Rice Bran Extract attenuates cognitive impairment by enhancing pancreatic β-cell insulin secretion in STZ-induced diabetic rats targeting the PPARγ/PDX1 pathway

Rice Bran Extract attenuates cognitive impairment by enhancing pancreatic β-cell insulin secretion in STZ-induced diabetic rats targeting the PPARγ/PDX1 pathway | 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 Rice Bran Extract attenuates cognitive impairment by enhancing pancreatic β-cell insulin secretion in STZ-induced diabetic rats targeting the PPARγ/PDX1 pathway Madonna Magdy Youssef, Mohammed Farrag El-Yamany, Reham Mahmoud Abdel-Kader, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5702421/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Jun, 2025 Read the published version in Metabolic Brain Disease → Version 1 posted 4 You are reading this latest preprint version Abstract Type I diabetes (T1D), also known as juvenile diabetes, is an autoimmune disease that causes gradual destruction of pancreatic cells and leads to intellectual disability, neuropathy, cognitive impairment, and impaired learning ability in children. Despite standard treatment with synthetic human insulin, T1D patients can maintain up to 40% of their insulin-producing islets. PPARγ receptor activation research that aims to restore β-cell biology could help reverse the loss of pancreatic mass that comes with getting older and improve β-cell function. Egyptian RB ethanol extract (RBE), previously reported with PPARγ agonist activity, showed an increase in insulin secretion both in vivo and in INS-1 cells. The exact antidiabetic RBE mechanism is still unclear. The present study aims to investigate the molecular RBE mechanism in glucose-stimulating insulin secretion and restoration of β cell function. A diabetic rat streptozotocin (STZ) model was used; five groups were designed. The STZ-diabetic rats were treated with RBE daily for 21 days compared to an insulin-treated group. Biochemical parameters and quantitative RT-PCR of β-cell genes related to the PPAR/PDX1 signaling pathway were performed, and the influence on cognitive ability was confirmed by behavioral testing (Y-maze and NOR) and histological examination. The RBE-treated group reversed blood glucose, Glut2, Ca2+, and insulin levels in diabetic rats, with pancreatic insulin levels significantly increasing compared to the insulin group. With the exception of PDX1, RBE boosted PPARγ, SERCA, and PrKC gene expression. RBE also restored cognitive functions. This study suggests that RBE may enhance memory and cognition by increasing peripheral insulin secretion through PPARγ regulator activity. insulin diabetes rice bran extract PPARγ and cognition Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Highlights Glucose transport in β-cells plays a significant role for insulin secretion. Egyptian Rice bran extract treatment enhanced insulin secretion. Egyptian Rice bran extract boosted PPARℽ, SERCA, and PrKC gene expression. Egyptian Rice bran extract restored pancreatic structure more effectively. RBE may enhance memory and cognition by increasing peripheral insulin secretion. 1 Introduction Diabetes mellitus is a prevalent chronic illness globally. Type 1 diabetes (T1D) is a long-term, organ-specific autoimmune disorder that destroys pancreatic β-cells gradually and is known as juvenile diabetes (age > 20). Diabetes mellitus is the seventh most common cause of death in the United States ( Sapra et al., 2020 ; Leslie et al., 2021 ; Kim et al., 2021 ). In 2021, the International Diabetes Federation (IDF) reported 1.2 million cases of children and adolescents with T1D worldwide, with an expected annual increase of 184,100 cases and prevalence of 2% in Africa and 10% of cases in Egypt (IDF, 2021). Anomalous glucose and insulin levels in childhood T1D patients can lead to mental impairment and neuropathy ( Jin et al., 2022 ; Li et al., 2021 ; Xu et al., 2021 ). This is a common microvascular diabetes complication ( Galiero et al., 2023 ) resulting in cognitive disturbances and limited learning ability in children ( Lacy et al., 2022 ) with a significant medical and financial burden (IDF, 2021) . Typical treatment for T1DM is synthetic human insulin. However, its administration has numerous negative consequences in all age groups, where severe uncontrollable hypoglycemic events negatively impact cognitive and neuronal function ( Hultström et al., 2014 ; Jin et al., 2022 ). It is believed that T1D patients almost completely lose β-cells at the onset of the disease. Further research implies a functional deficit rather than absolute β-cell loss, which may preserve up to 40% of insulin-producing islets and restore insulin production ( Coppieters et al., 2012 ; Krogvold et al., 2015 a; Leete et al., 2016 ). Also, isolated islets from T1D patients were reported to restore insulin production in a non-diabetic environment ( Krogvold et al., 2015 b). Improving β-cell biology is a promising research area for T1D treatment ( Atkinson et al., 2019 ; Cobo-Vuilleumier et al., 2018 ). Activation of PPARγ (Peroxisome Proliferator-Activated Receptor), a transcriptional regulator involved in glucose metabolism, and its synthetic agonists as thiazolidinediones (TZD family) have been reported to maintain β-cell proliferation and reverse the age-related reduction in pancreatic mass in both rats and mice ( Shimabukuro et al., 1998 ; Higa et al., 1999 ; Finegood et al., 2001 ). TZDs have been reported to enhance insulin secretion by controlling several key β-cell genes that potentiate glucose-stimulating insulin secretion (GSIS) ( Evans-Molina et al., 2009 ; Moibi et al., 2007 ). However, TZDs are not recommended as first-line medication due to their numerous negative consequences, including edema, heart failure, liver damage, and bladder cancer (Eggleton and Jialal, 202; Hwang et al., 2021 ). Thus, the proven use of some traditional medicinal plant products as “supportive therapy” for improving glycemic abnormalities in individuals with type 1 and type 2 diabetes was reported. Their use provided an alternative approach to alleviate hyperglycemia with a safe, practical, cost-effective, and convenient way to treat diabetic complications ( Rahman et al., 2022 ). Rice bran, a product of rice milling, is used in traditional medicine to treat various health disorders, supported by experimental and clinical evidence (Ahuja et al., 2012; Umadevi et al., 2012 ). According to in vitro research, RB can reduce hyperglycemia by increasing glucose uptake in 3T3-L1 adipocytes, triggering the expression of glucose transporters, and blocking the activity of α-glucosidase and α-amylase ( Boue et al., 2016 ; Wahyuni et al., 2016 ). RB oil is commonly used for cooking in Thailand and India. A blend of 80% RB oil and 20% sesame oil found significant reductions in fasting blood glucose, postprandial glucose, and glycated hemoglobin levels ( Devarajan et al., 2016 ). One of the recently documented rice bran products with PPARγ agonistic activity is the standardized ethanolic RBE ( Abd El Fattah et al., 2020 ; El-Din et al., 2021 ; Mostafa et al., 2018 ). RBE is one of the innovative natural products of the Egyptian rice bran and holds several health benefits ( Bhatia et al., 2016 : Jolfaie et al., 2016 : Kaup et al., 2012 : Meselhy et al., 2014 : Shendy et al., 2024 ). Kaup et al. reported a RBE antidiabetic effect through a concentration-dependent increase in insulin levels in INS-1 cells and in vivo in plasma (Kaup et al. 2012 ). RBE comprises a splendid set of active phytochemical components, including ℽ oryzanol, tocopherols, tocotrienols, policosanol, and polyunsaturated fatty acids ( Al-Okbi et al., 2014 ; Kalita et al., 2022 ). However, the exact underlying mechanism of RBE for the increased insulin release remains unclear and needs more investigation. In view of RBE's recently documented agonistic effect on PPARγ ( Abd El Fattah et al., 2020 ; El-Din et al., 2021 ; Mostafa et al., 2018 ), we propose a possible mechanism for RBE to restore β-cell function via PPARγ regulation. In this study, we investigated the effect of RBE on the PPARγ/PDX1 pathway, suggesting that RBE PPARγ agonistic activation would promote the sarcoendoplasmic reticulum calcium ATPase pump (SERCA2) to transfer Ca 2+ molecules across the ER membrane. This maintains high Ca 2+ levels within the ER lumen. The suggested increase in Ca 2+ subsequently would activate protein kinase C (PrKC βII) ( Kono et al., 2012 ; Cohenler and Taraska, 2017). PrKC βII redistributes glucose transporter GLUT2, transporting glucose molecules inside the β-cell ( Cohen et al., 2014 ). This in turn activates PDX1, a transcriptional regulator that controls insulin gene expression ( Xia et al., 2014 ; Zhou et al., 2014 ). Therefore, the PPARγ-targeted activation approach in insulin secretion raised our concern about how RBE would affect β-cell function and insulin secretion. Given the recently reported RBE-PPARγ agonist activity and the documented glycemic control effect of RB products and their constituents, we focused on investigating the RBE underlying mechanism. This was done in the diabetic rat STZ model compared to exogenous insulin. 