.66 Rat 6 5.66 20.00 16.33 15.05 Rat 31 3.94 Too High 18.05 10.38 Rat 7 5.77 29.33 27.00 21.83 Rat 32 4.61 Too High 20.50 15.83 Rat 8 5.27 24.77 17.88 15.38 Rat 33 5.77 Too High 25.27 21.88 Rat 9 6.83 21.05 9.94 8.94 Rat 34 4.05 26.55 17.00 10.55 Rat 10 5.88 24.66 13.94 6.83 Rat 35 4.55 31.88 16.38 8.72 Rat 11 5.16 28.50 16.94 8.83 Rat 36 5.77 6.44 6.50 5.83 Rat 12 4.33 14.27 13.61 13.72 Rat 37 5.11 6.83 7.00 7.94 Rat 13 4.55 25.50 20.00 14.77 Rat 38 5.88 6.77 7.22 7.77 Rat 14 4.61 27.77 26.33 25.61 Rat 39 5.38 5.72 6.88 6.77 Rat 15 4.61 7.11 6.94 6.94 Rat 40 4.11 4.94 6.33 6.16 Rat 16 5.05 30.50 24.55 20.66 Rat 41 5.44 6.11 6.77 5.66 Rat 17 4.94 31.55 26.72 28.11 Rat 42 4.00 7.38 6.94 8.77 Rat 18 4.38 Too High 28.11 24.88 Rat 43 3.88 4.611 7.27 Rat 19 4.83 Too High Too High Too High Rat 44 3.66 6.33 7.05 Rat 20 5.94 30.77 22.83 20.16 Rat 45 5.11 6.44 7.00 Rat 21 5.72 27.61 26.55 Rat 46 4.05 5.33 5.83 5.33 Rat 22 4.16 8.22 7.94 Rat 47 4.77 5.77 6.16 5.88 Rat 23 5.44 22.16 26.22 32.94 Rat 48 5.16 5.66 5.50 Rat 24 4.72 Too High Too High Too High Rat 49 5.11 5.88 6.38 Rat 25 4.5 Too High Too High 32.22 Rat 50 6.05 5.44 6.05 There were marked hyperglycemias in Rats 1–35 at 30min following simultaneous intraperitoneal glucose administration with test drugs (Table 1 , Fig. 1 ). These hyperglycemias were not noticeable with Rats 36–50 on OGTT- Drug route, owing to the incretin effect, with slower and regulated rates of glucose absorption likely due to amylin effect since incretin mediated insulin release has reported reduced efficacy ( 56 ). Ethyl acetate fractions containing 10mg/kg and 20mg/kg 5,7-dimethoxycoumarins (Rats 26–30 and Rats 11–15) had comparable (Fig. 1 ) plasma glucose control on IPGTT with the positive control and negative control, probably due to its higher content of 5,7 – dimethoxycoumarin (85.66%). Methanol fractions containing 20mg/kg 5,7 - dimethoxycoumarin was less effective than both controls (with significant p values differences = 0.002–0.041). This is most likely due to its lower content of 5,7 – dimethoxycoumarin (70.60%) and suppression of pancreatic functions by its other constituents. Plasma C – Peptide Analysis Table 2 Plasma C - Peptide Assay (pg/ml) for the 2-hour IPGTT for Rats 1–25 . RAT 0 MIN 30 MIN 60 MIN 120 MIN 1 130.18 118.39 144.14 205.00 2 120.76 120.76 123.13 127.84 3 141.83 7507.56 162.48 127.84 4 123.13 123.13 263.49 7958.94 5 - - - - 6 123.13 125.49 123.13 123.13 7 120.76 120.79 113.64 148.75 8 137.19 185.02 120.79 120.76 9 132.52 125.49 99.19 123.13 10 - - - - 11 123.13 118.39 182.79 96.76 12 125.49 116.02 125.49 132.52 13 127.84 125.49 187.26 125.49 14 130.18 125.49 141.83 7682.84 15 139.51 123.13 144.14 125.49 16 530.43 127.84 125.49 139.51 17 134.86 259.22 134.89 123.13 18 118.39 125.49 7895.44 127.84 19 116.02 116.02 130.18 94.32 20 125.49 116.02 134.86 132.52 21 127.84 118.39 7761.47 22 120.76 157.92 8070.9 23 118.39 132.52 132.52 132.52 24 118.39 137.19 127.84 263.49 25 187.26 261.35 130.18 198.37 Plasma C - peptide concentrations data were used to determine and analyze insulin secretion since insulin has very short lifespan in plasma. In Rats 16–20 (methanol fraction containing 20mg/kg 5,7-dimethoxycoumarin) (Table 2 and Fig. 2 ), the C - peptide concentration decreased progressively on the average from 0mins to 120min. This again showed pancreatic suppression by the methanol fraction. Oxidative stress index (OSI) is calculated as Total Oxidant Status (TOS) /Total Antioxidant Status (TAS). Due to unavailability of Total Oxidant Status kit, OSI was calculated as Malondialdehyde /TAS (Table 3 , Table 4 , Table 5 ). OSI ratio (Table 3 ) was highest on the average for Rats 1–22 in the 30min of IPGTT and lowest on the average at 60min of IPGTT for Rats 1–22. For Rats 11–15 (Ethyl acetate fraction containing 20mg/kg 5,7-dimethoxycoumarin), malondialdehyde (Table 5 ) had least concentration at 60mins.The C – peptide (Table 2 , Fig. 2 ) release was highest at 60mins (p = 0.043) where oxidative stress was lowest and lowest at 30mins where oxidative stress and hyperglycemia were highest, showing that 5,7-dimethoxycoumarin mediated insulin release was mainly as a result of its antioxidant effect. This was in contrast with Glimepiride positive control, (Table 2 and Fig. 2 ) where C – peptide release was highest at 30min (highest hyperglycemia and oxidative stress point) and lowest at 60mins (p = 0.173) (lowest point of oxidative stress) showing that the insulin mediated release of glimepiride was direct and dependent on hyperglycemia and not on antioxidant effect. The fact that 5,7-dimethoxycoumarin insulin mediated release was mainly as a result of its antioxidant effect was confirmed where its antioxidant property was neutralized as in Rats 23, when administered simultaneously with 6% H 2 O 2 . In this case, the C – peptide concentration remained constant at 132.5pg/ml from 30min throughout the entire study period, while the plasma glucose concentration steadily increased. Table 3 Oxidative Stress Index Calculated as Malondialdehyde/TAS for Rats 1–25 over 2-hour IPGTT RAT 0 MIN 30 MIN 60 MIN 120 MIN 1 0.89 0.86 0.56 0.89 2 2.03 1.71 0.96 0.42 3 1.29 0.65 0.20 0.55 4 0.90 1.43 0.99 0.56 5 - - - - 6 0.95 1.28 0.88 0.77 7 0.66 0.96 0.71 0.80 8 1.19 0.61 0.49 0.58 9 0.42 0.43 0.38 0.26 10 - - - - 11 0.11 0.62 0.39 0.45 12 2.14 0.99 0.18 0.70 13 3.08 3.72 1.45 0.85 14 2.44 1.73 0.41 0.20 15 1.25 0.65 0.67 0.87 16 1..25 1.57 0.63 0.99 17 1.87 0.97 0.71 0.94 18 0.18 0.58 0.58 1.22 19 0.42 0.41 0.35 0.47 20 0.95 0.90 0.23 0.44 21 1.60 1.44 1.14 22 0.55 0.57 0.55 23 1.27 0.84 0.76 0.30 24 1.87 0.63 0.28 0.54 25 1.19 0.42 0.30 0.31 Table 4 Plasma Total Antioxidant Status TAS (micromol/L) for the 2-hour IPGTT for Rats 1–25. Rat 0MIN 30MIN 60MIN 120MIN 1 1953 1903 1498 1241 2 1075 1092 1465 1410 3 1229 985 1137 1206 4 1851 1077 1299 1505 5 - - - - 6 1264 1197 1164 1358 7 1209 1333 1418 1448 8 1142 1174 1050 1779 9 1271 1132 1142 1204 10 - - - - 11 978 985 920 910 12 1052 881 1020 1206 13 1448 1129 1418 1786 14 1311 1204 1381 1378 15 1455 1177 990 1002 16 1500 1047 1388 1092 17 1754 1368 1905 1363 18 1291 1236 1281 1007 19 1346 1378 1751 1701 20 1396 1420 1102 1214 21 1152 1284 1236 22 1159 1254 1306 23 1873 1614 1677 1697 24 1483 4861 4774 4796 25 1682 4769 4759 4794 Table 5 Plasma Malondialdehyde Assay (nmol/ml) for the 2-hour IPGTT for Rats 1–25. Rat 0MIN 30MIN 60MIN 120MIN 1 1744 1641 846 1103 2 2179 1872 1410 590 3 1590 641 231 667 4 1667 1538 1282 846 5 - - - - 6 1205 1538 1026 1051 7 795 1282 1000 1154 8 1359 718 513 1026 9 538 487 436 308 10 - - - - 11 103 615 359 410 12 2256 872 179 846 13 4462 4205 2051 1513 14 3205 2077 564 282 15 1846 769 667 872 16 1872 1641 872 1077 17 3282 1333 1359 1282 18 231 718 744 1231 19 564 564 615 795 20 1333 1282 256 538 21 1846 1846 1410 22 641 718 718 23 2385 1359 1282 513 24 2769 3077 1333 2590 25 2000 2000 1436 1487 Plasma Insulin Analysis Table 6 Plasma Insulin Assay (mU/L) for the 2-hour IPGTT for Rats 1–25. RAT 0 MIN 30 MIN 60 MIN 120 MIN 1 26.60 1.25 1.19 1.00 2 1.06 1.25 1.50 1.06 3 1.31 0.81 1.25 1.56 4 1.19 1.25 1.31 1.25 5 - - - - 6 1.31 1.75 1.19 1.13 7 1.50 1.25 12.50 1.13 8 1.31 1.06 1.13 9 2.31 1.31 1.50 1.75 10 - - - - 11 1.50 1.50 2.50 1.13 12 1.69 1.31 1.56 1.06 13 1.25 1.31 1.50 1.69 14 1.13 1.25 1.19 1.13 15 1.13 1.13 1.13 0.69 16 1.31 1.31 1.19 0.81 17 1.75 1.31 2.31 1.06 18 1.50 10.00 1.13 1.13 19 1.69 1.56 1.69 1.13 20 1.06 1.31 15.10 21 1.25 1.19 1.25 22 1.25 1.19 1.13 23 1.25 1.56 2.13 1.19 24 1.25 1.13 1.19 1.25 25 1.31 10.95 65.98 1.25 The laboratory results for plasma insulin (Table 6 ) had similar characteristics to those of C- peptide above. The statistical analysis and interpretations for insulin were determined using C- peptide data (which are more reliable due to longer lifespan of C – peptide in plasma) as stated above Plasma Amylin Analysis Table 7 Plasma Amylin Assay (pg/ml) for the 2-hour IPGTT for Rats 1–25. RAT 0 MIN 30 MIN 60 MIN 120 MIN 1 31.83 13.26 4.71 8.39 2 0.42 0.90 0.78 0.71 3 0.86 0.40 0.99 11.53 4 0.91 0.63 0.54 17.08 5 - - - - 6 5.97 0.60 0.87 6.51 7 0.61 0.52 1.21 9.73 8 2.45 4.19 2.99 9.55 9 5.91 3.20 25.71 31.19 10 - - - - 11 0.80 11.78 0.72 41.04 12 0.51 1.06 6.12 28.08 13 0.32 0.60 10.68 26.25 14 5.73 0.64 0.55 33.68 15 0.48 0.39 0.60 4.22 16 1.45 0.27 0.41 34.41 17 1.59 0.39 7.39 37.00 18 14.91 0.21 6.44 20.10 19 6.19 8.88 21.72 21.66 20 0.78 10.37 6.11 21 11.28 0.11 33.01 22 0.31 0.52 0.42 23 0.38 0.22 21.24 20.02 24 2.35 1.77 0.29 19.07 25 0.83 11.41 12.22 68.42 The groups plasma amylin analysis comparison (Table 7 , Fig. 3 ) showed no significant findings in the initial periods of the study, but this changed at 120 mins where 5,7- dimethoxycoumarin induced amylin synthesis and secretion in Rats 11–15 (20mg/kg ethyl acetate 5,7 - Dimethoxycoumarin) (p = 0.015) and Rats 16–20 (20mg/kg methanol 5,7 - dimethoxycoumarin) (p = 0.09), 2 times that produced by glimepiride (p = 0.003) and 3 times that of negative control (p = 0.129). The increased amounts of 5,7-dimethoxycoumarin mediated amylin secretion in Rats 11–15 and Rats 16–20 occurred after a fall in insulin and C- peptide concentration from 60min to 120min (Table 2 , Fig. 2 ). This suggests that the amylin induction, synthesis and secretion may be from other tissues (GIT), since amylin is produced in the beta cells of the pancreas, co-localized, co-packaged and co-secreted with insulin and C – peptide. Plasma Proinsulin Analysis Table 8 Plasma Proinsulin Assay (mU/L) for the 2-hour IPGTT for Rats 1–25. RAT 0 MIN 30 MIN 60 MIN 120 MIN 1 1.40 1.48 2.74 3.83 2 1.10 1.10 3.21 3.70 3 1.47 1.26 3.21 4.05 4 1.19 1.73 3.05 5.00 5 - - - - 6 1.26 1.73 6.90 3.86 7 1.26 1.43 5.25 5.00 8 1.04 1.52 3.70 6.20 9 1.35 1.35 3.70 3.70 10 - - - - 11 1.35 1.60 3.35 3.70 12 0.80 1.52 4.25 3.54 13 1.26 1.65 3.86 5.00 14 1.04 2.89 3.54 4.50 15 1.26 3.35 4.25 3.05 16 1.10 2.35 6.50 4.70 17 1.19 2.10 4.25 4.05 18 1.26 2.25 3.21 3.35 19 1.26 2.25 3.86 3.05 20 1.04 2.10 4.70 21 2.00 3.35 4.05 22 1.40 3.70 3.70 23 1.40 5.54 5.00 3.05 24 1.40 3.35 5.54 5.00 25 1.26 3.21 3.70 4.25 There was a progressive increase in plasma proinsulin levels from 0min to 120mins for all 25 Rats on IPGTT except for Rats 23 (6% H 2 O 2 plus 20mg/kg 5,7-dimethoxycoumarin) (Table 8 ). This progressive increase suggests increase induction, synthesis and secretion of insulin and C-peptide in all the rats in response to the IPGTT induced hyperglycemia. The decrease in proinsulin level in Rat 23 from 30min to 120min suggest concentrated H 2 O 2 prooxidant mediated suppression of pancreatic functions. Acute Drug Toxicity Study Each of Rats 51–60 received intraperitoneally one of either sterile water, ethyl acetate fraction containing 10mg/kg or 20mg/kg 5, 7 - Dimethoxycoumarin, and were monitored for signs of acute drug toxicity for over 24 hours. After which they were sacrificed by cervical dislocation. The preliminary acute toxicity studies report (supplementary Fig. 2) of ethyl acetate fraction containing 5,7 - Dimethoxycoumarin study drug showed no toxic effects on important organs of interest by histopathological analysis. DISCUSSION Oxidative stress reduces insulin secretion through glucolipotoxicity of pancreatic islet cells. Prooxidants like high dose vitamin C and H 2 O 2 worsen oxidative stress and resultant hyperglycemia. Some natural plants secondary metabolites like flavonoids and coumarins mediate insulin secretion through their antioxidant effects. Their insulin releasing properties are counteracted by prooxidants or in severe cases of oxidative stress. 5,7-dimethoxycoumarin in addition to its antioxidant mediated insulin release equally directly induces the secretion of amylin 2 times than glimepiride and 3 times negative control, making it potential useful agent in management of obesity. The methanol fraction (oily, viscous fraction) containing 20mg/kg 5,7 – dimethoxycoumarin suppressed pancreatic function (inhibits C – peptide secretion throughout the study), while the ethyl acetate fraction (dry fraction) indirectly stimulated pancreatic functions (increased insulin and C –peptide release and reduced blood glucose level). But both fractions stimulated similar Amylin release at 120mins, 2 times that of glimepiride, after a fall in C- peptide concentration from 60min to 120min. This confirms that this Amylin release is Extrapancreatic. Simultaneous administration of high dose (1,000mg/kg) vitamin C and 5,7-dimethoxycoumarin during IPGTT in Rats 24–25 in this study (Table 1 ) produced the highest hyperglycemia of all the groups in this study (too high to be measured by the glucometer) which persisted from the 30min to the end of the study. The total antioxidant status (Table 4 ) increased markedly in both rats with progressive significant reduction in measured oxidative stress (Table 3 ), even when there was evident severe tissue oxidative stress with marked hyperglycemia. This raises question on the accuracy of total antioxidant status measuring kits in high dose vitamin C, due to its changing roles from antioxidant to prooxidant. This innate error in the kit’s measurement is due to its reliance on the reduction of ferric (Fe 3+ ) to Ferrous (Fe 2+ ) by antioxidants (vitamin C in this case) which make the kit accurate with low dose vitamin C, but grossly inaccurate with high dose vitamin C. Because this is equally the mechanism through which vitamin C exerts its prooxidant effect, due to the subsequent reaction of Fe 2+ and H 2 O 2 (Fenton) to give rise to reactive hydroxyl radicals. The limitation of this study is working with impure fractions of 5,7-imethoxycoumarin, which makes the conclusions contestable. Future research work is to determine the extrapancreatic amylin induction, synthesis, and secretion effects of pure (100%) fractions of 5,7 – dimethoxycoumarin in vitro on Amylin releasing cell lines, isolated pancreatic islet cells and cell lines from the Gastrointestinal tracts (GIT). To determine the Amylin releasing effects of increasing doses of pure fractions of 5,7 – dimethoxycoumarin (10mg/kg, 20mg/kg, 30mg/kg, 40mg/kg and 50mg/kg) over 4-hour course of intraperitoneal and oral glucose tolerance tests in Wistar rats. And also, to carry out detailed toxicological (acute, subchronic, chronic, hematological, chemistry, biochemistry, histopathology) effects of this study. To study the effect of 5,7- Dimethoxycoumarin on human amylin aggregation. CONCLUSION The following conclusions were reached at the end of the study. Ethyl acetate fractions containing 10mg/kg and 20mg/kg dimethoxycoumarin had comparable plasma glucose control with glimepiride. The 20mg/kg methanol fraction of 5,7-dimethoxycoumarin showed less effectiveness in blood glucose reduction, probably due lower concentration of 5,7 - dimethoxycoumarin. Both the ethyl acetate and methanol fractions containing 5, 7 -dimethoxy coumarins induced the synthesis and secretion of amylin at 120 mins about 2 times that of glimepiride positive control and 3 times the negative control. This secretion occurred after a fall in insulin and C - peptide concentration from 60 min to 120 mins, raising suspicion of amylin secretion from other tissues of GIT. Both the methanol and ethyl acetate fractions had similar Amylin secretions at 120 mins, even though the methanol fraction suppressed the pancreas and the ethyl acetate fraction stimulated the pancreatic functions. This confirms mainly Extrapancreatic Amylin mediated secretion. 