2 Material and Methods 1.1 Animals Male Sprague-Dawley rats weighing 180 to 230 g were used in the study. They were obtained from the central administration animal colony (National Organization for Drug Control and Research, Giza, Egypt) and maintained with a standard laboratory diet and water ad libitum. Animals were maintained in a temperature- and pressure-controlled room (23–24°C and 40–60% relative humidity) and exposed to 12-h dark and light cycles. Before being used in the experiment, the animals went through an acclimatization phase. 1.2 Adherence to the Ethical Standard The Research Ethics Committee at Cairo University (Cairo, Egypt, PT 3080) approved this research methodology. The guidelines for the care and use of laboratory animals, issued by the United States National Institute of Health (NIH publication No. 85 − 23, revised 1996), strictly governed the handling of animals and all procedures (Clark et al., 1996) 1.3 Chemicals Stabilized RBE was acquired from Health Tech Company at 87 Ramsis Street, Cairo, Egypt, and administered orally at a dose of 100 mg/kg/day dissolved in 0.4% DMSO (Mostafa et al., 2018 ). Long-acting insulin (100 UI/mL Insulin Lantus) was acquired from Sanofi-Aventis, France, and administered via a daily subcutaneous (SC) injection at a dose of 5 IU/200 g of body weight/day ( Luippold et al., 2016 , Schaschkow et al., 2016 ). STZ was acquired from Sigma-Aldrich, Germany, and administered via an intraperitoneal injection (IP) for 4 days at a dose of 20 mg/kg of body weight per day. 1.4 Preparation of Stabilized RBE Initially, the lipase enzyme in rice bran was inactivated after milling by the high-temperature short-term method (HTST) to produce stabilized rice bran. Then, for ethanol extraction, rice bran powder was mixed with 95% alcohol at a ratio of 1:3 and then macerated overnight at 50°C for three consecutive times. The extract was vacuum-evaporated at a temperature not higher than 50°C. The phytochemical profile of RBE was identified as previously published (supplementary data S1-S4) . The content of γ-oryzanol and vitamin E was identified using HPLC analysis (Agilent 1100). Fatty acid methyl esters analysis was performed by GLC using the Agilent GC system. The analysis of the polyphenolic content of RBE was measured using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) with an Exion LC AC system for separation and a SCIEX Triple Quad 5500 + MS/MS system equipped using electrospray ionization (ESI) for detection. The oily extract was kept in the refrigerator and warmed immediately before use to 37°C in a water bath. 1.5 Diabetes induction Type 1 diabetes was induced by intraperitoneal injection of multiple low doses (20 mg/kg for four consecutive days) of freshly prepared Streptozotocin (STZ) dissolved in 0.1 M citrate buffer (pH 4.5) after an overnight fast, given only a 5% glucose solution to prevent initial hypoglycaemic mortality ( Youssef et al., 2020 ). Diabetes was confirmed by drawing blood from the retro-orbital vein and assessing blood glucose level using a colorimetric assay kit (Cat. No. GL 1320, Biodiagnostic, Cairo, Egypt) . Animals displaying fasting blood glucose levels greater than 450 mg/dl were used in the present study. Worth mentioning is that in this period (4 days), control groups received citrate buffer I.P. 1.6 Experimental Design Type 1 diabetes was induced by intraperitoneal injection of multiple low doses (20 mg/kg for four consecutive days) of freshly prepared streptozotocin (STZ) dissolved in 0.1 M citrate buffer (pH 4.5) after an overnight fast, given only a 5% glucose solution to prevent initial hypoglycemic mortality ( Youssef et al., 2020 ). Diabetes was confirmed by drawing blood from the retro-orbital vein and assessing blood glucose level using a colorimetric assay kit (Cat. No. GL 1320, Biodiagnostic, Cairo, Egypt) . Animals displaying fasting blood glucose levels greater than 450 mg/dl were used in the present study. Worth mentioning is that in this period (4 days), control groups received citrate buffer I.P. 1.7 Biochemical analysis 2.7.1 Estimation of glucose level in blood The glucose level in the blood was determined using a colorimetric assay kit ( Cat. No. GL 1320, Biodiagnostic, Cairo, Egypt) according to the method of Trinder et al. (1969) . Following the manufacturer's instructions, the amount of glucose present was estimated as absorbance O.D. and measured at 405 nm using a single-beam spectrophotometer (Shimadzu UV-2401PC). 2.7.2 Estimation of Calcium level in pancreatic tissue Pancreatic calcium level content was determined by a colorimetric assay kit (Cat. No. GL 13 20, Biodiagnostic, Cairo, Egypt) according to the Gindler and King method ( Gindler and King 1972 ) . The manufacturer's instructions were followed to detect calcium quantity existing at absorbance O.D. and measured at 585 nm using a single-beam spectrophotometer {Shimadzu UV-2401PC}. 2.7.3 Estimation of insulin level (INS) in blood/pancreatic tissue Quantitative measurements of INS levels in blood samples and pancreatic tissue were assayed using an INS rat ELISA kit (Sunlong, SL0373Ra) . Appropriate assay procedures were followed according to the manufacturer's instructions. Insulin levels were estimated as absorbance O.D. within 15 minutes and measured at 450 nm using a titer plate reader (BioTek/SN 263732). 2.7.4 Estimation of Glucose Transporter 2 level (GLUT 2) in pancreatic tissue. Quantitative measurement of the GLUT 2 level was assayed using a GLUT 2 rat ELISA kit (Bioassay Technology Laboratory, E1058Ra) . The manufacturer's instructions for appropriate assay procedures had been followed. Pancreatic GLUT 2 levels were assessed as absorbance O.D. within 10 minutes and measured at 450 nm using a titer plate reader {BioTek/SN 263732}. 2.7.5 Homeostasis model assessment of β-cell function (HOMA-β) HOMA-β, an index of insulin secretory function, was calculated based upon the measurement of blood glucose and blood insulin concentrations according to the following equation: HOMA-beta = [blood insulin concentration (µU/ml) × 20] / [blood glucose (mmol/L) − 3.5] ( Reaven 2009 ) . 1.8 Quantitative real-time PCR gene expression of PPARγ, SERCA, PrKC, and PDX1 genes in pancreatic tissue Total RNA was extracted from 60 rats' pancreatic tissues using the RNeasy Mini kit (Cat. No. 74101, Qiagen, Germany) following the manufacturer's instructions. The concentration and purity of the extracted RNA were determined using a nanodrop spectrophotometer (2000 c, Thermoscientific, USA). For purification of the RNA, 1500 ng/µl of the sample was added to 2 µl of wipe-out buffer (7x) and nuclease-free water to make a final volume of 14 µl. Incubate for 2 minutes at 42ºC in a thermocycler (BIO-RAD T100, USA) . A mixture was prepared for cDNA synthesis using a QuantiTect reverse transcription kit with a 1:4:1 ratio of RT primer mix, Quantiscript RT buffer, and Quantiscript reverse transcriptase, and then added to the extracted RNA (14 µl). The samples were incubated in a thermocycler for 30 minutes at 42°C and 95°C and then stored at -80°C until analyzed. For each sample, four genes were measured (PPARγ, SERCA, PrKC, and PDX1) using the RT2 Syber Green kit (Cat. No. 330524, Qiagen, Germany). The RT-PCR was performed using Design & Analysis Software (DA2) version 2.6.0 for Applied Biosystems QuantStudio 5 DX, involving adding 1 µl cDNA of each sample, 12.5 µl RT2 Syber Green, and 10.5 µl nuclease-free water. (Thermo Fisher Scientific, USA). Relative quantification for gene expression (RQ) was calculated by the 2-ΔΔCT equation according to Livak and Schmittgen ( 2001 ) using the β-actin reference gene for the normalizer as follows: ΔCt control = CTtarget-CT endogenous β-actin ΔCt sample = CTtarget-CT endogenous β-actin ΔΔCt = ΔCt sample - ΔCt control 1.9 Histopathological examination of pancreatic tissue Autopsy samples were taken from the pancreas of rats in all groups and fixed in 10% neutral buffer formalin for 12 hours. Washing was done with tap water, and then serial dilutions of methyl alcohol (70%, 80%, 90%, 95%, and 100% consecutively) were used for dehydration. Samples were cleared in xylene for 1 hour twice and embedded in soft paraffin, then hard paraffin, each for 1 hr. Finally, paraffin blocks were prepared for sectioning by microtome 2–4 µ. For pancreas routine examination using a light electron microscope, the obtained tissue sections were collected on glass slides, deparaffinized, and stained with hematoxylin and eosin stain ( Bancroft and Stevens, 1996 ). Congo red staining was performed for the brains of rats in all groups using the established protocol. Formalin-fixed and paraffin-embedded tissue was cut into 6-µm-thick sections, deparaffinized, and dyed with 2.5 g of Congo red (Merck Millipore, Darmstadt, Germany) and 1 g potassium hydroxide (Merck Millipore) dissolved into 500 ml. of 80% ethanol ( Menter et al., 2016 ). 