5,7-dimethoxycoumarin a calcium channel blocker can mainly stimulate insulin release through indirect mechanism. Total antioxidant status measuring kit may not provide accurate information on the antioxidant status of high dose vitamin C due to its changing roles from antioxidant to prooxidant.. High dose vitamin C therapy should be discouraged, particularly in patients with type 2 diabetes due to the possibility of serious suppression of pancreatic functions, owing to severe prooxidant effect. 5,7 - Dimethoxycoumarin mediated amylin secretion will find application in the management of obesity. 5,7-dimethoxycoumarin will find special application in diabetics with chronic complications, against coagulopathy, platelet hyperactivity, thrombosis ( 14 ) ( 13 ), vasoconstriction, atherosclerosis ( 57 ), neuropathic pains and peripheral neuropathy ( 58 ), Amyloidosis ( 37 ) ( 38 ) ( 39 ) and effects of advanced glycation end products ( 59 ). Since the overall plasma glucose regulation is achieved through amylin and insulin synergy, attention should be shifted from insulin-based to amylin-based therapy. Extrapancreatic Amylin mediated secretion with natural compounds (coumarins) holds the key to future management of diabetes, as it will provide a more suitable alternative to insulin in the management of diabetes due to negative issues of insulin resistance, weight gain, hyperinsulinism and insulin mitogenicity in diabetics ( 60 ). Declarations Data Availability Data are available upon reasonable request from the corresponding author. Funding This study received some financial support from Federal Scholarship Board, Nigeria. Author Information Emeka Ofodire (E.O.) is the principal investigator and researcher for this study. Author Contribution E.O. conceptualized the research topic, designed the protocol, wrote the draft proposal, obtained fund for the study, extracted and fractionated the grapefruit peel bioactive components, procured the laboratory animals and test kits, carried out the study, laboratory and statistical analysis and wrote the manuscript. S.G., E.U.U., T.O.M. and I.C.O assisted E.O. to carry out the study. S.G. and A.M. moderated, supervised and coordinated the study. E.U.U. assisted in housing, feeding and caring for the laboratory animals. T.O.M. assisted in laboratory analysis. E.C.M. assisted in extraction and fractionation of bioactive components. Corresponding Author E.O. is the corresponding author. All correspondence to [email protected] Conflicts of Interest There were no conflicts of interest in this study. Ethical Approval Ethical approval for the study was obtained from the University of Nigeria Nsukka College of Medicine Research Ethics Committee. Informed Consent. Informed consent not required for this type of study. References Adeneye AA Methanol Seed Extract of Citrus Paradisi Macfad Lowers Blood Glucose, Lipids and Cardiovascular Disease Risk Indices in Normal Wistar Rats. 1, 2008, Nig Q J Hosp Med, Vol. 18, pp. 16–20. https://doi.org/10.4314/nqjhm.v18i1.44950 Mohammed MS, Warda TF Tasnim TM. Antidiabetic and Antihyperglycemic Effect of Citrus. S2 , (2022), International journal of Health Sciences, Vol. 6, pp. 8299–8308. https://doi.org/10.53730/ijhs.v6ns2.7112 Hung W, Suh JH, Wang Y Chemistry and health effects of furanocoumarins in grapefruits. 1, 2017, Journal of Food and Drug Analysis, Vol. 25, pp. 71–83. https://doi.org/10.1016/j.fda.2016.11.008 Sun C, Liu Y, Zhan L Anti-diabetic effects of natual antioxidants from fruits. 2021, Trends in Food Science and Technology, Vol. 117, pp. 3–14. https://doi.org/10.1016/j.tifs.2020.07.024 Sukhikh S, Babich O, Prosekov A Antidiabetic Poperties of Plant Secondary Metabolites. 4, 2023, Metabolites, Vol. 13, p. 513. https://doi.org/10.3390/metabo13040513 Ofodire E Bifunctional Antidiabetic - Anticancer Active Vitamins and Minerals: Drug Delivery Systems Enhancement. 3, 2023, Adv Bioeng Biomed Sci Res, Vol. 6, 9–16. https://doi.org/10.33140/ABBSR.06.01.002 Ofodire E Bifunctional Antidiabetic - Anticancer Dual - Active Phytochemicals: Adjuncts or Alternatives to Conventional Therapies. 5, 2023, Adv Bioeng Biomed Sci Res, Vol. 6, 46–70. https://doi.org/10.33140//ABBSR.06.05.002 Lv X, Zhao S, Zeng H et al Citrus fruits as a treasure trove of active natural metabolites that potentially povide benefits for human health. 2015. Chem Cent J, Vol. 9 , p. 68. https://doi.org/10.1186/s13065-015-0145-9 Ofodire E Bifunctional Antidiabetic - Anticancer Dual - Active Plants: New Roles, Challenges and Prospects. 5 , (2023), Adv Bioeng Biomed Sci Res, Vol. 6, 25–45. https://doi.org/10.33140//ABBSR.06.05.001 Dugrand - Judek A, et al. The Distribution of Coumarins and Furanocoumarins in Citrus Species Closely Matches Citrus Phylogeny and Reflects the Oganization of Biosynthetic Pathways. 11 , (2015), PLoS One, Vol. 10. https://doi.org/10.1371/journal.pone.0142757 Randelovic S andBipat RA. Review of Coumarins and Coumarin - Related Compounds for Their Potential Antidiabetic Effect. 2021 . Clin Med Insights Endocrinol Diabetes, Vol. 14 , p. 11795514211042023. https://doi.org/10.1177/11795514211042023 Akkol EK, Genc Y, Karpuz B et al Coumarins and Coumarin - Related Compounds in Pharmacotherapy of Cancer. 7 , (2020), Cancers (Basel), Vol. 12, p. 1959. https://doi.org/10.3390/cancers12071959 Najmanova I, Dosedel M, Hrdina Cadiovascular effects of coumarins besides their antioxidant activity. 9, 2015, Curr Top Med Chem, Vol. 15, pp. 830 – 49. https://doi.org/10.2174/1568026615666150220112437 Lu P, Liao T, Chen Y Coumarins Derivatives Inhibit ADP - Induced Platelet Activation and Aggregation. 13, 2022, Molecules, Vol. 27, p. 4054. https://doi.org/10.3390/molecules27134054 Vuorela H, Vuorela P Tornquist K and Alaranta S. Calcium channel blocking activity: Screening methods for plant derived compounds. 2 , (1997), Phytomedicine, Vol. 4, pp. 167 – 80. https://doi.org/10.1016/S0944-7113(97)80064-5 Program National Toxicology. NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1993, Natl Toxicol Program Tech Rep Ser, Vol. 422, pp. 1–340. Born SL, Api AM, Ford RA Comparative metabolism and kinetics of coumarin in mice and rats. 2, Food Chem Toxicol, Vol. 41, pp. 247 – 58. https://doi.org/10.1016/j.tiv.2005.08.001 Carlton BD, Aubrun J and Simon GS. Effects of Coumarin Following Perinatal and Chronic Exposure in Sprague-Dawley Rats and CD – 1 Mice. 1, 1996, Toxicological Sciences, Vol. 30, pp. 145–151. https://doi.org/10.1093/toxsci/30.1.145 Gu J, Walker VE, Lipinskas TW Intraperitoneal Administration of Coumarin Causes Tissue-Selective Depletion of Cytochromes P450 and Cytotoxicity in Olfactory Mucosa. 1, 1997, Toxicology and Applied Pharmacology, Vol. 146, pp. 134–143. Hedges SC, Vostinaru O, Mogosan C et al Safety Profile of Nutraceuticals Rich in coumarins: An Update. 2022. Front Pharmacol, Vol. 13 , p. 803338. https://doi.org/10.3389/fphar.2022.803338 Hazleton LW, Tusing TW Zeitlin BR, Toxicity of Coumarin. 3, 1956, The Journal of Pharmacology and Experimental Therapeutics, Vol. 118, pp. 348–358. Lake BG Coumarin Metabolism, Toxicity and Carcinogenicity: Relevance for Human Risk Assessment. 4 , (1999), Food Chem Toxicol. Vol. 37, P. 423–453. https://doi.org/10.1016/s0278-6915(99)00010-1 Knowles NG, Landchild MA, Fujimoto WY, Kahn SE Insulin and Amylin Release Are Both Diminished in First-Degree Relatives of Subjects With Type 2 Diabetes. 2 , (2002), Diabetes Care, Vol. 25, pp. 292–297. https://doi.org/10.2337/diacare.25.2.292 Katzung BG, Trevor AJ Basic and Clinical Pharmacology. 13th. s.l.: Lange., 2015. p. 1066. 9780071826419. Pan Y, Liu T Wang X and Sun J. Research progress of coumarins and their derivatives in the treatment of diabetes. 1, 2022, J Enzyme Inhib Med Chem, Vol. 37, pp. 616–628. https://doi.org/10.1080/14756366.2021.2024526 Robertson RP Oxidative Stress and Impaired Insulin Secetion in Type 2 Diabetes. 6 , (2006), Curr Opin Pharmacol., Vol. 6, pp. 615-9. https://doi.org/10.1016/j.coph.2006.09.002 Keane KN, Cruzat VF, Carlessi R et al Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and B-Cell Dysfunction. 2015, Oxid Med Cell Longev, p. 181643. https://doi.org/10.1155/2015/181643 Hassanein EHN, Sayed AM et al Coumarins as Modulatos of the Keap 1/Nrf2/AE Signaling Pathway. 2020. Oxid Med Cell Longev, Vol. (2020), p. 1675957. https://doi.org/10.1155/2020/1675957 Liu M, Weiss MA, Arunagiri A et al Biosynthesis, Structure, and Folding of the Insulin Precursor Protein. (Suppl 2), (2018), Diabetes Obes Metab, Vol. 20, pp. 28–50. https://doi.org/10.1111/dom.13378 Cao NK, Zhu SS, Chen YM A new prenylated coumarin digloside with insulin-release promoting activity from Clausena dunniana. 4, 2021, J Asian Nat Prod Res, Vol. 23, pp. 385–391. https://doi.org/10.1080/10286020.2020.1810671 Ahmed S, Nur-e-Alam M, Parveen I et al Stimulation of insulin secretion by 5-methylcoumarins and its sulfur analogues isolated from Clutia lanceolata Forssk. (2020), Phytochemistry, Vol. 170, p. 112213. https://doi,org/10.1016/j.phytochem.2019.112213 Kuranov S, Marenina M et al The Study of Hypoglycemic Activitry of 7 - Terpenylcoumarins. (2022), Molecules Vol. 27, P. 8663. https://doi.org/10.3390/molecules27248663 Abedini A, Schmidt AM Mechanism of Islet Amyloidosis Toxicity in Type 2 Diabetes. (2015), FEBS Lett, Vol 587, 1119–1127. https://doi.org/10.1016/j.febslet.2013.01.017 Hieronymus L, Griffin S Role of Amylin in Type 1 and 2 Diabetes. (1 Suppl) , (2015), Diabetes Educ, Vol. 41, pp. 47S – 56S. https://doi.org/10.1177/0145721715607642 Riddle MC, Drucker DJ Emerging Therapies Mimicking the Effects of Amylin and Glucagon - Like Peptide 1. (2006), Diabetes Care Vol. 29, 435–449. https://doi.org/10.1337/DIACARE.29.02.06.DC05-1267 Young A Tissue Expression of and Secretion of Amylin. 2005, Adv Pharmacol, Vol. 52, pp. 19–45. https://doi.org/10.1016/S1054-3589(05)52002-7 Abu-Aisheh MN, Al-Aboudi A, Mustafa MS et al Coumarin derivatives as acetyl- and butyrylcholinesterase inhibitors: An in vitro, molecular docking, and molecular dynamics simulations study. 4, 2019, Heliyon, Vol. 5 , e01552 Bruhlmann C, Ooms F, Carrupt P Coumarins Derivatives as Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase. 2001, J Med Chem, Vol. 44, 3195–3198. https://doi.org/101021/JM0108940 Orhan IE, Gulcan HO Coumarins: Auspicious Cholinesterase and Monamine Oxidase Inhibitors. 17 , (2015), Med Chem, Vol. 15, 1673–82. https://doi.org/10.2174/1568026615666150427113103 Alkahtane AA, Alghamdi HA, Almutairi B et al Inhibition of human amylin aggregation by Flavonoid Chrysin: An in-silico and in-vitro approach.1, 2021. Int J Med Sci, Vol. 18 , 199–206. https://doi.org/10.7150/ijms.51382 Erzen S, Tonin G et al Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity. 2024. Int J Mol Sci Vol 25 , 1517. https://doi.org/10.3390/ijms25031517 Mauvais - Jarvis F. Gender differences in glucose homeostasis and diabetes. (2018), Physiol Behav, Vol. 187, pp. 20–23. https://doi.org/10.1016/j.physbeh.2017.08.016 Geer EB and Shen Wei. Gender Differences in Insulin Resistance, Body Composition, and Energy Balance. (2009), Gend Med, Vol. 6 (Suppl 1), pp. 60–75. https://doi.org/10.1016/j.genm.2009.02.002 Lluis L, Muuoz M, Nogues MR et al Toxicology Evaluation of a Procyanin-rich Extract From Grape Skin and Seed. (2011), Food Chem. Toxicol, Vol. 49, pp. 1450–1454. https://doi,org/10.1016/j.fct.2011.03.042 Inoue K, Morikawa T, Takahashi M A 13-Week Subchronic Toxicity Study of Grape Skin Extract in F344 Rats. 2013, J. Toxicol. Sci, Vol. 38, pp. 557–570. https://doii.org/10.2131/jts.38.559 Abubakar A, Hague M Preparation of Medicinal Plants: Basic Extraction and Fractionation Procedures for Experimental Purposes. 1, 2020, J Pharm Bioallied Sci, Vol. 12, pp. 1–10. https://doi.org/10.4103/jpbs.JPBS_175_19 Sultana B Anwar F and Ashiraf M. Effect of Extraction Solvent/Technique on the Antioxidant Activity of Selected Medicinal Plant Extracts. 6 , (2009), Molecules, Vol. 14, pp. 2167–2180. https://doi.org/10.3390/molecules14062167 Bourgaud F Poutaraud A and Guckert A. Extraction of coumarins from plant material (Leguminosae). 3 , (1994), Phytochemical Analysis, Vol. 5, pp. 127–132. https://doi.org/10.1002/pca.2800050308 Leighton E, Sainsbury CAR Jones GC. A Practical Review of C - Peptide Testing in Diabetes. 3, 2017, Diabetes Therapy, Vol. 8, pp. 475–487. https://doi.org/10.1007/s13300-017-0265-4 Patel R, Barker J, ElShaer A Pharmaceutical Excipients and Dug Metabolism: A Mini-Review. 21, 2020. Int J Mol Sci, Vol. 21 , p. 8224. https://doi.org/103390/ijms21218224 Nagaraju B and Anilkumar KV. Pharmacodynamic and pharmacokinetic interaction of losartan with glimepiride-metformin combination in rats and rabbits https://doi.org /10.4103/ijp.IJP_845_19 . 6 , (2021), Indian J Pharmacol, Vol. 53, pp. 465–470. Basit A, Riaz M, Fawwad A Glimepiride: Evidence - Based Facts, Trends, and Observations. (2012), Vasc Health Risk Mana, Vol. 8, 463–472. https://doi.org/10.2147/HIV.S33194 Donaubauer HH, Mayer D Acute, Subchronic and Chronic Toxicity of the New Sulfonylurea Glimepiride in Rats. 5, 1993, Arzneimittelforschung, Vol. 43, pp. 547–9. PMID: 8328999. Sotler R, Poljsak B, Dahmane R : Prooxidant Activities of Antioxidants and their Impact on Health. 4, 2019, Acta Clin Croat, Vol. 58, pp. 726–736. https://doi.org/10.20471/acc.2019.58.04.20 Ghalibaf MHE, Kianian F, Beigoli S et al The effects of vitamin C on respiatory, allergic and immunological diseases: an experimental and clinical- based review. (2023), Inflammopharmacol, Vol. 31, pp. 653–672. https://doi.org/10.1007/s10787-023-01169-1 Mingrone G, Panunzi S, Gaetano A Insulin sensitivity depends on the route of glucose administration. 2020, Diabetologia Vol 63, 1382–1395. https://doi.org/10.1007/s00125-020.05157-w Savage S, Miller LA, Schrier RW The future of calcium channel blocker therapy in diabetes mellitus. 1, 1991, J Cardiovasc Pharmacol, Vol. 18, S19–24. https://doi.org/10/1097/00005344-199100181-00005 Usman M, Malik H, Tokhi A et al 5,7 - Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT3 receptors and monoamines. 2023 . Front Pharmacol, Vol. 14 , 1213763. https://doi.org/10.3389/fphar.2023.1213763 Lee EJ, Kang MK, Kim YH et al Coumarin Ameliorates Impaired Bone Turnover by Inhibiting the Formation of Advanced Glycation End Products in Diabetic Osteoblasts and Osteoclasts. 7, (2020), Biomolecules, Vol. 10, 1052. https://doi.org/10.3390/biom10071052 Ofodire E Hyperinsulinism Gateway Between Diabetes and Cancer: New Roles for Bifunctional Antidiabetic - Anticancer Active Somatostatins, IGF – 1 Inhibitors. 2023, Adv Bioeng Biomed Sci Res, Vol 6, P.17–24. https://doi.org/10.33140//ABBSR.06.03.003 Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryTable1WeightsofRatsinGrams.docx SupplementaryTable2RatsHemoglobinLevelsingperdl.docx SupplementaryFigure1FractionsGCMSAnalysisResults.pdf SupplementaryFigure2AcuteDrugToxicityStudy.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4751863","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":327869090,"identity":"a944247e-21ef-4b15-aed2-967e55ec2082","order_by":0,"name":"Emeka Ofodire","email":"data:image/png;base64,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","orcid":"","institution":"University of Nigeria Nsukka","correspondingAuthor":true,"prefix":"","firstName":"Emeka","middleName":"","lastName":"Ofodire","suffix":""},{"id":327869091,"identity":"02fe6621-caf8-45df-979d-9aab0c5a6124","order_by":1,"name":"Samuel Ghasi","email":"","orcid":"","institution":"University of Nigeria Nsukka","correspondingAuthor":false,"prefix":"","firstName":"Samuel","middleName":"","lastName":"Ghasi","suffix":""},{"id":327869092,"identity":"e1bbf30a-3b54-4663-9125-0925db8569c2","order_by":2,"name":"Anthony Mbah","email":"","orcid":"","institution":"University of Nigeria Nsukka","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"Mbah","suffix":""},{"id":327869093,"identity":"9e627859-393f-48cc-87ac-ef2af78227a0","order_by":3,"name":"Edith U. Ugwu","email":"","orcid":"","institution":"Enugu State University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Edith","middleName":"U.","lastName":"Ugwu","suffix":""},{"id":327869094,"identity":"bcfcd67b-f21f-46cc-9ff7-23342d5426de","order_by":4,"name":"Theophilus O. Mbah","email":"","orcid":"","institution":"University of Nigeria Teaching Hospital Enugu","correspondingAuthor":false,"prefix":"","firstName":"Theophilus","middleName":"O.","lastName":"Mbah","suffix":""},{"id":327869095,"identity":"5934aea6-4e81-4f0d-ac66-486929e2e0f3","order_by":5,"name":"Emmanuel C. Mbaoji","email":"","orcid":"","institution":"University of Nigeria Nsukka","correspondingAuthor":false,"prefix":"","firstName":"Emmanuel","middleName":"C.","lastName":"Mbaoji","suffix":""},{"id":327869096,"identity":"070bfa04-f901-4efd-8dce-f48952245b46","order_by":6,"name":"Ifeoma C. Onah","email":"","orcid":"","institution":"University of Nigeria Teaching Hospital Enugu","correspondingAuthor":false,"prefix":"","firstName":"Ifeoma","middleName":"C.","lastName":"Onah","suffix":""}],"badges":[],"createdAt":"2024-07-16 18:38:15","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true},"doi":"10.21203/rs.3.rs-4751863/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4751863/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60575094,"identity":"7c1c785f-b137-45ca-be14-3d3449e23240","added_by":"auto","created_at":"2024-07-18 10:22:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":173271,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical analysis showing Plasma Glucose Results (mmol/L) for the 2-hour IPGTT.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4751863/v1/bb99ba5337bd076dac5dd730.png"},{"id":60575095,"identity":"438a079c-6a73-40c1-b644-21576b816cb4","added_by":"auto","created_at":"2024-07-18 10:22:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":120816,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical analysis showing Plasma C-Peptide Results (pg/ml) for the 2-hour IPGTT.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4751863/v1/c77c1fa89262cbb4889ab9f6.png"},{"id":60575098,"identity":"29b5a019-7d64-4558-b405-f4df681e8924","added_by":"auto","created_at":"2024-07-18 10:22:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":129248,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical analysis showing Plasma Amylin Results (pg/ml) for the 2-hour IPGTT.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4751863/v1/2f86eedcdf035c67306bd12e.png"},{"id":60575961,"identity":"a5ff43f1-0834-41a4-acd7-4c0b4b97df52","added_by":"auto","created_at":"2024-07-18 10:38:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1947611,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4751863/v1/093e27e7-f98d-479e-a532-20150106fb26.pdf"},{"id":60575527,"identity":"358e3f94-fcd7-4d2b-b1eb-a38da3348559","added_by":"auto","created_at":"2024-07-18 10:30:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11564,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1WeightsofRatsinGrams.docx","url":"https://assets-eu.researchsquare.com/files/rs-4751863/v1/753064ea111c73b9bbd1f2e0.docx"},{"id":60575096,"identity":"37840158-cda9-4c4f-a3c9-e74ce89bde31","added_by":"auto","created_at":"2024-07-18 10:22:50","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":11273,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable2RatsHemoglobinLevelsingperdl.docx","url":"https://assets-eu.researchsquare.com/files/rs-4751863/v1/7c2d7050d129f91af976b1e3.docx"},{"id":60575100,"identity":"b7cc43ff-3d5d-4492-b5c7-cfee4996c8d7","added_by":"auto","created_at":"2024-07-18 10:22:51","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":190053,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1FractionsGCMSAnalysisResults.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4751863/v1/c51291c8ddeb36d756c5e57c.pdf"},{"id":60575101,"identity":"901a86e3-aad9-4864-b423-c56d18d1951f","added_by":"auto","created_at":"2024-07-18 10:22:51","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":7563916,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure2AcuteDrugToxicityStudy.docx","url":"https://assets-eu.researchsquare.com/files/rs-4751863/v1/3cd42a039a483059d51b1095.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e5,7- Dimethoxycoumarin Enhances Insulin Release and Stimulates Extrapancreatic Secretion of Amylin.\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eGrapefruits (Citrus paradisi) are known to have antidiabetic and cardiovascular effects (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) with flavonoids as their main bioactive constituents (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Natural plant antioxidants like phenolic compounds, polysaccharides and vitamin C equally have antidiabetic effects (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Citrus fruits also contain other secondary metabolites like alkaloids, coumarins, carotenoids, limonoids, essential oils (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Flavanones and furanocoumarins are the main components of grapefruits implicated in grapefruits - drugs interactions by inhibiting the cytochrome P \u0026ndash; 450 metabolisms (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCitrus plants biosynthesize both coumarins and furanocoumarins, with grapefruits contributing about 73% of furanocoumarins in western diet (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The highest concentration of coumarins and furanocoumarins are found in the peel of citrus fruits, just like flavonoids (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Most of the flavonoids in grapefruit occur as glycosides while Coumarins occur in free forms, as glycosides, esters, and sublimates (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Coumarins and flavonoids are heterocyclic molecules and they are also isomers.\u003c/p\u003e \u003cp\u003eCoumarins are used in the treatment of prostate cancer, renal cell carcinoma and leukemia (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) They have been reported to neutralize the side effects of radiotherapy (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eUnlike the flavonoids whose effects are predominantly antioxidant in nature, coumarins have direct anticoagulation pharmacological activities on the cardiovascular systems, not linked to antioxidant effects(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) by inhibiting the activation of Vitamin K and blocking the synthesis of coagulation factors. Coumarins also have direct antiplatelet effects by inhibiting ADP(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and vasodilating activities by inhibition of calcium influx into the cell through calcium channel blockage (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCoumarins are known to be hepatotoxic and carcinogenic following chronic oral gavages in rats (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).. Coumarin - linked toxicity are also known to be species-specific and metabolism - dependent (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCoumarin \u0026ndash; mediated toxicity in rat liver and mouse lung cancer are linked to the production of coumarin 3, 4- epoxide (CE) the preferential metabolite in rats.\u003c/p\u003e \u003cp\u003eSeveral studies in 1989 and 1998 in animals treated with dihydrocoumarin (DHC), a structural analog of coumarin saturated at the 3, 4-position, impossible to form an epoxide, showed neither hepatotoxicity nor Lung cancer (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere were no liver nor lung cancers in F344 rats in the National Toxicology Program oral gavage studies in 1993 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Also, CD \u0026ndash; 1 mice exposed to dietary coumarin at 0, 27, 89 and 276mg/kg/day in utero, via lactation and weaning, and chronically for two years afterwards, reported no increased incidence in liver nor lung cancers (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Sprague \u0026ndash; Dawley rats given up to 234mg/kg/day of coumarin in the diet for two years showed no tumors until they exceeded the maximum tolerated dose (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWhile a single Intraperitoneal injection of coumarin (25mg/kg, 50mg/kg) caused tissue \u0026ndash; selective cytotoxicity in olfactory mucosa of Wistar rats and C57BL/6 mice, there were no reduction of P450 components in the liver of either rats nor mice at 50mg/kg, after 48 hours of injection (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Intraperitoneal administration of 7-hydroxycoumarin or 3,4-dihydrocoumarin at 50mg/kg did not lead to reduction of olfactory nor liver P450.\u003c/p\u003e \u003cp\u003eThis shows that toxicity is not mediated by P450-catalyzed coumarin 7 \u0026ndash; hydroxylation and greatly supports the theory that the production of coumarin 3, 4-epoxide is the cause of the toxicity (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCoumarins oral LD50 is 290-680mg/kg in rats, 196-780mg/kg in mice. Intraperitoneal LD50 is 710mg/kg in mice. The no sign of oral acute toxicity level in rats is 125mg/kg (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The maximal allowed daily intake from diet is 3.5mg/day,(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) while the maximal allowed coumarins levels in foods prepared with cinnamon flavor in EU are 50mg/kg in bakery products and 5mg/kg in desserts (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Recommended clinical doses of coumarins varies from 8mg for treatment of venous constriction to 7000mg/day in chemotherapies (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn type 1 diabetes (10% of Diabetes), there is deficient insulin and amylin production and secretion. This results in their low baseline serum concentrations and decreased or absence response of these hormones to caloric intake, leading to chronic hyperglycemia. Type 2 diabetes (90% of diabetes) is characterized by hyperglycemia, insulin resistance and abnormal beta cell function (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). 