1.10 Behavioral assessment 2.10.1 Y-maze test: This test evaluates short-term spatial memory. A three-armed, opaque wooden Y-shaped apparatus measuring 32 mm in length, 10 mm in height, and 5 cm in width and angled at a 120° angle from one another was utilized. Following an introduction to the center of the maze, the rat was given eight minutes to freely investigate each of the three arms, and the order in which it entered each arm was recorded. When its working memory is intact, the rat would prefer to explore a new section of the maze than go back to a previously explored one. The percent alternation is calculated as: (Number of alternations/number of entries-2)×100. Where the number of alternations is any three successive choices of three different arms that are counted as a correct choice and the number of entries are the total possible alternations ( Arai et al., 2001 ). 2.10.2 Novel Object Recognition Test: This test assesses different interspecies aspects of non-spatial recognition memory. The main arena was a wooden, white, opaque chamber (around 40 cm x 40 cm x 60 cm). On the first day, for habituation, each rat was allowed to freely explore the arena without any objects for 10 min. On the following day, each rat goes through a training session for visual exploration of two identical objects for 10 min, then, after a 2-h retention interval, a testing session where one of the previously explored objects is substituted with a novel object, and the animal is left 5 min to explore. In the testing session, a video was recorded of the rats' behavior. Since rodents have an innate preference for novelty, the rat with intact memory will spend more time exploring the novel object. In all sessions, each rat was removed from its home cage and placed in the middle of the open arena, and at the end, the rat was removed and placed in a holding cage. Between each rat, the apparatus was cleaned using 70% ethanol. Objects were different enough to be easily discriminated by the rat but had a similar degree of complexity (texture, shape, color patterning, and brightness) to minimize any possible induced object preference. The discrimination ratio (DR) was calculated as the time spent exploring the novel object minus the time spent exploring the familiar object divided by total exploration time ( Antunes and Biala, 2011 ; Lueptow, 2017 ). 3 Statistical analysis All results were expressed as the mean ± S.E.M. (standard error of the mean). Data were analyzed with a one-way analysis of variance (ANOVA) followed by a Tukey-Kramer post-test for one-variable multiple-group comparison. Only blood glucose and blood insulin were analyzed with a two-way analysis of variance (ANOVA) followed by the Bonferroni post-test for two-variable multiple-group comparisons. In all cases, a p-value less than 0.05 was considered statistically significant. Statistical analysis was performed using instant automated software (GraphPad Prism Software version 5.01). The F distribution formed by the variance ratios according to the degree of freedom combinations was represented by the F value to serve as a reference for the P value location in the data distribution ( Kim, 2017 ) . The winsorization (weight modification method) approach was used for treating the outliers ( Kwak and Kim, 2017 ). Histopathological score values were considered non-parametric values, so data were analyzed by the Kruskal-Wallis test followed by a Dunn's post-test. 4 Results 4.1 Effect of Rice bran extract and Insulin on biochemical parameters 4.1.1 blood glucose levels in STZ diabetic rat As shown in Fig. 2 , blood glucose levels differed greatly between the CON groups and the diabetic groups in all weeks of the experiment (F (220, 4) = 2481.55, P < 0.0001). Just after induction, before treatment, the diabetic groups showed a significant increase in blood glucose levels compared with the CON group of 189.8%. At week 3, compared to the diabetic group, blood glucose levels in the INS-treated group decreased by 21.36% significantly, and blood glucose levels in the RB-treated groups decreased by 10.62% non-significantly. There was also a significant difference between weeks within each group (F (220, 3) = 80.86, P < 0.0001). There was a significant decrease in blood glucose levels in both treated groups at week 3 compared to week 1 in each individual treated group. 4.1.2 blood insulin levels in STZ diabetic rat Throughout all weeks of the experiment, as presented in Fig. 3 , the blood insulin level was highly significantly different between the various groups (F (100, 4) = 35.68). All diabetic groups displayed a significant increase in blood insulin levels after the induction by 74.119% (P < 0.001). At weeks 2 and 3, the diabetic group's blood insulin level decreased, showing significantly lower levels than the CON group by 26.079% (P = 0.0061) and 33.567% (P = 0.004). On the other hand, in week 3, in the treated groups, the diabetic + INS group and diabetic + RB group, insulin blood levels increased significantly by 62.15% and 122.62%, respectively, compared to the diabetic group. Interestingly, at week 3, in the CON + RB group, blood insulin level increased by 47.89%, a P < 0.001 significant increase from the untreated diabetic group. As well, within each group revealed in Fig. 3 f, there was a significant difference among weeks (F (220, 3) = 38.86, P < 0.001). At week 3, In the INS diabetic-treated group, insulin blood level showed no significant difference compared to its level in the same group at week 2. Where, in the RB diabetic treated group, there was a significant rise in insulin blood level compared to its level in the same group at week 2. Interestingly, the CON + RB group insulin blood level increased significantly at week 3 compared with week 2. 4.1.3 Effect of Rice bran extract and Insulin on β-cell insulin secretory function (HOMA-β) In Fig. 4 a, all diabetic rats, after induction, displayed a significant decline in β-cell capacity in insulin secretion compared to control groups. However, in both diabetic-treated groups there was a continuous decline through weeks 1 and 2, whereas at week 3, the RB diabetic-treated group showed a numerically insignificant increase in the HOMA-β index compared to the diabetic group. Interestingly, the CON + RB group showed a higher, non-significant increase in the HOMA-β index compared to the CON group at the end of the experiment. Using a correlation matrix in Fig. 4 b, we could evaluate the RB-treated diabetic group strong relationship with CON and CON-RB groups (P = 0.592, 0.472 respectively), with a weaker relationship in relevance to the untreated diabetic group (P = 0.441), in contrast with the diabetic INS-treated group that holds a week relationship with CON and CON-RB groups (P = 0.821, 0.935 respectively) and a stronger relationship in relevance to the untreated diabetic group (P = 0.285). Where the P-value represents the probability of finding the correlation coefficient’s value indicating a greater correlation degree, given that the two variables are not actually correlated (null hypothesis). 4.1.4 Pancreatic insulin level in STZ diabetic rat As shown in Fig. 5 a, rats' pancreatic insulin levels vary between different groups (F (25, 4) = 19.47). Results presented a significant decline in pancreatic insulin levels in the diabetic group by 73.57 (P < 0.001) compared to the CON group and 73.77% (P < 0.001) compared to the CON + RB group. INS-treated diabetic group insulin level decreased with no significant difference from the diabetic rats. While surprisingly, in the RB-treated diabetic group, insulin levels returned to normal levels, with a significant difference from the diabetic rats by 149.13%. (P = 0.024). 4.1.5 Pancreatic Glut2 Level in STZ diabetic rat Figure 5 b reflects the variation in rats' pancreatic Glut2 levels between different groups (F (25, 4) = 251.8, P < 0.001). The diabetic group displayed a significant decrease in pancreatic Glut2 level from the CON group by 80.937% and from the CON + RB group by 80.887%. When compared to the diabetic group, the diabetic INS-treated group's pancreatic Glut2 level remained unchanged. In contrast, the diabetic RB-treated group's pancreatic Glut2 levels increased significantly by 126.495%. Noteworthy, there is still a significant difference between diabetic RB-treated group pancreatic Glut2 levels related to the CON group. Remarkably, in the CON + RB group, pancreatic Glut2 levels increased significantly compared to the CON group. 4.1.6 Pancreatic Calcium Levels in STZ diabetic rat The disparity in pancreatic calcium levels among groups is revealed in Fig. 5 c (F (25, 4) = 498.2, P < 0.001). Diabetic group pancreatic calcium level significantly dropped by 76.168% from CON and 76.339% from CON + RB. The INS-treated group's pancreatic calcium levels do not differ from those of the diabetic group. In contrast, the diabetic group treated with RB had a significant increase in pancreatic calcium levels of 54.589% when compared to the diabetic group. However, it is important to note that the pancreatic calcium level of the diabetic RB-treated group differs significantly from that of the CON group. 