30% or more of type 2 diabetes patients will benefit from insulin therapy to control blood glucose (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCoumarins have been reported to show antidiabetic effects through several mechanisms and pathways in vitro and in vivo (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOxidative stress is implicated in type 2 diabetes pathogenesis through glucolipotoxicity of the pancreatic islets and non-islet tissues, leading to deterioration of islet function and insulin sensitivity, with alterations in insulin gene expression leading to severely reduced levels of transcription factors MafA and Pdx-1 (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Glucolipotoxicity affects mitochondria function like impairment of electron transport chain activity, leading to reactive oxygen species generation, triggering inflammation in peripheral tissues and insulin secreting β-cells (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCoumarins have shown ability to activate the Nrf2 pathway in various cells. The Keap/Nrf2/ARE system is a major defensive pathway against oxidative stress (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInsulin production in β-cells of pancreas is initiated as preproinsulin, which is translated and translocated across the endoplasmic reticulum, oriented, folded and cleaved to form proinsulin (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Folded proinsulin transit through the Golgi apparatus where they are packaged in secretory vesicles.\u003c/p\u003e \u003cp\u003eThe mature insulin will be exocytose in equimolar amounts with C \u0026ndash; Peptide, from the cells into circulation upon activation by metabolic signals and vagal nerve stimulation. After each meal, the β \u0026ndash; cells release insulin to enhance glucose uptake by cells.\u003c/p\u003e \u003cp\u003eInsulin release is divided into 3 phases viz., cephalic, early and late enteric. ATP \u0026ndash; sensitive K\u003csup\u003e+\u003c/sup\u003e channel activity couple β-cell metabolism to voltage - gated Ca\u003csup\u003e2+\u003c/sup\u003e channels.\u003c/p\u003e \u003cp\u003eA study on the in vitro cell culture with a new prenylated coumarin diglycoside and five known flavonoid glycosides reported insulin release enhancing activities (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Another study showed that coumarins extracted from Clutia lanceolate Forssk promoted glucose-triggered secretion of insulin from pancreatic islet (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Coumarins are equally known to inhibit Dipeptidyl peptidase - IV enzyme in vitro (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmylin (islet amyloid polypeptide) is formed in pancreatic islet β-cells. it was originally discovered as the main component of pancreatic amyloid deposit (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). It is co-localized, co-packaged and co-secreted with insulin in response to caloric intake in the ratio 1:100 (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).But its immunoreactivity and mRNA are equally found in islet somatostatin - producing δ - cells; in the lungs, stomach, duodenum, jejunum, ileum, colon, and rectum; and all through the CNS (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe secreted ratio of amylin: insulin in acute states is constant, but chronic hyperglycemia may enhance the induction of amylin synthesis and secretion over that of insulin. The degree of amylin deficiency correlates with the degree of insulin deficiency (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Amylin plasma concentration is 4\u0026ndash;8 pmol/L in fasting and 15\u0026ndash;25 pmol/L in postprandial states and these levels correlate with those of insulin (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). The molecular weight of amylin is 1378.6g/mol.\u003c/p\u003e \u003cp\u003eThe tendency of human amylin to form amyloid aggregation has limited research on the development of pharmacological agents that can stimulate endogenous amylin secretion and has led to the development of synthetic amylin analogs like pramlintide, that is more resistant to fibril formation.\u003c/p\u003e \u003cp\u003eCoumarins due to their aromatic structures, are known to potently inhibit cholinesterases (acetylcholinesterase, and butyrylcholinesterase) enzymes that promote and propagate β - amyloid aggregation (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), and also Monamine Oxidase (MAO) which induces β - amyloid deposition (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Various flavonoids inhibit human amylin amyloidosis through unknown mechanism (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmylin is a 37 - amino acid peptide member of the calcitonin gene family, with G- Protein - functionally linked receptors. Amylin gene is located on the p arm of human chromosome 12 (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). It functions in glycemic control by enhancing satiety, inhibiting postprandial glucagon release, slowing gastric emptying, inhibiting secretion of digestive enzymes (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e), inhibition of bone resorption (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) and synergizes with leptin to cause weight loss (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study strives to be the first to focus on extrapancreatic stimulation of amylin release by natural compounds in the management of diabetes.\u003c/p\u003e \u003cp\u003eFlavonoids are known to modulate insulin and amylin secretion through mainly their antioxidant activities, but the effects of coumarins on insulin and amylin secretion have not been thoroughly studied and elucidated. Coumarins with direct effects on the cardiovascular system will be of utmost benefit in the management of diabetics, since the chronic complications of diabetes are mainly vascular in nature.\u003c/p\u003e \u003cp\u003eThe \u003cb\u003eaim\u003c/b\u003e of this study is to investigate in vivo the effects of 5,7-dimethoxycoumarin (Citropten) fractions present in grapefruit peel extract on insulin and amylin secretions in normal male Wistar rats.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy Area\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research was carried out at the Department of Laboratory Animals, Enugu State University of Science and Technology, Enugu (ESUT). The draft proposal was reviewed and approved by the Department of Pharmacology and Therapeutics, College of Medicine University of Nigeria Enugu Campus. The study protocol was approved by the college of medicine research ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Animals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e60 male Wistar rats approximately of same aged (12 -16week old) and weight (160 \u0026ndash; 273g) (Supplementary Table 1 and Supplementary Table 2) were sourced from ESUT\u0026nbsp;animal house. Only male rats were used for the study due to considerable gender differences in glucose regulation and insulin sensitivity (42)\u0026nbsp;(43).\u003c/p\u003e\n\u003cp\u003eThey were kept in 12 cages (5 rats per cage), weighed and fed with standard laboratory diet, and had free access to water for 1 month. The rodent cages were temperature, humidity and light-controlled housing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was carried out in line with conventional laboratory principles on the use of animals based on the European Community Guidelines 1986.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Plant\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFresh grapefruit peels were obtained from one of the grapefruit trees in the garden of Ofodire Emeka (the principal investigator) for the study.\u003c/p\u003e\n\u003cp\u003eThe LD50 of grapefruit peel and seed extract is 5,000mg/kg (44). The No-observed-adverse-effect-level (NOAEL) for male rats is 600mg/kg/day (45) .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Preparation\u003c/strong\u003e: \u0026nbsp;Samples of grapefruit peels were first dried in air. The dried samples were coarse ground to particles less than 0.5mm to improve the extraction efficiency and weighed 1.187kg.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtraction of Coumarins from Grapefruit Peel\u0026nbsp;\u003c/strong\u003ewas carried out in Department of Chemistry Laboratory, University of Nigeria, Nsukka.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCold maceration method of extraction was used as studies have shown it to be suitable and convenient method for coarse ground plant materials (46) and phenolic compounds (46)\u0026nbsp;(47). Methanol was chosen as the solvent of extraction as studies reported it to have the highest extractability among other solvents for phenolic compounds (47)\u0026nbsp; \u0026nbsp;and coumarins (48).\u003c/p\u003e\n\u003cp\u003e90% methanol was added to the sample at menstruum: sample ratio 4:1. The mixture was constantly agitated and left for 72 hours. Filtration was carried out using number 1 Whatman filter paper.\u003c/p\u003e\n\u003cp\u003eThe micelle was concentrated using Rotary evaporator under vacuum to remove the menstruum from the extract, and water bath used for cooling. The crude extract was weighed and measured 212g, and the marc discarded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSeparation of the Extract into Factions:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ewas carried out using Vacuum Liquid Chromatography (VLC)\u0026nbsp;in Department of Chemistry Laboratory, University of Nigeria, Nsukka.\u003c/p\u003e\n\u003cp\u003eThe crude extract was mixed with silica gel adsorbent (solid phase) of size 100 \u0026ndash; 200 mesh to form homogeneous mixture. The mixture was allowed to dry and was further ground into fine powder using porcelain (ceramic) mortar. Then, it was gently and neatly packed into glass column of length 1m and diameter 4cm.The column was connected to a vacuum pump and the pump switched on.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe fractionation took place based on choice solvent (mobile phase), N-Hexane, Ethyl Acetate and methanol in increasing order of polarity. The fractions were concentrated by exposing them to dry air. The weights of the concentrated fractions were as follows: n-Hexane (dry fraction) = 0.02g, Ethyl Acetate (dry fraction) = 1.01g, Methanol (oily, waxy, viscous fraction) = 78.20g.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGas Chromatography \u0026ndash; Mass Spectrometry (GCMS):\u003c/strong\u003e was carried out at Ebic Integrated Services Limited Laboratory Port Harcourt Nigeria (Supplementary figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe analyzed results for the 3 fractions reported the most abundant constituents as follows:\u003c/p\u003e\n\u003cp\u003ea)\u0026nbsp; \u0026nbsp;\u0026nbsp;\u003cstrong\u003eEthyl Acetate Fraction:\u003c/strong\u003e2H-1-Benzopyran-2-one, 5,7-dimethoxy- (Citropten Coumarin C\u003csub\u003e11\u003c/sub\u003e H\u003csub\u003e10\u003c/sub\u003e O\u003csub\u003e4\u003c/sub\u003e) 85.66%, Phytol (Diterpenes) 1.96%, 7H \u0026ndash; Furo(3,2-g)(1) benzopyran \u0026ndash; 7- one, 4-methoxy- (bergapten Furanocoumarin C\u003csub\u003e12\u003c/sub\u003e H\u003csub\u003e8\u0026nbsp;\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e) 1.05%, Carveol (Tarpenoid alcohols) 0.63%.\u003c/p\u003e\n\u003cp\u003eb)\u0026nbsp; \u0026nbsp;\u0026nbsp;\u003cstrong\u003eMethanol Fraction:\u003c/strong\u003e2H-1-Benzopyran-2-one, 5,7-dimethoxy- (Citropten Coumarin) 70.60%, 7H \u0026ndash; Furo(3,2-g)(1) benzopyran \u0026ndash; 7- one, 4-methoxy- (bergapten Furanocoumarin) 4.70%, Diisooctyl phthalate (Phthalate esters) 1.16%, Phytol (Diterpenes) 0.64%.\u003c/p\u003e\n\u003cp\u003ec)\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003cstrong\u003e\u0026nbsp;n-Hexane Fraction:\u003c/strong\u003e\u0026nbsp; Bis(2-ethylhexyl) phthalate (Phythalate esters) 51.03%, beta-Bisabolene (sesquiterpenes) 8.70%.\u003c/p\u003e\n\u003cp\u003eFurther purification of fractions was not possible due to unavailability of specified High Performance Liquid Chromatography and Nuclear Magnetic Resonance equipment in Nigeria at time of study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was Randomized Controlled Blinded and divided into experiments. Because we were dealing with homogenous rat population that were in cages (clusters), multistage cluster sampling method was used for selection. The mean values of obtained results sets were used. Heparinized sample bottles were used for blood samples collection. Plasma was used for assessing hormones due to their short lifespan in serum (49).\u003c/p\u003e\n\u003cp\u003e0.5% polysorbate 20 excipient (Tween 20) served as diluents and vehicle for the methanol and ethyl acetate fractions of 5,7 \u0026ndash; dimethoxycoumarin and the controls (50).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntraperitoneal Glucose Tolerance Tests\u0026nbsp;\u003c/strong\u003e(IPGTT) was used in the study 1) to produce hyperglycemia, 2) for on-the-spot determination of glucose levels with Glucometer, 3) for simultaneous injection of glucose (50% dextrose 2g/kg), grapefruit peel fractions and drugs, 4) for determination of plasma parameters at 0min, 30min, 60min and 120min intervals of time, after overnight fast (12 hours), 5) as an alternative route of administering coumarins. \u0026nbsp;About 3mls of blood was collected from retro-orbital plexus puncturing of each animal for the entire study. The samples were immediately centrifuged after collection and plasma separated from blood cells. The plasma was stored at \u0026ndash; 20degrees Celsius and analysis started immediately.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Experiments on All Parameters:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 rats (Rats 1 \u0026ndash; 5) were used as negative control on IPGTT. 1ml of sterile water was given simultaneously (in quick succession) with 2g/kg of glucose intraperitoneally over 30 seconds.\u003c/p\u003e\n\u003cp\u003e2)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 rats (Rats 6 -10) as positive control on IPGTT. 0.2mg/kg of glimepiride (equivalent of 2mg daily dosing in humans)\u0026nbsp;(51)\u0026nbsp;given simultaneously with 2g/kg of glucose. Glimepiride was chosen as positive control drug because has better safety profile, does not interfere with insulin and glucagon homeostasis and is less prone to profound hypoglycemia compared to other sulfonylureas\u0026nbsp;(52). Oral LD50 of glimepiride in rats is \u0026gt;10000mg/kg, intraperitoneal LD50 in rats is 3950mg/kg \u0026nbsp;(53).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 rats (Rats 11 -15) test for direct insulin releasing effects of ethyl acetate fractions containing 5,7-dimethoxycoumarin on IPGTT. 2g/kg of glucose was given simultaneously with ethyl acetate fraction containing 20mg/kg of 5,7-dimethoxycoumarin. (1g of ethyl acetate fraction contains 856.6mg of 5,7-dimethoxycoumarin).\u003c/p\u003e\n\u003cp\u003e4)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 rats (Rats 16 \u0026ndash; 20) test for direct insulin releasing effects of methanol fractions containing 5,7-dimethoxycoumarin on IPGTT. 2g/kg of glucose was given simultaneously with methanol fraction containing 20mg/kg of 5,7-dimethoxycoumarin.\u003c/p\u003e\n\u003cp\u003e5)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 rats (Rats 21 \u0026ndash; 25) test for pro-oxidant actions of H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e and high dose vitamin C on effects of ethyl acetate fractions containing 5,7-dimethoxycoumarin on IPGTT.\u003c/p\u003e\n\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e is an oxidizing agent implicated in the pathogenesis of oxidative stress. The LD50 is 600 \u0026ndash; 1617mg/kg (Y.Li, unpublished; Ito et al., 1976). It is generally safe at 3%.\u003c/p\u003e\n\u003cp\u003eHousehold concentration varies from 3 \u0026ndash; 9% (Nelson AL, et al., 2023). 2g/kg of glucose was given simultaneously with 1ml of 6% H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e and 20mg/kg of 5,7-dimethoxycoumarin, intraperitoneally in Rat 23. Repeat with 0.6% H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003efor Rats 21 \u0026ndash; 22.\u003c/p\u003e\n\u003cp\u003eVitamin C acts as antioxidant at low doses (30 \u0026ndash; 100 mg/kg) and pro-oxidant at high doses (1000mg/kg) (54). The LD50 of vitamin C is 11,900mg/kg in rats (55). 2g/kg of glucose was given simultaneously with 1000mg/kg of vitamin C and 20mg/kg of 5,7-dimethoxycoumarin, in Rats 24 - 25.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary (Supplemental) Experiments on Plasma Glucose Effect Only:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e6)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 Rats (Rats 26 \u0026ndash; 30) test for ethyl acetate fraction containing 10mg/kg 5,7-dimethoxycoumarin on IPGTT.\u003c/p\u003e\n\u003cp\u003e7)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 Rats (Rats 31 \u0026ndash; 35) test for methanol fraction containing 10mg/kg 5,7-dimethoxycoumarin on IPGTT.\u003c/p\u003e\n\u003cp\u003e8)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 Rats (Rats 36 \u0026ndash; 40) negative control on Oral Glucose Tolerance Test (OGTT).\u003c/p\u003e\n\u003cp\u003e9)\u0026nbsp; \u0026nbsp;\u0026nbsp;5 Rats (Rats 41 \u0026ndash; 45) positive (glimepiride) control on OGTT.\u003c/p\u003e\n\u003cp\u003e10) \u0026nbsp; 5 Rats (Rats 46 \u0026ndash; 50) test for ethyl acetate fraction containing 20mg/kg 5,7-dimethoxycoumarin on OGTT.\u003c/p\u003e"},{"header":"RESULTS AND ANALYSIS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eTest kits and Laboratory Analysis\u003c/h2\u003e \u003cp\u003eRat ELISA Test Kits for insulin, amylin, c- peptide and proinsulin, were procured from Solarbio Life Sciences and Technology Co., Ltd Beijing China, and also total antioxidant status (TAS) and malondialdehyde sourced locally.\u003c/p\u003e \u003cp\u003eLaboratory analysis was carried out at the Department of Chemical Pathology Laboratory and Molecular Virology Laboratory University of Nigeria Teaching Hospital, Enugu following the procedures outlined in the kits\u0026rsquo; manual.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was carried out with IBM SPSS version 25. Data were summarized using mean and standard deviation and presented in graphs. Bars were used to represent different groups. Comparison between groups was done using one-way independent ANOVA with Fisher's Least Significant Difference (LSD) for the post-hoc multiple comparisons. Comparison within group was done using paired samples t-test. Differences were considered significant when p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePlasma Glucose Analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma Glucose Results (mmol/L) for the 2-hour IPGTT and OGTT for Rats 1\u0026ndash;50.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e30MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e60MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e120MIN\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e15.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e28.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e13.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e25.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e21.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e22.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e12.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e18.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e15.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e25.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e21.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e31.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.611\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat 25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eToo High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRat 50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere were marked hyperglycemias in Rats 1\u0026ndash;35 at 30min following simultaneous intraperitoneal glucose administration with test drugs (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These hyperglycemias were not noticeable with Rats 36\u0026ndash;50 on OGTT- Drug route, owing to the incretin effect, with slower and regulated rates of glucose absorption likely due to amylin effect since incretin mediated insulin release has reported reduced efficacy (\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEthyl acetate fractions containing 10mg/kg and 20mg/kg 5,7-dimethoxycoumarins (Rats 26\u0026ndash;30 and Rats 11\u0026ndash;15) had comparable (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) plasma glucose control on IPGTT with the positive control and negative control, probably due to its higher content of 5,7 \u0026ndash; dimethoxycoumarin (85.66%). Methanol fractions containing 20mg/kg 5,7 - dimethoxycoumarin was less effective than both controls (with significant p values differences\u0026thinsp;=\u0026thinsp;0.002\u0026ndash;0.041). This is most likely due to its lower content of 5,7 \u0026ndash; dimethoxycoumarin (70.60%) and suppression of pancreatic functions by its other constituents.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePlasma C \u0026ndash; Peptide Analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003ePlasma C - Peptide Assay (pg/ml) for the 2-hour IPGTT for Rats 1\u0026ndash;25\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120 MIN\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e144.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e205.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e127.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7507.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e162.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e127.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e263.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7958.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e113.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e148.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e132.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e182.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e132.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e187.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e141.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7682.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e144.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e530.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e127.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e139.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e134.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e259.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e134.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e123.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7895.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e127.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e125.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e134.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e132.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7761.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e157.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8070.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e132.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e132.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e137.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e127.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e263.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e187.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e261.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e198.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePlasma C - peptide concentrations data were used to determine and analyze insulin secretion since insulin has very short lifespan in plasma.\u003c/p\u003e \u003cp\u003eIn Rats 16\u0026ndash;20 (methanol fraction containing 20mg/kg 5,7-dimethoxycoumarin) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), the C - peptide concentration decreased progressively on the average from 0mins to 120min. This again showed pancreatic suppression by the methanol fraction.\u003c/p\u003e \u003cp\u003eOxidative stress index (OSI) is calculated as Total Oxidant Status (TOS) /Total Antioxidant Status (TAS). Due to unavailability of Total Oxidant Status kit, OSI was calculated as Malondialdehyde /TAS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). OSI ratio (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) was highest on the average for Rats 1\u0026ndash;22 in the 30min of IPGTT and lowest on the average at 60min of IPGTT for Rats 1\u0026ndash;22.\u003c/p\u003e \u003cp\u003eFor Rats 11\u0026ndash;15 (Ethyl acetate fraction containing 20mg/kg 5,7-dimethoxycoumarin), malondialdehyde (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) had least concentration at 60mins.The C \u0026ndash; peptide (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) release was highest at 60mins (p\u0026thinsp;=\u0026thinsp;0.043) where oxidative stress was lowest and lowest at 30mins where oxidative stress and hyperglycemia were highest, showing that 5,7-dimethoxycoumarin mediated insulin release was mainly as a result of its antioxidant effect.\u003c/p\u003e \u003cp\u003eThis was in contrast with Glimepiride positive control, (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) where C \u0026ndash; peptide release was highest at 30min (highest hyperglycemia and oxidative stress point) and lowest at 60mins (p\u0026thinsp;=\u0026thinsp;0.173) (lowest point of oxidative stress) showing that the insulin mediated release of glimepiride was direct and dependent on hyperglycemia and not on antioxidant effect.\u003c/p\u003e \u003cp\u003eThe fact that 5,7-dimethoxycoumarin insulin mediated release was mainly as a result of its antioxidant effect was confirmed where its antioxidant property was neutralized as in Rats 23, when administered simultaneously with 6% H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e. In this case, the C \u0026ndash; peptide concentration remained constant at 132.5pg/ml from 30min throughout the entire study period, while the plasma glucose concentration steadily increased.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOxidative Stress Index Calculated as Malondialdehyde/TAS for Rats 1\u0026ndash;25 over 2-hour IPGTT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120 MIN\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1..25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma Total Antioxidant Status TAS (micromol/L) for the 2-hour IPGTT for Rats 1\u0026ndash;25.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120MIN\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1953\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1903\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1498\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1465\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1410\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1229\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e985\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1206\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1851\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1505\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1448\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1050\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1779\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1204\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e978\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e985\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e920\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e910\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e881\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1206\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1448\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1786\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1381\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1378\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1455\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1754\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1905\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1363\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1291\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1281\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1346\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1378\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1751\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1701\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1420\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1214\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1306\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1614\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1677\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1697\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4774\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4796\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1682\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4769\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4759\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4794\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma Malondialdehyde Assay (nmol/ml) for the 2-hour IPGTT for Rats 1\u0026ndash;25.