4.2 Effect of Rice bran extract and Insulin on pancreatic mRNA expression level of PPARℽ, SERCA, PrKc, and PDX1 genes involved in the regulation of insulin secretion in STZ diabetic rats. 4.2.1 PPARℽ Expression Levels As shown in Fig. 6 a, unexpectedly, the PPARℽ expression level in the diabetic group slightly decreased from the control groups (CON and CON + RB) with no significant difference. The INS-treated group showed no significant difference between the related control groups and the diabetic group. On the contrary, the RB-treated diabetic group demonstrated significant up-regulation (F (25, 4) = 83.09, P < 0.0001) in PPARℽ expression levels higher than the CON group by 1646.1% and higher than the diabetic group by 3303.797%. Also, there is no significant difference between the insulin-treated group related to the CON group or the diabetic group. 4.2.2 SERCA Expression Levels Figure 6 b showed a minor increase in SERCA expression levels in diabetic rats with no significant difference compared to control groups (CON and CON + RB). In addition, SERCA expression level up-regulation in the INS-treated diabetic group has no significance related to the diabetic group or control group. While SERCA Expression level significantly up-regulated in RB-diabetic-treated rats 3 times compared to the diabetic group, and 18 times compared to the CON group (F (25, 4) = 6.42, P < 0.05). 4.2.3 Prkc Expression Levels It was noticed in Fig. 6 C a slight rise in Prkc expression levels in the diabetic group with no significant difference related to the control group. As well, in the INS-treated diabetic group, Prkc expression level up-regulation showed no significant change compared to the CON and diabetic groups. However, in the RB-treated diabetic group, significant up-regulation in Prkc expression levels was 15 times compared to the diabetic group and 126 times compared to the CON group (F (25, 4) = 12.40, P < 0.05). 4.2.4 PDX1 Expression Levels Figure 6 d presented an unanticipated, non-significant rise in PDX1 expression levels in diabetic rats related to the control group. INS-treated rats revealed significant PDX1 expression up-regulation (F (25, 4) = 5.824, P < 0.005) by 316.262% related to the diabetic group. Rather unexpectedly, in the RB-treated diabetic group, PDX1 expression levels displayed no significant difference compared to the diabetic group. 4.3 Effect of Rice bran extract and Insulin on STZ-induced histological alteration in STZ diabetic rat 4.3.1 Pancreatic tissue (H&E stain) In Fig. 7 , the CON group displayed normal pancreatic architecture. The acinar cells that make up the exocrine (EX) portion of the pancreas are arranged into tiny lobules and tightly packed. The CON + RB group revealed the pancreas' distinct lobules and external secretory units involving several pyramidal cells. Furthermore, internal secretory units (IL) represented several hormone-secreting cells next to the blood vessel. In diabetic rats, the overall structure is deformed. Most exocrine acini displayed cell atrophy as a sign of acinar damage. Acini demonstrated a degree of decline. Degeneration, vacuolation, necrosis, and a significant decline in the number of beta cells lead the islets of Langerhans (IL) to decrease. Most of the areas showed thickly walled, dilated, and congested blood arteries. In Both treated groups Mononuclear cells (ICI) infiltrated and clogged up some blood vessels (BV) still present, however, both showed some progress whereas vacuolation is mild in both groups. Besides, in insulin-treated rats, minor acinar cell aging was exhibited. As well, it is worth taking a look at RB-treated rats' pancreas which revealed slight improvement in which Some IL inside the acinar cells has several beta cells and a regular shape and size. 4.3.2 Brain tissue (Congo red stain) As shown in Fig. 8 , Congo red staining of brain sections from the CON group and CON + RB group revealed normal faint staining with the absence of any dark-stained plaques. On the contrary, the diabetic group showed numerous red-stained plaques scattered within the brain tissue. The insulin-treated rats showed sporadic red-stained plaques in a few sections, whereas the RB-treated rats showed fewer red-stained plaques. 4.4 Effect of Rice bran extract and Insulin on rats' behavioral alterations 4.4.1 Y-maze Test in STZ-diabetic rats As displayed in Fig. 9 a, rats’ spatial memory performance differs significantly within the 5 groups (F (25, 4) = 13.69, P < 0.0001). The diabetic group showed an inability to opt for the correct choice, showing a significant decrease in the percentage of alteration compared to the CON group and CON + RB group by 56.99% and 50.05% respectively. RBE and INS-treated groups improved rats' spatial memory and displayed a significant increase in the percentage of alteration by 123.66% and 100%, respectively, from the diabetic group. Remarkably, both treated groups revealed no significant difference in the percentage of alteration from the normal CON group. 4.4.2 Novel object recognition Test in STZ-diabetic rats Figure 9 b demonstrates rats' recognition behavior altered among groups (F (25, 4) = 18.64). Results showed a significant decline in the discrimination ratio in the diabetic group (156%, P < 0. 001) compared to CON. Diabetic groups treated with RB and INS restored the ability to explore new objects and showed a significant increase by 217% (P = 0. 001) and 226% (P < 0.001), respectively, from the diabetic group. Remarkably, both treated groups revealed no significant difference in discrimination ratio from the normal CON group. 5 Discussion In the present experiment, administration of STZ for four sequential days induced T1D, which displayed an acute rise in blood glucose ( Fig. 2 a ) , reflecting a significant drop in β-cell insulin secretory function as indicated by the HOMA-β index ( Figs. 3 and 4 ). With sustained hyperglycemia ( Fig. 2 ) at the end of the experiment, the diabetic group showed a decline in pancreatic Ca 2+ levels as a result of the decrease in pancreatic GLUT2 levels ( Fig. 5 a, b and c) . The reduction in pancreatic GLUT2 levels is consistent with published research, which links GLUT2 expression decline to an increase in free fatty acids and triglycerides in the blood as a result of β-cell dysfunction ( Thorens, 2001 ). GLUT2 levels decline, reducing glucose uptake by β-cells and impairing glucose-6-phosphate phosphorylation and the production of ATP in the glycolysis process. This hinders glucose-inducing intracellular ATP levels from increasing the cytoplasmic ATP/ADP ratio for K+-ATP channel shutting and voltage-dependent Ca 2+ channel opening. This reduces Ca 2+ release, ultimately leading to inhibition of exocytotic insulin release from insulin-containing granules ( Sun et al., 2023 ). The observed fall in pancreatic GLUT2 and Ca 2+ levels in the diabetic group was also reflected in a drop in blood insulin levels ( Klec et al., 2019 ; Trexler and Taraska et al., 2017) , highlighting the role of glucose transport in β-cells in glucose-stimulating insulin secretion (GSIS) ( Saji et al., 2020 ). RB treatment had an inverse effect on insulin levels, showing a significant increase in blood insulin levels compared to the insulin-treated group, as shown at the end of the experiment ( Fig. 3 d ). Moreover, in pancreatic tissue, only RBE significantly increased pancreatic insulin levels compared to untreated and insulin-treated groups (p < 0.001, p < 0. 1) ( Fig. 5 . A). This effect was corroborated by the strong correlation of the HOMA-β index between the RB-treated group and control groups rather than with the insulin-treated group ( Fig. 4 ) . On the contrary, for blood glucose levels, only insulin therapy showed a significant reduction in diabetic rats, while RBE showed a slow, non-significant decline until the end of the experiment. Interestingly, the same finding regarding blood glucose levels was reported by Kaup et al. ( 2012 ) when examining the RBE administration for glucose-treated rats (2 g/kg BW) and abruptly elevated plasma insulin. The author argued that the organism requires tight glucose regulation in the long term and suggested prolonged RBE treatment to adjust blood glucose levels. This assumption is supported by the reported effect of tocotrienol, the rice bran oil fraction, on reducing fasting blood glucose and HbA1C in a T1D rat model after 8 weeks of diabetes induction (Siddiqui et al., 2010). It is well known that the antidiabetic effect of tocotrienols is a long-term PPAR-mediated activity ( Fang et al., 2010 ). Like other stabilized RB supplements, they reduced HbA1C in T2D patients after 12 weeks ( Cheng et al., 2010 ). Diabetic rats treated with RBE showed a significant rise in pancreatic GLUT2 levels compared to those treated with insulin ( Fig. 5 . B). This is the first study to report such an effect of RBE on GLUT2 levels in the pancreas. Nevertheless, it's worth noting that RBE vitamin E components, tocotrienols (δ- and γ-T3), have a dose-dependent effect on increasing GLUT2 expression in rat pancreatic islets ( Chia et al., 2016 ). The RBE control group showed an intriguingly significant increase in GLUT2 levels compared to the untreated control group ( Fig. 5 b ) , suggesting a possible effect of RBE on GLUT2 basal levels at normal conditions—an observation that needs further investigation. This, in turn, was consistent with a significant increase in intracellular Ca 2+ ion levels in the RBE-treated group compared to insulin ( Fig. 5 c ) . This infers an increase in glucose transport inside β-cells ( Saji et al., 2020 ), leading to an increase in Ca 2+ ion influx through ATP-induced Ca 2+ channel opening ( Sun et al., 2023 ). Vanillic acid, one of the phenolic compounds of the RBE phenolic fraction ( supplementary data S1-S4) , has been reported to increase Ca 2+ influx through a voltage-dependent calcium channel ( Mahendra et al., 2019 ). Additionally, another phenolic compound, ferulic acid, a main active metabolite of RBE γ-oryzanol ( Arumsari et al., 2019 ; Kokumai et al., 2019 ), stimulated Ca 2+ influx in INS-1 cells, supporting RBE active components in their role in GSIS ( Ruamyod et al., 2023 ). On the contrary, levels of pancreatic GLUT2 and Ca 2+ were not altered in the insulin-treated group in relation to the untreated diabetic group (Fig. 5 B &C ). This indicates no impact of insulin treatment on GSIS, in agreement with Persaud et al.'s ( 2001 ) , where the study disclosed the insulin-inhibitory effect of its own secretion in human islet cells. Other insulin therapy studies showed an acute decrease in β-cell GLUT2 in STZ-induced diabetic rats ( Thulesen et al., 1997 ). To reveal the molecular mechanism underlying the influence of RBE administration on insulin secretion signaling pathways, we analyzed the gene expression levels of PPARγ, SERCA, PKC, and PDX1. Interestingly, RBE showed a highly significant increase in PPARγ pancreatic gene expression in comparison to the untreated diabetic group ( Fig. 6 . A, p < 0.0001) . This finding supports our previously reported RBE-PPARγ agonist activity ( Abd El Fattah et al., 2020 ; El-Din SS et al., 2021 ; Mostafa et al., 2018 ). The potential of RBE in regulating molecules in the insulin signaling cascade is also evidenced by the reported effect of tocotrienols on increasing PPARγ expression in glucose-stimulated pancreatic β-islet cells ( Chia et al., 2016 ). On the contrary, although insulin is a PPARγ receptor regulator ( Rieusset et al., 1999 ), insulin treatment in the present study showed an insignificant effect on PPARγ gene expression compared to the untreated diabetic group. The precise impact of insulin on PPARγ expression is not well comprehended. However, the ERK proteins and activated signaling molecules provided a plausible explanation for PPARγ-insulin interaction through ERK-1/2-Junk phosphorylation of the PPARγ-insulin signaling cascade in adipose tissue. Studies have found that PPARγ phosphorylation decreased PPARγ ligand's transcriptional activity as proteasomal degradation increased, leading to the suppression of PPARγ expression ( Leonardini et al., 2009 ; Floyd and Stephens et al., 2002). RBE administration resulted in a significant increase in SERCA2 gene expression ( Fig. 6 b ) , surpassing both diabetic and control groups. This finding supports the link between PPARγ and SERCA2 gene expression, which is regulated by PPARγ interaction with the PPAR-responsive element in the human SERCA2 promoter ( Kono et al., 2012 ). The increase in SERCA2 expression aligns with the observed rise in Ca 2+ levels ( Fig. 5 a ) in the RBE-treated group, indicating that SERCA2 maintains high intracellular Ca 2+ levels ( Trexler and Taraska et al., 2017) . The use of RBE resulted in a notable increase in PrkC levels in the diabetes-treated groups compared to insulin (p > 0.001) ( Fig. 6 . C) . This finding suggests that the rise in Ca 2+ influx activates PrKC βII ( Shimabukuro et al., 1998 ), which in turn stimulates Na+-permeable channels, leading to membrane depolarization and insulin secretion ( Fleming and Storz, 2017 ). Moreover, the increase in PrKC βII is expected to redistribute GLUT2 to transport glucose molecules inside the β-cell ( Cohen et al., 2014 ). This condition was obviously detected in our current results, as illustrated before ( Fig. 5 . B). It is worth noting that ferulic acid can be reported to activate pathways like PKA, CaMKII, MAPK/ERK, and PI3K to influence PrkC expression ( Zeni et al., 2012 ), which may promote efficient GSIS. RBE Improving cognitive abilities was examined by evaluating the performance of diabetic rats in Y-maze and NOR behavioral tests. The findings of RBE administration demonstrated a significant improvement in cognitive functions, with no notable disparity observed between the treated groups ( Fig. 9 A, B ) compared to the diabetic group. The outcomes align with our earlier findings that Egyptian RBE enhances rats’ cognitive function in an LPS-induced neuroinflammatory animal model ( Mostafa et al., 2018 ). In a corresponding manner, Hagl et al. ( 2016 ) conducted a study that demonstrated the efficacy of RBE in restoring cognitive abilities in aged rats. This restoration was achieved through the activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which directly regulates PPARγ. Regarding insulin treatment, Strachan's (2005) findings reported the effectiveness of intranasal insulin therapy in improving declarative memory. Insulin, whether generated internally or externally, has been found to potentially promote synaptic remodeling and synaptogenesis, which are crucial for memory consolidation ( Cholerton et al., 2013 ; Skeberdis et al., 2001 ). Additionally, it induces the expression of neurotransmitters like acetylcholine and norepinephrine, regulating cognitive functions through the coordination of cholinergic and adrenergic pathways ( Cholerton et al., 2013 ; De Leo et al., 2023 ). Thus, the study suggests that RBE may enhance memory and cognition by increasing peripheral insulin secretion through PPARγ regulator activity, potentially acting in the central nervous system. Furthermore, Congo-red staining brain sections showed fewer red Aβ plaques in the brain tissue of the treated groups compared to untreated diabetic rats ( Fig. 8 ) . This observation indicates a decline in the formation of amyloid plaques, as demonstrated in our previous study on the neuroprotective mechanism of RBE in mice with LPS-induced neuroinflammation. ( Abd El Fattah et al., 2020 ). Insulin impacts tau phosphorylation and amyloid-β peptide clearance, which are Alzheimer's disease pathological features ( Boccardi et al., 2019 ). This lends credence to the association between diabetes and dementia. Histological examination results supported the RBE effect on restoring pancreatic structure more effectively than insulin treatment, as shown in Fig. 7 . Untreated diabetics showed distortion in pancreatic structure, atrophy in exocrine glands, and decreased β-cells and IL numbers, which corresponds to the acute rise in blood glucose ( Figs. 3 , 4 , and 5 ). Interestingly, rats treated with RBE showed several normal β-cells with regular shape and size, disclosing upgraded IL structure inside the acinar cell compared to insulin treatment. A result in alignment with the reported effect of red RBE on enhancing pancreatic structure in n mice treated with a high-fat diet ( Munkong et al., 2022 ) and reinforced by the role of pioglitazone PPARγ agonistic effect in shielding pancreatic β-cells from the effects of hyperglycemia, deficiencies in insulin secretion, and the impact of cell death. This protective mechanism is achieved by activation of the SERCA2b pump via direct enhancement of; SERCA2b gene expression. This supports our present results on the effect of RBE on SERCA2b gene expression. 