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120MIN\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1744\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1103\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1872\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e590\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1590\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e667\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e846\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1051\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1154\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e513\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e436\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e308\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e410\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e872\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e846\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4462\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1513\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e282\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e769\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e872\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1872\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e872\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1282\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e744\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1231\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e795\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e538\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2385\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e513\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2769\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2590\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1436\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1487\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePlasma Insulin Analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma Insulin Assay (mU/L) for the 2-hour IPGTT for Rats 1\u0026ndash;25.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120 MIN\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe laboratory results for plasma insulin (Table \u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e) had similar characteristics to those of C- peptide above. The statistical analysis and interpretations for insulin were determined using C- peptide data (which are more reliable due to longer lifespan of C \u0026ndash; peptide in plasma) as stated above\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePlasma Amylin Analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma Amylin Assay (pg/ml) for the 2-hour IPGTT for Rats 1\u0026ndash;25.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120 MIN\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe groups plasma amylin analysis comparison (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) showed no significant findings in the initial periods of the study, but this changed at 120 mins where 5,7- dimethoxycoumarin induced amylin synthesis and secretion in Rats 11\u0026ndash;15 (20mg/kg ethyl acetate 5,7 - Dimethoxycoumarin) (p\u0026thinsp;=\u0026thinsp;0.015) and Rats 16\u0026ndash;20 (20mg/kg methanol 5,7 - dimethoxycoumarin) (p\u0026thinsp;=\u0026thinsp;0.09), 2 times that produced by glimepiride (p\u0026thinsp;=\u0026thinsp;0.003) and 3 times that of negative control (p\u0026thinsp;=\u0026thinsp;0.129).\u003c/p\u003e \u003cp\u003eThe increased amounts of 5,7-dimethoxycoumarin mediated amylin secretion in Rats 11\u0026ndash;15 and Rats 16\u0026ndash;20 occurred after a fall in insulin and C- peptide concentration from 60min to 120min (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This suggests that the amylin induction, synthesis and secretion may be from other tissues (GIT), since amylin is produced in the beta cells of the pancreas, co-localized, co-packaged and co-secreted with insulin and C \u0026ndash; peptide.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePlasma Proinsulin Analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab8\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma Proinsulin Assay (mU/L) for the 2-hour IPGTT for Rats 1\u0026ndash;25.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 MIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120 MIN\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThere was a progressive increase in plasma proinsulin levels from 0min to 120mins for all 25 Rats on IPGTT except for Rats 23 (6% H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e plus 20mg/kg 5,7-dimethoxycoumarin) (Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis progressive increase suggests increase induction, synthesis and secretion of insulin and C-peptide in all the rats in response to the IPGTT induced hyperglycemia. The decrease in proinsulin level in Rat 23 from 30min to 120min suggest concentrated H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e prooxidant mediated suppression of pancreatic functions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAcute Drug Toxicity Study\u003c/h2\u003e \u003cp\u003eEach of Rats 51\u0026ndash;60 received intraperitoneally one of either sterile water, ethyl acetate fraction containing 10mg/kg or 20mg/kg 5, 7 - Dimethoxycoumarin, and were monitored for signs of acute drug toxicity for over 24 hours. After which they were sacrificed by cervical dislocation. The preliminary acute toxicity studies report (supplementary Fig.\u0026nbsp;2) of ethyl acetate fraction containing 5,7 - Dimethoxycoumarin study drug showed no toxic effects on important organs of interest by histopathological analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOxidative stress reduces insulin secretion through glucolipotoxicity of pancreatic islet cells. Prooxidants like high dose vitamin C and H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e worsen oxidative stress and resultant hyperglycemia.\u003c/p\u003e \u003cp\u003eSome natural plants secondary metabolites like flavonoids and coumarins mediate insulin secretion through their antioxidant effects. Their insulin releasing properties are counteracted by prooxidants or in severe cases of oxidative stress.\u003c/p\u003e \u003cp\u003e5,7-dimethoxycoumarin in addition to its antioxidant mediated insulin release equally directly induces the secretion of amylin 2 times than glimepiride and 3 times negative control, making it potential useful agent in management of obesity.\u003c/p\u003e \u003cp\u003eThe methanol fraction (oily, viscous fraction) containing 20mg/kg 5,7 \u0026ndash; dimethoxycoumarin suppressed pancreatic function (inhibits C \u0026ndash; peptide secretion throughout the study), while the ethyl acetate fraction (dry fraction) indirectly stimulated pancreatic functions (increased insulin and C \u0026ndash;peptide release and reduced blood glucose level). But both fractions stimulated similar Amylin release at 120mins, 2 times that of glimepiride, after a fall in C- peptide concentration from 60min to 120min. This confirms that this Amylin release is Extrapancreatic.\u003c/p\u003e \u003cp\u003eSimultaneous administration of high dose (1,000mg/kg) vitamin C and 5,7-dimethoxycoumarin during IPGTT in Rats 24\u0026ndash;25 in this study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) produced the highest hyperglycemia of all the groups in this study (too high to be measured by the glucometer) which persisted from the 30min to the end of the study.\u003c/p\u003e \u003cp\u003eThe total antioxidant status (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) increased markedly in both rats with progressive significant reduction in measured oxidative stress (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), even when there was evident severe tissue oxidative stress with marked hyperglycemia.\u003c/p\u003e \u003cp\u003eThis raises question on the accuracy of total antioxidant status measuring kits in high dose vitamin C, due to its changing roles from antioxidant to prooxidant. This innate error in the kit\u0026rsquo;s measurement is due to its reliance on the reduction of ferric (Fe\u003csup\u003e3+\u003c/sup\u003e) to Ferrous (Fe\u003csup\u003e2+\u003c/sup\u003e) by antioxidants (vitamin C in this case) which make the kit accurate with low dose vitamin C, but grossly inaccurate with high dose vitamin C. Because this is equally the mechanism through which vitamin C exerts its prooxidant effect, due to the subsequent reaction of Fe\u003csup\u003e2+\u003c/sup\u003e and H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (Fenton) to give rise to reactive hydroxyl radicals.\u003c/p\u003e \u003cp\u003eThe \u003cb\u003elimitation\u003c/b\u003e of this study is working with impure fractions of 5,7-imethoxycoumarin, which makes the conclusions contestable.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFuture research work\u003c/b\u003e is to determine the extrapancreatic amylin induction, synthesis, and secretion effects of pure (100%) fractions of 5,7 \u0026ndash; dimethoxycoumarin in vitro on Amylin releasing cell lines, isolated pancreatic islet cells and cell lines from the Gastrointestinal tracts (GIT).\u003c/p\u003e \u003cp\u003eTo determine the Amylin releasing effects of increasing doses of pure fractions of 5,7 \u0026ndash; dimethoxycoumarin (10mg/kg, 20mg/kg, 30mg/kg, 40mg/kg and 50mg/kg) over 4-hour course of intraperitoneal and oral glucose tolerance tests in Wistar rats. And also, to carry out detailed toxicological (acute, subchronic, chronic, hematological, chemistry, biochemistry, histopathology) effects of this study.\u003c/p\u003e \u003cp\u003eTo study the effect of 5,7- Dimethoxycoumarin on human amylin aggregation.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe following conclusions were reached at the end of the study.\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEthyl acetate fractions containing 10mg/kg and 20mg/kg dimethoxycoumarin had comparable plasma glucose control with glimepiride. The 20mg/kg methanol fraction of 5,7-dimethoxycoumarin showed less effectiveness in blood glucose reduction, probably due lower concentration of 5,7 - dimethoxycoumarin.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eBoth the ethyl acetate and methanol fractions containing 5, 7 -dimethoxy coumarins induced the synthesis and secretion of amylin at 120 mins about 2 times that of glimepiride positive control and 3 times the negative control. This secretion occurred after a fall in insulin and C - peptide concentration from 60 min to 120 mins, raising suspicion of amylin secretion from other tissues of GIT.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eBoth the methanol and ethyl acetate fractions had similar Amylin secretions at 120 mins, even though the methanol fraction suppressed the pancreas and the ethyl acetate fraction stimulated the pancreatic functions. This confirms mainly Extrapancreatic Amylin mediated secretion.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e5,7-dimethoxycoumarin a calcium channel blocker can mainly stimulate insulin release through indirect mechanism.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTotal antioxidant status measuring kit may not provide accurate information on the antioxidant status of high dose vitamin C due to its changing roles from antioxidant to prooxidant..\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHigh dose vitamin C therapy should be discouraged, particularly in patients with type 2 diabetes due to the possibility of serious suppression of pancreatic functions, owing to severe prooxidant effect.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e5,7 - Dimethoxycoumarin mediated amylin secretion will find application in the management of obesity.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e5,7-dimethoxycoumarin will find special application in diabetics with chronic complications, against coagulopathy, platelet hyperactivity, thrombosis (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), vasoconstriction, atherosclerosis (\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e), neuropathic pains and peripheral neuropathy (\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e), Amyloidosis (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) and effects of advanced glycation end products (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSince the overall plasma glucose regulation is achieved through amylin and insulin synergy, attention should be shifted from insulin-based to amylin-based therapy.