6 Conclusion In conclusion, our RBE treatment enhanced insulin secretion, obviously with little influence on glucose levels, which we suggest it should be reversed by longer-term supplementation. This finding suggests that RBE's beneficial effect on cognitive performance may be related to an increase in insulin levels in the brain. The RBE effect on enhancing β cell insulin secretion provides further insights into the RBE mechanism of action by targeting the PPARγ/PDX1 signaling pathway. This is evidence-based action by RBE components. Abbreviations T1D Type 1 diabetes PPAR-γ Peroxisome proliferator-activated receptor TZDs Thiazolidinediones GSIS Glucose-stimulating insulin secretion PDX1 Pancreatic and duodenal homeobox 1 GLUT2 Glucose transport 2 SERCA Sarcoendoplasmic reticulum calcium ATPase PrKC Protein Kinase C PDX1 Pancreatic and duodenal homeobox 1 DCVs Dense core vesicles RBE Rice bran Extract PGC1α proliferator-activated receptor gamma coactivator 1-alpha Declarations Ethics approval The Research Ethics Committee at Cairo University (Cairo, Egypt, PT 3080) approved this research methodology. The guidelines for the care and use of laboratory animals, issued by the United States National Institute of Health (NI. Graphical abstract: (Legend): Schematic pathway for insulin secretion via PPAR-γ dependent pathway in type 1 diabetes Funding This research was funded by the strategic program for Biotechnology and Genetic Engineering—Science and Technological Cooperation Center—Academic of Scientific Research and Technology (ASRT). Author Contribution The study conception and design. Material preparation, data collection: Madonna Magdy Youssef, Mohammed Farrag Elyamny, Ola Ahmed Heikal. Statistical analysis and interpretation of the data: Madonna Magdy Youssef, Mohammed Farrag Elyamny, Ola Ahmed Heikal. Reham Mahmoud Abdelkader. The first draft of the manuscript was written by: Madonna Magdy Youssef, Ola Ahmed Heikal and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgement The authors express their gratitude for the funding support provided by the Strategic Program for Biotechnology and Genetic Engineering, Science and Technological Cooperation Center (STC) - Academy of Scientific Research and Technology (ASRT). Additionally, the authors thank Health Tec Company (Health Tech®) for supplying the research with RBE.Regarding histopathological examination, Assistant Professor Dr. Heba Ali Abd Elrahman from the Faculty of Science at Cairo University provided valuable assistance. The authors are also thankful to Omnia Samir Hosni, MSc in Genetics, Histology, and Cell Biology from the Zoology Department at Cairo University, who is a Senior Technical Support and Molecular Genetics Specialist, for her help in Quantitative Real Time PCR analysis. References Abd El Fattah MA, Abdelhamid YA, Elyamany MF, Badary OA, Heikal OA (2020) Rice Bran Extract Protected against LPS-Induced Neuroinflammation in Mice through Targeting PPAR-γ Nuclear Receptor. 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Supplementary Files finalsupplementarydata.docx GraphicalAbstract.jpg Cite Share Download PDF Status: Published Journal Publication published 19 Jun, 2025 Read the published version in Metabolic Brain Disease → Version 1 posted Editorial decision: Revision requested 09 Jan, 2025 Editor assigned by journal 08 Jan, 2025 Submission checks completed at journal 08 Jan, 2025 First submitted to journal 23 Dec, 2024 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. 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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-5702421","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":399739009,"identity":"8be899fe-ed89-477b-a0af-392d4bc5b724","order_by":0,"name":"Madonna Magdy Youssef","email":"data:image/png;base64,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","orcid":"","institution":"Egyptian Drug Authority","correspondingAuthor":true,"prefix":"","firstName":"Madonna","middleName":"Magdy","lastName":"Youssef","suffix":""},{"id":399739010,"identity":"6a847dd8-9fed-43ea-b1f9-dd920d74cab7","order_by":1,"name":"Mohammed Farrag El-Yamany","email":"","orcid":"","institution":"Cairo University","correspondingAuthor":false,"prefix":"","firstName":"Mohammed","middleName":"Farrag","lastName":"El-Yamany","suffix":""},{"id":399739011,"identity":"a3fc7123-7780-4428-a3e6-3b3a672c248f","order_by":2,"name":"Reham Mahmoud Abdel-Kader","email":"","orcid":"","institution":"German University","correspondingAuthor":false,"prefix":"","firstName":"Reham","middleName":"Mahmoud","lastName":"Abdel-Kader","suffix":""},{"id":399739012,"identity":"88ee5b30-bb5b-4a4a-8073-c10dc86e088b","order_by":3,"name":"Ola Ahmed Heikal","email":"","orcid":"","institution":"National Research Center","correspondingAuthor":false,"prefix":"","firstName":"Ola","middleName":"Ahmed","lastName":"Heikal","suffix":""}],"badges":[],"createdAt":"2024-12-23 23:53:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5702421/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5702421/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11011-025-01639-1","type":"published","date":"2025-06-19T15:57:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":73519920,"identity":"41a14c9d-aace-404c-9f15-d4793f4433d2","added_by":"auto","created_at":"2025-01-10 18:11:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":158991,"visible":true,"origin":"","legend":"\u003cp\u003eThe timeline for experimental animal induction, administration of drugs, and behavioral assessment\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/6bd2aac857c1da5e17e12c5c.jpg"},{"id":73518646,"identity":"0c36ccab-e48d-4fd4-89dc-2ccfed37a5b0","added_by":"auto","created_at":"2025-01-10 18:03:47","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":94432,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of oral treatment with RB (100 mg/kg/day) and Ins (5 U/kg/day) on blood glucose level\u003c/p\u003e\n\u003cp\u003e(Legend): Effect of treatment with RB (100 mg/kg/day, p.o), and Ins (5 U/kg/day, p.o) on blood glucose level a) after induction b) after week 1 c) after week 2 d) after week 3 e) Along weeks of the experiment in STZ diabetic rats.\u003c/p\u003e\n\u003cp\u003eRats were injected with multiple low doses of STZ on the first four days\u003c/p\u003e\n\u003cp\u003eValues are presented as mean ± SEM (n=12)\u003c/p\u003e\n\u003cp\u003eFor every single week, Statistical analysis was done using One-way ANOVA followed by a Tukey post-test\u003c/p\u003e\n\u003cp\u003eAlong the weeks, Statistical analysis was done using two-way ANOVA followed by a Bonferroni post-test\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/cdff106639644a5c413d55aa.jpg"},{"id":73519927,"identity":"74c0e7d9-78e3-49f7-b0e0-ccc4401102a6","added_by":"auto","created_at":"2025-01-10 18:11:47","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":89589,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of oral treatment with RB (100 mg/kg/day) and Ins (5 U/kg/day) on blood insulin level\u003c/p\u003e\n\u003cp\u003e(Legend): Effect of treatment with RB (100 mg/kg/day, p.o), and Ins (5 U/kg/day, p.o) on blood insulin level a) after induction b) after week 1 c) after week 2 d) after week 3 e) Along weeks of the experiment in STZ diabetic rats.\u003c/p\u003e\n\u003cp\u003eRats were injected with multiple low doses of STZ on the first four days\u003c/p\u003e\n\u003cp\u003eValues are presented as mean ± SEM (n=6).\u003c/p\u003e\n\u003cp\u003eFor every single week, Statistical analysis was done using One-way ANOVA followed by a Tukey post-test\u003c/p\u003e\n\u003cp\u003eAlong the weeks, Statistical analysis was done using two-way ANOVA followed by a Bonferroni post-test\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/15da934a7476a7ca13e6e2bc.jpg"},{"id":73519931,"identity":"a956304f-5638-4da1-9870-51b031b22e7e","added_by":"auto","created_at":"2025-01-10 18:11:48","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":38985,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of daily oral treatment with RB (100 mg/kg) and Ins (5 U/kg) on HOMA-β\u003c/p\u003e\n\u003cp\u003e(Legend): Effect of treatment with RB (100 mg/kg/day, p.o), and Ins (5 U/kg/day, p.o) on HOMA-β Along weeks of the experiment in STZ diabetic rats.\u003c/p\u003e\n\u003cp\u003eRats were injected with multiple low doses of STZ on the first four days\u003c/p\u003e\n\u003cp\u003eHOMA-beta values calculated as:] blood insulin concentration (μU/ml) ×20[ / ]blood glucose (mmol/L) -3.5[\u003c/p\u003e\n\u003cp\u003e(a): Statistical analysis was done using two-way ANOVA followed by a Bonferroni post-test\u003c/p\u003e\n\u003cp\u003e(b): Pearson correlation map for HOMA-beta values. The correlation coefficient is shown by the color bar: dark blue indicates strongly positive correlations, light blue indicates week positive correlation, white denotes negative correlations, and red denotes strongly negative correlations\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/697f272c2bbeccce36441317.jpg"},{"id":73518662,"identity":"26592e2c-2acd-4603-8349-ab7cb5f30619","added_by":"auto","created_at":"2025-01-10 18:03:47","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":54787,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of daily oral treatment with RB (100 mg/kg/day) and Ins (5 U/kg/day) on pancreatic biochemical parameters\u003c/p\u003e\n\u003cp\u003e(Legend): Effect of treatment with RB (100 mg/kg/day, p.o), and Ins (5 U/kg/day, p.o) on pancreatic tissue levels for a) insulin b) GLUT2 c) calcium at the end of the experiment in STZ diabetic rats.