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eExtrapancreatic Amylin mediated secretion with natural compounds (coumarins) holds the key to future management of diabetes, as it will provide a more suitable alternative to insulin in the management of diabetes due to negative issues of insulin resistance, weight gain, hyperinsulinism and insulin mitogenicity in diabetics (\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available upon reasonable request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received some financial support from Federal Scholarship Board, Nigeria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEmeka Ofodire (E.O.) is the principal investigator and researcher for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eE.O. conceptualized the research topic, designed the protocol, wrote the draft proposal, obtained fund for the study, extracted and fractionated the grapefruit peel bioactive components, procured the laboratory animals and test kits, carried out the study, laboratory and statistical analysis and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003eS.G., E.U.U., T.O.M. and I.C.O assisted E.O. to carry out the study. S.G. and A.M. moderated, supervised and coordinated the study. E.U.U. assisted in housing, feeding and caring for the laboratory animals. T.O.M. assisted in laboratory analysis. E.C.M. assisted in extraction and fractionation of bioactive components.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding Author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eE.O. is the corresponding author. All correspondence to [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no conflicts of interest in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for the study was obtained from the University of Nigeria Nsukka College of Medicine Research Ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent not required for this type of study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAdeneye AA \u003cem\u003eMethanol Seed Extract of Citrus Paradisi Macfad Lowers Blood Glucose, Lipids and Cardiovascular Disease Risk Indices in Normal Wistar Rats. 1, 2008, Nig Q J Hosp Med, Vol. 18, pp. 16\u0026ndash;20.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4314/nqjhm.v18i1.44950\u003c/span\u003e\u003cspan address=\"https://doi.org/10.4314/nqjhm.v18i1.44950\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohammed MS, Warda TF \u003cem\u003eTasnim TM. Antidiabetic and Antihyperglycemic Effect of Citrus. S2\u003c/em\u003e, (2022), \u003cem\u003eInternational journal of Health Sciences, Vol. 6, pp. 8299\u0026ndash;8308.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.53730/ijhs.v6ns2.7112\u003c/span\u003e\u003cspan address=\"https://doi.org/10.53730/ijhs.v6ns2.7112\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHung W, Suh JH, Wang Y \u003cem\u003eChemistry and health effects of furanocoumarins in grapefruits. 1, 2017, Journal of Food and Drug Analysis, Vol. 25, pp. 71\u0026ndash;83.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.fda.2016.11.008\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/j.fda.2016.11.008\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun C, Liu Y, Zhan L \u003cem\u003eAnti-diabetic effects of natual antioxidants from fruits. 2021, Trends in Food Science and Technology, Vol. 117, pp. 3\u0026ndash;14.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.tifs.2020.07.024\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/j.tifs.2020.07.024\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSukhikh S, Babich O, Prosekov A \u003cem\u003eAntidiabetic Poperties of Plant Secondary Metabolites. 4, 2023, Metabolites, Vol. 13, p. 513.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/metabo13040513\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3390/metabo13040513\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOfodire E \u003cem\u003eBifunctional Antidiabetic\u003c/em\u003e - \u003cem\u003eAnticancer Active Vitamins and Minerals: Drug Delivery Systems Enhancement. 3, 2023, Adv Bioeng Biomed Sci Res, Vol. 6, 9\u0026ndash;16.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.33140/ABBSR.06.01.002\u003c/span\u003e\u003cspan address=\"https://doi.org/10.33140/ABBSR.06.01.002\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOfodire E \u003cem\u003eBifunctional Antidiabetic\u003c/em\u003e - \u003cem\u003eAnticancer Dual\u003c/em\u003e - \u003cem\u003eActive Phytochemicals: Adjuncts or Alternatives to Conventional Therapies. 5, 2023, Adv Bioeng Biomed Sci Res, Vol. 6, 46\u0026ndash;70.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.33140//ABBSR.06.05.002\u003c/span\u003e\u003cspan address=\"https://doi.org/10.33140//ABBSR.06.05.002\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLv X, Zhao S, Zeng H et al Citrus fruits as a treasure trove of active natural metabolites that potentially povide benefits for human health. 2015. Chem Cent J, \u003cem\u003eVol. 9\u003c/em\u003e, \u003cem\u003ep.\u003c/em\u003e 68. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13065-015-0145-9\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1186/s13065-015-0145-9\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOfodire E \u003cem\u003eBifunctional Antidiabetic\u003c/em\u003e - \u003cem\u003eAnticancer Dual\u003c/em\u003e - \u003cem\u003eActive Plants: New Roles, Challenges and Prospects. 5\u003c/em\u003e, (2023), \u003cem\u003eAdv Bioeng Biomed Sci Res, Vol. 6, 25\u0026ndash;45.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.33140//ABBSR.06.05.001\u003c/span\u003e\u003cspan address=\"https://doi.org/10.33140//ABBSR.06.05.001\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u003cem\u003eDugrand\u003c/em\u003e - \u003cem\u003eJudek A, et al. The Distribution of Coumarins and Furanocoumarins in Citrus Species Closely Matches Citrus Phylogeny and Reflects the Oganization of Biosynthetic Pathways. 11\u003c/em\u003e, (2015), \u003cem\u003ePLoS One, Vol. 10.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1371/journal.pone.0142757\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1371/journal.pone.0142757\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRandelovic S \u003cem\u003eandBipat RA. Review of Coumarins and Coumarin\u003c/em\u003e - \u003cem\u003eRelated Compounds for Their Potential Antidiabetic Effect. 2021\u003c/em\u003e. Clin Med Insights Endocrinol Diabetes, \u003cem\u003eVol. 14\u003c/em\u003e, \u003cem\u003ep.\u003c/em\u003e 11795514211042023. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/11795514211042023\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1177/11795514211042023\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAkkol EK, Genc Y, Karpuz B et al Coumarins and Coumarin - \u003cem\u003eRelated Compounds in Pharmacotherapy of Cancer. 7\u003c/em\u003e, (2020), \u003cem\u003eCancers (Basel), Vol. 12, p. 1959.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/cancers12071959\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3390/cancers12071959\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNajmanova I, Dosedel M, Hrdina \u003cem\u003eCadiovascular effects of coumarins besides their antioxidant activity. 9, 2015, Curr Top Med Chem, Vol. 15, pp. 830\u0026thinsp;\u0026ndash;\u0026thinsp;49.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2174/1568026615666150220112437\u003c/span\u003e\u003cspan address=\"https://doi.org/10.2174/1568026615666150220112437\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLu P, Liao T, Chen Y \u003cem\u003eCoumarins Derivatives Inhibit ADP\u003c/em\u003e - \u003cem\u003eInduced Platelet Activation and Aggregation. 13, 2022, Molecules, Vol. 27, p. 4054.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/molecules27134054\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3390/molecules27134054\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVuorela H, Vuorela P \u003cem\u003eTornquist K and Alaranta S. Calcium channel blocking activity: Screening methods for plant derived compounds. 2\u003c/em\u003e, (1997), \u003cem\u003ePhytomedicine, Vol. 4, pp. 167\u0026thinsp;\u0026ndash;\u0026thinsp;80.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0944-7113(97)80064-5\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/S0944-7113(97)80064-5\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProgram National \u003cem\u003eToxicology. NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1993, Natl Toxicol Program Tech Rep Ser, Vol. 422, pp. 1\u0026ndash;340.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorn SL, Api AM, Ford RA \u003cem\u003eComparative metabolism and kinetics of coumarin in mice and rats. 2, Food Chem Toxicol, Vol. 41, pp. 247\u0026thinsp;\u0026ndash;\u0026thinsp;58.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.tiv.2005.08.001\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/j.tiv.2005.08.001\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarlton BD, Aubrun J \u003cem\u003eand Simon GS. Effects of Coumarin Following Perinatal and Chronic Exposure in Sprague-Dawley Rats and CD \u0026ndash;\u0026thinsp;1 Mice. 1, 1996, Toxicological Sciences, Vol. 30, pp. 145\u0026ndash;151.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/toxsci/30.1.145\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1093/toxsci/30.1.145\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGu J, Walker VE, Lipinskas TW \u003cem\u003eIntraperitoneal Administration of Coumarin Causes Tissue-Selective Depletion of Cytochromes P450 and Cytotoxicity in Olfactory Mucosa. 1, 1997, Toxicology and Applied Pharmacology, Vol. 146, pp. 134\u0026ndash;143.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHedges SC, Vostinaru O, Mogosan C et al Safety Profile of Nutraceuticals Rich in coumarins: An Update. 2022. Front Pharmacol, \u003cem\u003eVol. 13\u003c/em\u003e, \u003cem\u003ep.\u003c/em\u003e 803338. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fphar.2022.803338\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3389/fphar.2022.803338\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHazleton LW, Tusing TW \u003cem\u003eZeitlin BR, Toxicity of Coumarin. 3, 1956, The Journal of Pharmacology and Experimental Therapeutics, Vol. 118, pp. 348\u0026ndash;358.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLake BG \u003cem\u003eCoumarin Metabolism, Toxicity and Carcinogenicity: Relevance for Human Risk Assessment. 4\u003c/em\u003e, (1999), \u003cem\u003eFood Chem Toxicol. Vol. 37, P. 423\u0026ndash;453.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0278-6915(99)00010-1\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/s0278-6915(99)00010-1\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnowles NG, Landchild MA, Fujimoto WY, Kahn SE \u003cem\u003eInsulin and Amylin Release Are Both Diminished in First-Degree Relatives of Subjects With Type 2 Diabetes. 2\u003c/em\u003e, (2002), \u003cem\u003eDiabetes Care, Vol. 25, pp. 292\u0026ndash;297.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2337/diacare.25.2.292\u003c/span\u003e\u003cspan address=\"https://doi.org/10.2337/diacare.25.2.292\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatzung BG, Trevor AJ \u003cem\u003eBasic and Clinical Pharmacology. 13th. s.l.: Lange., 2015. p. 1066. 9780071826419.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan Y, Liu T \u003cem\u003eWang X and Sun J. Research progress of coumarins and their derivatives in the treatment of diabetes. 1, 2022, J Enzyme Inhib Med Chem, Vol. 37, pp. 616\u0026ndash;628.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/14756366.2021.2024526\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1080/14756366.2021.2024526\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobertson RP \u003cem\u003eOxidative Stress and Impaired Insulin Secetion in Type 2 Diabetes. 6\u003c/em\u003e, (2006), \u003cem\u003eCurr Opin Pharmacol., Vol. 6, pp. 615-9.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.coph.2006.09.002\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/j.coph.2006.09.002\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeane KN, Cruzat VF, Carlessi R et al Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and B-Cell Dysfunction. 2015, Oxid Med Cell Longev, \u003cem\u003ep.\u003c/em\u003e 181643. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2015/181643\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1155/2015/181643\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHassanein EHN, Sayed AM et al Coumarins as Modulatos of the Keap 1/Nrf2/AE Signaling Pathway. 2020. Oxid Med Cell Longev, \u003cem\u003eVol.\u003c/em\u003e (2020), \u003cem\u003ep.\u003c/em\u003e 1675957. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2020/1675957\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1155/2020/1675957\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu M, Weiss MA, Arunagiri A et al Biosynthesis, Structure, and Folding of the Insulin Precursor Protein. (Suppl 2), (2018), \u003cem\u003eDiabetes Obes Metab, Vol. 20, pp. 28\u0026ndash;50.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/dom.13378\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1111/dom.13378\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao NK, Zhu SS, Chen YM \u003cem\u003eA new prenylated coumarin digloside with insulin-release promoting activity from Clausena dunniana. 4, 2021, J Asian Nat Prod Res, Vol. 23, pp. 385\u0026ndash;391.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/10286020.2020.1810671\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1080/10286020.2020.1810671\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmed S, Nur-e-Alam M, Parveen I et al Stimulation of insulin secretion by 5-methylcoumarins and its sulfur analogues isolated from Clutia lanceolata Forssk. (2020), \u003cem\u003ePhytochemistry, Vol. 170, p. 112213.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi,org/10.1016/j.phytochem.2019.112213\u003c/span\u003e\u003cspan address=\"https://doi,org/10.1016/j.phytochem.2019.112213\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuranov S, Marenina M et al The Study of Hypoglycemic Activitry of 7 - \u003cem\u003eTerpenylcoumarins.\u003c/em\u003e (2022), \u003cem\u003eMolecules Vol. 27, P. 8663.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/molecules27248663\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3390/molecules27248663\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbedini A, Schmidt AM \u003cem\u003eMechanism of Islet Amyloidosis Toxicity in Type 2 Diabetes.\u003c/em\u003e (2015), \u003cem\u003eFEBS Lett, Vol 587, 1119\u0026ndash;1127.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.febslet.2013.01.017\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/j.febslet.2013.01.017\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHieronymus L, Griffin S \u003cem\u003eRole of Amylin in Type 1 and 2 Diabetes. (1 Suppl)\u003c/em\u003e, (2015), \u003cem\u003eDiabetes Educ, Vol. 41, pp. 47S \u0026ndash;\u0026thinsp;56S.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/0145721715607642\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1177/0145721715607642\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiddle MC, Drucker DJ \u003cem\u003eEmerging Therapies Mimicking the Effects of Amylin and Glucagon\u003c/em\u003e - \u003cem\u003eLike Peptide 1.\u003c/em\u003e (2006), \u003cem\u003eDiabetes Care Vol. 29, 435\u0026ndash;449.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1337/DIACARE.29.02.06.DC05-1267\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1337/DIACARE.29.02.06.DC05-1267\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoung A \u003cem\u003eTissue Expression of and Secretion of Amylin. 2005, Adv Pharmacol, Vol. 52, pp. 19\u0026ndash;45.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S1054-3589(05)52002-7\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/S1054-3589(05)52002-7\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbu-Aisheh MN, Al-Aboudi A, Mustafa MS et al Coumarin derivatives as acetyl- and butyrylcholinesterase inhibitors: An in vitro, molecular docking, and molecular dynamics simulations study. 4, 2019, Heliyon, \u003cem\u003eVol. 5\u003c/em\u003e, e01552\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBruhlmann C, Ooms F, Carrupt P \u003cem\u003eCoumarins Derivatives as Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase. 2001, J Med Chem, Vol. 44, 3195\u0026ndash;3198.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/101021/JM0108940\u003c/span\u003e\u003cspan address=\"https://doi.org/101021/JM0108940\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrhan IE, Gulcan HO \u003cem\u003eCoumarins: Auspicious Cholinesterase and Monamine Oxidase Inhibitors. 17\u003c/em\u003e, (2015), \u003cem\u003eMed Chem, Vol. 15, 1673\u0026ndash;82.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2174/1568026615666150427113103\u003c/span\u003e\u003cspan address=\"https://doi.org/10.2174/1568026615666150427113103\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlkahtane AA, Alghamdi HA, Almutairi B et al Inhibition of human amylin aggregation by Flavonoid Chrysin: An in-silico and in-vitro approach.1, 2021. Int J Med Sci, \u003cem\u003eVol. 18\u003c/em\u003e, 199\u0026ndash;206. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7150/ijms.51382\u003c/span\u003e\u003cspan address=\"https://doi.org/10.7150/ijms.51382\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eErzen S, Tonin G et al Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity. 2024. Int J Mol Sci Vol \u003cem\u003e25\u003c/em\u003e, 1517. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/ijms25031517\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3390/ijms25031517\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMauvais - \u003cem\u003eJarvis F. Gender differences in glucose homeostasis and diabetes.\u003c/em\u003e (2018), \u003cem\u003ePhysiol Behav, Vol. 187, pp. 20\u0026ndash;23.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.physbeh.2017.08.016\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/j.physbeh.2017.08.016\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeer EB \u003cem\u003eand Shen Wei. Gender Differences in Insulin Resistance, Body Composition, and Energy Balance.\u003c/em\u003e (2009), \u003cem\u003eGend Med, Vol. 6 (Suppl 1), pp. 60\u0026ndash;75.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.genm.2009.02.002\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1016/j.genm.2009.02.002\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLluis L, Muuoz M, Nogues MR et al Toxicology Evaluation of a Procyanin-rich Extract From Grape Skin and Seed. (2011), \u003cem\u003eFood Chem. Toxicol, Vol. 49, pp. 1450\u0026ndash;1454.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi,org/10.1016/j.fct.2011.03.042\u003c/span\u003e\u003cspan address=\"https://doi,org/10.1016/j.fct.2011.03.042\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInoue K, Morikawa T, Takahashi M \u003cem\u003eA 13-Week Subchronic Toxicity Study of Grape Skin Extract in F344 Rats. 2013, J. Toxicol. Sci, Vol. 38, pp. 557\u0026ndash;570.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doii.org/10.2131/jts.38.559\u003c/span\u003e\u003cspan address=\"https://doii.org/10.2131/jts.38.559\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbubakar A, Hague M \u003cem\u003ePreparation of Medicinal Plants: Basic Extraction and Fractionation Procedures for Experimental Purposes. 1, 2020, J Pharm Bioallied Sci, Vol. 12, pp. 1\u0026ndash;10.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4103/jpbs.JPBS_175_19\u003c/span\u003e\u003cspan address=\"https://doi.org/10.4103/jpbs.JPBS_175_19\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSultana B \u003cem\u003eAnwar F and Ashiraf M. Effect of Extraction Solvent/Technique on the Antioxidant Activity of Selected Medicinal Plant Extracts. 6\u003c/em\u003e, (2009), \u003cem\u003eMolecules, Vol. 14, pp. 2167\u0026ndash;2180.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/molecules14062167\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3390/molecules14062167\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourgaud F \u003cem\u003ePoutaraud A and Guckert A. Extraction of coumarins from plant material (Leguminosae). 3\u003c/em\u003e, (1994), \u003cem\u003ePhytochemical Analysis, Vol. 5, pp. 127\u0026ndash;132.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/pca.2800050308\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1002/pca.2800050308\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeighton E, Sainsbury CAR \u003cem\u003eJones GC. A Practical Review of C\u003c/em\u003e - \u003cem\u003ePeptide Testing in Diabetes. 3, 2017, Diabetes Therapy, Vol. 8, pp. 475\u0026ndash;487.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s13300-017-0265-4\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1007/s13300-017-0265-4\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel R, Barker J, ElShaer A Pharmaceutical Excipients and Dug Metabolism: A Mini-Review. 21, 2020. Int J Mol Sci, \u003cem\u003eVol. 21\u003c/em\u003e, \u003cem\u003ep.\u003c/em\u003e 8224. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/103390/ijms21218224\u003c/span\u003e\u003cspan address=\"https://doi.org/103390/ijms21218224\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagaraju B \u003cem\u003eand Anilkumar KV. Pharmacodynamic and pharmacokinetic interaction of losartan with glimepiride-metformin combination in rats and rabbits https://doi.org\u003c/em\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e/10.4103/ijp.IJP_845_19\u003c/span\u003e\u003cspan address=\"http:///10.4103/ijp.IJP_845_19\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. \u003cem\u003e6\u003c/em\u003e, (2021), \u003cem\u003eIndian J Pharmacol, Vol. 53, pp. 465\u0026ndash;470.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasit A, Riaz M, Fawwad A \u003cem\u003eGlimepiride: Evidence\u003c/em\u003e - \u003cem\u003eBased Facts, Trends, and Observations.\u003c/em\u003e(2012), \u003cem\u003eVasc Health Risk Mana, Vol. 8, 463\u0026ndash;472.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/HIV.S33194\u003c/span\u003e\u003cspan address=\"https://doi.org/10.2147/HIV.S33194\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonaubauer HH, Mayer D \u003cem\u003eAcute, Subchronic and Chronic Toxicity of the New Sulfonylurea Glimepiride in Rats. 5, 1993, Arzneimittelforschung, Vol. 43, pp. 547\u0026ndash;9. PMID: 8328999.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSotler R, Poljsak B, Dahmane R : \u003cem\u003eProoxidant Activities of Antioxidants and their Impact on Health. 4, 2019, Acta Clin Croat, Vol. 58, pp. 726\u0026ndash;736.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.20471/acc.2019.58.04.20\u003c/span\u003e\u003cspan address=\"https://doi.org/10.20471/acc.2019.58.04.20\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhalibaf MHE, Kianian F, Beigoli S et al The effects of vitamin C on respiatory, allergic and immunological diseases: an experimental and clinical- based review. (2023), \u003cem\u003eInflammopharmacol, Vol. 31, pp. 653\u0026ndash;672.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10787-023-01169-1\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1007/s10787-023-01169-1\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMingrone G, Panunzi S, Gaetano A \u003cem\u003eInsulin sensitivity depends on the route of glucose administration. 2020, Diabetologia Vol 63, 1382\u0026ndash;1395.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00125-020.05157-w\u003c/span\u003e\u003cspan address=\"https://doi.org/10.1007/s00125-020.05157-w\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSavage S, Miller LA, Schrier RW \u003cem\u003eThe future of calcium channel blocker therapy in diabetes mellitus. 1, 1991, J Cardiovasc Pharmacol, Vol. 18, S19\u0026ndash;24.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10/1097/00005344-199100181-00005\u003c/span\u003e\u003cspan address=\"https://doi.org/10/1097/00005344-199100181-00005\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUsman M, Malik H, Tokhi A et al \u003cem\u003e5,7\u003c/em\u003e - \u003cem\u003eDimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT3 receptors and monoamines. 2023\u003c/em\u003e. Front Pharmacol, \u003cem\u003eVol. 14\u003c/em\u003e, 1213763. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fphar.2023.1213763\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3389/fphar.2023.1213763\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee EJ, Kang MK, Kim YH et al Coumarin Ameliorates Impaired Bone Turnover by Inhibiting the Formation of Advanced Glycation End Products in Diabetic Osteoblasts and Osteoclasts. 7, (2020), \u003cem\u003eBiomolecules, Vol. 10, 1052.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/biom10071052\u003c/span\u003e\u003cspan address=\"https://doi.org/10.3390/biom10071052\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOfodire E \u003cem\u003eHyperinsulinism Gateway Between Diabetes and Cancer: New Roles for Bifunctional Antidiabetic\u003c/em\u003e - \u003cem\u003eAnticancer Active Somatostatins, IGF \u0026ndash;\u0026thinsp;1 Inhibitors. 2023, Adv Bioeng Biomed Sci Res, Vol 6, P.17\u0026ndash;24.\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.33140//ABBSR.06.03.003\u003c/span\u003e\u003cspan address=\"https://doi.org/10.33140//ABBSR.06.03.003\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Nigeria","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Coumarin, Antidiabetic, Insulin, Extrapancreatic, Amylin, Secretion","lastPublishedDoi":"10.21203/rs.3.rs-4751863/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4751863/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOxidative stress decreases the ability of β-cells to secrete insulin through glucolipotoxicity of the pancreatic islets. Flavonoids modulate insulin and amylin secretion through mainly antioxidant activities. Coumarins isomers of flavonoids have direct effects on the cardiovascular system, not linked to antioxidant activities. This study aimed to investigate the effects of 5,7-dimethoxycoumarin (Citropten) fractions present in grapefruit peel on insulin and amylin secretions in normal male Wistar rats.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMethanol extract of grapefruit peels was fractionated using vacuum assisted liquid chromatography with n-Hexane, Ethyl acetate and Methanol. Gas Chromatography Mass Spectrometry analysis reported ethyl acetate fraction with highest concentration (85.66%) of 5,7-dimethoxycoumarin. Intraperitoneal Glucose Tolerance Test was performed on 5 sets of 5 rats receiving intraperitoneally: 1) negative control, 1ml of sterile water 2) positive control, 0.2mg/kg glimepiride, 3) ethyl acetate fraction containing 10mg/kg, 20mg/kg 5,7-dimethoxycoumarin, 4) methanol fraction containing 10mg/kg, 20mg/kg 5,7-dimethoxycoumarin 5a)1ml H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2 \u003c/sub\u003e(0.6%, 6%) plus 20mg/kg 5,7-dimethoxycoumarin, and 5b)1000mg/kg Vitamin C plus 20mg/kg 5,7-dimethoxycoumarin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResults showed ethyl acetate fractions containing 10mg/kg and 20mg/kg 5,7-dimethoxycoumarin had comparable plasma glucose control with glimepiride, with indirect insulin secretion effect unlike direct acting glimepiride; the methanol fraction was less effective. Both ethyl acetate and methanol fractions of 5,7- dimethoxycoumarin induced extrapancreatic amylin synthesis and secretion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e5,7-dimethoxycoumarin will find special applications in the management of obesity, and diabetics with chronic complications. Since the overall plasma glucose regulation is achieved through amylin and insulin synergy, attention should be shifted from insulin-based to amylin-based therapy. There is need to focus on natural compounds that stimulate extrapancreatic amylin release.\u003c/p\u003e","manuscriptTitle":"5,7- Dimethoxycoumarin Enhances Insulin Release and Stimulates Extrapancreatic Secretion of Amylin.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 10:22:46","doi":"10.21203/rs.3.rs-4751863/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f534a486-b29c-40b5-a153-23df7ef65c17","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34783761,"name":"Drug Discovery, Design, \u0026 Development"}],"tags":[],"updatedAt":"2024-07-18T10:22:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-18 10:22:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4751863","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4751863","identity":"rs-4751863","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}