\u003c/p\u003e\n\u003cp\u003eRats were injected with multiple low doses of STZ on the first four days\u003c/p\u003e\n\u003cp\u003eValues are presented as mean ± SEM (n=6)\u003c/p\u003e\n\u003cp\u003eStatistical analysis was done using One-way ANOVA followed by a Tukey post-test\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/759974fe9596e041346aa741.jpg"},{"id":73518664,"identity":"b19beae7-df4c-47c5-a673-1fcc7b9f9424","added_by":"auto","created_at":"2025-01-10 18:03:47","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":75935,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of oral treatment with RB (100 mg/kg/day), and Ins (5 U/kg/day) on pancreatic gene Expression\u003c/p\u003e\n\u003cp\u003e(Legend): Effect of treatment with RB (100 mg/kg/day, p.o), and Ins (5 U/kg/day, p.o) on pancreatic gene Expression Levels for a) PPARℽ b) SERCA c) Prkc d)Pdx1 at the end of the experiment in control groups\u003c/p\u003e\n\u003cp\u003eRats were injected with multiple low doses of STZ on the first four days\u003c/p\u003e\n\u003cp\u003eValues are presented as mean ± SEM (n=6).\u003c/p\u003e\n\u003cp\u003eStatistical analysis was done using One-way ANOVA followed by a Tukey post-test\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/520d0a1e8bdf916c2453d3ef.jpg"},{"id":73518654,"identity":"97d613b8-f941-4bea-a502-825736200cd4","added_by":"auto","created_at":"2025-01-10 18:03:47","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":186796,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of oral treatment with RB (100 mg/kg/day), and Ins (5 U/kg/day) on brain histopathology\u003c/p\u003e\n\u003cp\u003e(Legend): Effect of treatment with RB (100 mg/kg/day, p.o), and Ins (5 U/kg/day, p.o) on brain histopathology in STZ- diabetic rats\u003c/p\u003e\n\u003cp\u003ePhotomicrographs of rat pancreas sections stained with H\u0026amp;E (X100), a) control rats b) RB- control treated rats, c) Diabetic rats d) RB-treated Diabetic rats e) INS- treated diabetic rats\u003c/p\u003e\n\u003cp\u003eAs shown, the control groups, the pancreas exhibited a normal histopathological structure.\u003c/p\u003e\n\u003cp\u003eThe pancreas in STZ-diabetic rats showed exocrine acini (EX) cell atrophy, vacuolation (arrow), necrosis, and a significant decline in the number of beta cells leading to the islets of Langerhans (IL), dilated (double head arrow), congested (*) blood arteries and mononuclear cells (ICI) infiltrated.\u003c/p\u003e\n\u003cp\u003eRB-treated diabetic rats had apparently mild vacuolation (arrow), congested (*) blood arteries and mononuclear cells (ICI) infiltrated. As well as a moderate increase in Islets of Langerhans (IL).\u003c/p\u003e\n\u003cp\u003eThe pancreas of INS-treated diabetic rats displayed moderate vacuolation (arrow), congested (*) blood arteries and mononuclear cells (ICI) infiltrated. As well as a moderate increase in Islets of Langerhans (IL).\u003c/p\u003e\n\u003cp\u003eStatistical analysis was done using the Kruskal-Wallis test followed by a Dunn’s post-test.\u003c/p\u003e\n\u003cp\u003eValues are presented as mean ± SEM\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/eba060ded06fbd5c93b35756.jpg"},{"id":73518669,"identity":"90d582fd-6a2f-40e9-9db4-2889be542758","added_by":"auto","created_at":"2025-01-10 18:03:48","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":391470,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of treatment with RB (100 mg/kg/day) and Ins (5 U/kg/day) on Amyloid plaque formation\u003c/p\u003e\n\u003cp\u003e(Legend): Photomicrographs of rat brain sections stained with Congo red (X25), a) control rats, b) RB-control-treated rats, c) Diabetic rats, d) RB-treated Diabetic rats, e) INS-treated diabetic rats\u003c/p\u003e\n\u003cp\u003eControl groups showed normal staining with Congo red. Diabetic group presented numerous dark red-stained plaques (arrows). INS-treated diabetic rats revealed sporadic red-stained plaque (arrow). RB-treated diabetic rats had few red-stained plaques (arrows).\u003c/p\u003e","description":"","filename":"figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/9c37478091a3a69402c0b065.png"},{"id":73519921,"identity":"74c2df85-3440-4b92-8e5f-a84634196d65","added_by":"auto","created_at":"2025-01-10 18:11:47","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":41519,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of oral treatment with RB (100 mg/kg/day) and Ins (5 U/kg/day) on behavioral tests\u003c/p\u003e\n\u003cp\u003e(Legend):\u003c/p\u003e\n\u003cp\u003eEffect of treatment with RB (100 mg/kg/day, p.o.) and Ins (5 U/kg/day, p.o.) on (a) percentage alteration in the Y-mase test and (b) discrimination index in the Novel Object Recognition (NOR) test at the end of the experiment in STZ diabetic rats.\u003c/p\u003e\n\u003cp\u003eRats were injected with multiple low doses of STZ on the first four days\u003c/p\u003e\n\u003cp\u003eValues are presented as mean ± SEM (n = 6).\u003c/p\u003e\n\u003cp\u003eStatistical analysis was done using one-way ANOVA followed by a Tukey post-test\u003c/p\u003e","description":"","filename":"Figure9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/35803abb5146762316ca9fff.jpg"},{"id":85231348,"identity":"6aaff176-cc40-4fb5-8401-7bb076d45f0a","added_by":"auto","created_at":"2025-06-23 16:06:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3018847,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/b5ccdd60-a08c-4112-8b47-66d0704722c6.pdf"},{"id":73520347,"identity":"5da67699-f1ef-47ff-8c58-1ae4fc4d4293","added_by":"auto","created_at":"2025-01-10 18:19:47","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":648618,"visible":true,"origin":"","legend":"","description":"","filename":"finalsupplementarydata.docx","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/33ea9517cc578616181a8c79.docx"},{"id":73519923,"identity":"dca5d057-37de-4bb0-b04c-0b55df889689","added_by":"auto","created_at":"2025-01-10 18:11:47","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":110655,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5702421/v1/76f6c2c065e6de49235b25ae.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rice Bran Extract attenuates cognitive impairment by enhancing pancreatic β-cell insulin secretion in STZ-induced diabetic rats targeting the PPARγ/PDX1 pathway","fulltext":[{"header":"Highlights","content":"\u003cp\u003eGlucose transport in β-cells plays a significant role for insulin secretion.\u003c/p\u003e\u003cp\u003eEgyptian Rice bran extract treatment enhanced insulin secretion.\u003c/p\u003e\u003cp\u003eEgyptian Rice bran extract boosted PPARℽ, SERCA, and PrKC gene expression.\u003c/p\u003e\u003cp\u003eEgyptian Rice bran extract restored pancreatic structure more effectively.\u003c/p\u003e\u003cp\u003eRBE may enhance memory and cognition by increasing peripheral insulin secretion.\u003c/p\u003e"},{"header":"1 Introduction","content":"\u003cp\u003eDiabetes mellitus is a prevalent chronic illness globally. Type 1 diabetes (T1D) is a long-term, organ-specific autoimmune disorder that destroys pancreatic β-cells gradually and is known as juvenile diabetes (age\u0026thinsp;\u0026gt;\u0026thinsp;20). Diabetes mellitus is the seventh most common cause of death in the United States \u003cb\u003e(\u003c/b\u003eSapra et al., \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Leslie et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Kim et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In 2021, the International Diabetes Federation (IDF) reported 1.2\u0026nbsp;million cases of children and adolescents with T1D worldwide, with an expected annual increase of 184,100 cases and prevalence of 2% in Africa and 10% of cases in Egypt \u003cb\u003e(IDF, 2021).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAnomalous glucose and insulin levels in childhood T1D patients can lead to mental impairment and neuropathy \u003cb\u003e(\u003c/b\u003eJin et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Li et al., \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Xu et al., \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). This is a common microvascular diabetes complication \u003cb\u003e(\u003c/b\u003eGaliero et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) resulting in cognitive disturbances and limited learning ability in children \u003cb\u003e(\u003c/b\u003eLacy et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) with a significant medical and financial burden \u003cb\u003e(IDF, 2021)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eTypical treatment for T1DM is synthetic human insulin. However, its administration has numerous negative consequences in all age groups, where severe uncontrollable hypoglycemic events negatively impact cognitive and neuronal function \u003cb\u003e(\u003c/b\u003eHultstr\u0026ouml;m et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Jin et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is believed that T1D patients almost completely lose β-cells at the onset of the disease. Further research implies a functional deficit rather than absolute β-cell loss, which may preserve up to 40% of insulin-producing islets and restore insulin production \u003cb\u003e(\u003c/b\u003eCoppieters et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Krogvold et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2015\u003c/span\u003ea; Leete et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Also, isolated islets from T1D patients were reported to restore insulin production in a non-diabetic environment \u003cb\u003e(\u003c/b\u003eKrogvold et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2015\u003c/span\u003eb). Improving β-cell biology is a promising research area for T1D treatment \u003cb\u003e(\u003c/b\u003eAtkinson et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Cobo-Vuilleumier et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Activation of PPARγ (Peroxisome Proliferator-Activated Receptor), a transcriptional regulator involved in glucose metabolism, and its synthetic agonists as thiazolidinediones (TZD family) have been reported to maintain β-cell proliferation and reverse the age-related reduction in pancreatic mass in both rats and mice \u003cb\u003e(\u003c/b\u003eShimabukuro et al., \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Higa et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Finegood et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). TZDs have been reported to enhance insulin secretion by controlling several key β-cell genes that potentiate glucose-stimulating insulin secretion (GSIS) \u003cb\u003e(\u003c/b\u003eEvans-Molina et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Moibi et al., \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). However, TZDs are not recommended as first-line medication due to their numerous negative consequences, including edema, heart failure, liver damage, and bladder cancer \u003cb\u003e(Eggleton and Jialal, 202;\u003c/b\u003e Hwang et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThus, the proven use of some traditional medicinal plant products as \u0026ldquo;supportive therapy\u0026rdquo; for improving glycemic abnormalities in individuals with type 1 and type 2 diabetes was reported. Their use provided an alternative approach to alleviate hyperglycemia with a safe, practical, cost-effective, and convenient way to treat diabetic complications \u003cb\u003e(\u003c/b\u003eRahman et al., \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRice bran, a product of rice milling, is used in traditional medicine to treat various health disorders, supported by experimental and clinical evidence \u003cb\u003e(Ahuja et al., 2012;\u003c/b\u003e Umadevi et al., \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). According to in vitro research, RB can reduce hyperglycemia by increasing glucose uptake in 3T3-L1 adipocytes, triggering the expression of glucose transporters, and blocking the activity of α-glucosidase and α-amylase \u003cb\u003e(\u003c/b\u003eBoue et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Wahyuni et al., \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). RB oil is commonly used for cooking in Thailand and India. A blend of 80% RB oil and 20% sesame oil found significant reductions in fasting blood glucose, postprandial glucose, and glycated hemoglobin levels \u003cb\u003e(\u003c/b\u003eDevarajan et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne of the recently documented rice bran products with PPARγ agonistic activity is the standardized ethanolic RBE \u003cb\u003e(\u003c/b\u003eAbd El Fattah et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; El-Din et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). RBE is one of the innovative natural products of the Egyptian rice bran and holds several health benefits \u003cb\u003e(\u003c/b\u003eBhatia et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2016\u003c/span\u003e: Jolfaie et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2016\u003c/span\u003e: Kaup et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2012\u003c/span\u003e: \u003cb\u003eMeselhy et al., 2014\u003c/b\u003e: Shendy et al., \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). \u003cb\u003eKaup et al.\u003c/b\u003e reported a RBE antidiabetic effect through a concentration-dependent increase in insulin levels in INS-1 cells and in vivo in plasma (Kaup et al. \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). RBE comprises a splendid set of active phytochemical components, including ℽ oryzanol, tocopherols, tocotrienols, policosanol, and polyunsaturated fatty acids \u003cb\u003e(\u003c/b\u003eAl-Okbi et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Kalita et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, the exact underlying mechanism of RBE for the increased insulin release remains unclear and needs more investigation. In view of RBE's recently documented agonistic effect on PPARγ \u003cb\u003e(\u003c/b\u003eAbd El Fattah et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; El-Din et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), we propose a possible mechanism for RBE to restore β-cell function via PPARγ regulation.\u003c/p\u003e \u003cp\u003eIn this study, we investigated the effect of RBE on the PPARγ/PDX1 pathway, suggesting that RBE PPARγ agonistic activation would promote the sarcoendoplasmic reticulum calcium ATPase pump (SERCA2) to transfer Ca\u003csup\u003e2+\u003c/sup\u003e molecules across the ER membrane. This maintains high Ca\u003csup\u003e2+\u003c/sup\u003e levels within the ER lumen. The suggested increase in Ca\u003csup\u003e2+\u003c/sup\u003e subsequently would activate protein kinase C (PrKC βII) \u003cb\u003e(\u003c/b\u003eKono et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; \u003cb\u003eCohenler and Taraska, 2017).\u003c/b\u003e PrKC βII redistributes glucose transporter GLUT2, transporting glucose molecules inside the β-cell \u003cb\u003e(\u003c/b\u003eCohen et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). This in turn activates PDX1, a transcriptional regulator that controls insulin gene expression \u003cb\u003e(\u003c/b\u003eXia et al., \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Zhou et al., \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTherefore, the PPARγ-targeted activation approach in insulin secretion raised our concern about how RBE would affect β-cell function and insulin secretion. Given the recently reported RBE-PPARγ agonist activity and the documented glycemic control effect of RB products and their constituents, we focused on investigating the RBE underlying mechanism. This was done in the diabetic rat STZ model compared to exogenous insulin.\u003c/p\u003e"},{"header":"2 Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.1 Animals\u003c/h2\u003e \u003cp\u003eMale Sprague-Dawley rats weighing 180 to 230 g were used in the study. They were obtained from the central administration animal colony (National Organization for Drug Control and Research, Giza, Egypt) and maintained with a standard laboratory diet and water ad libitum. Animals were maintained in a temperature- and pressure-controlled room (23\u0026ndash;24\u0026deg;C and 40\u0026ndash;60% relative humidity) and exposed to 12-h dark and light cycles. Before being used in the experiment, the animals went through an acclimatization phase.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.2 Adherence to the Ethical Standard\u003c/h2\u003e \u003cp\u003e The Research Ethics Committee at Cairo University (Cairo, Egypt, PT 3080) approved this research methodology. The guidelines for the care and use of laboratory animals, issued by the United States National Institute of Health (NIH publication No. 85\u0026thinsp;\u0026minus;\u0026thinsp;23, revised 1996), strictly governed the handling of animals and all procedures \u003cb\u003e(Clark et al., 1996)\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e1.3 Chemicals\u003c/h2\u003e \u003cp\u003eStabilized RBE was acquired from Health Tech Company at 87 Ramsis Street, Cairo, Egypt, and administered orally at a dose of 100 mg/kg/day dissolved in 0.4% DMSO (Mostafa et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Long-acting insulin (100 UI/mL Insulin Lantus) was acquired from Sanofi-Aventis, France, and administered via a daily subcutaneous (SC) injection at a dose of 5 IU/200 g of body weight/day \u003cb\u003e(\u003c/b\u003eLuippold et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2016\u003c/span\u003e, Schaschkow et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). STZ was acquired from Sigma-Aldrich, Germany, and administered via an intraperitoneal injection (IP) for 4 days at a dose of 20 mg/kg of body weight per day.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e1.4 Preparation of Stabilized RBE\u003c/h2\u003e \u003cp\u003eInitially, the lipase enzyme in rice bran was inactivated after milling by the high-temperature short-term method (HTST) to produce stabilized rice bran. Then, for ethanol extraction, rice bran powder was mixed with 95% alcohol at a ratio of 1:3 and then macerated overnight at 50\u0026deg;C for three consecutive times. The extract was vacuum-evaporated at a temperature not higher than 50\u0026deg;C. The phytochemical profile of RBE was identified as previously published \u003cb\u003e(supplementary data S1-S4)\u003c/b\u003e. The content of γ-oryzanol and vitamin E was identified using HPLC analysis (Agilent 1100). Fatty acid methyl esters analysis was performed by GLC using the Agilent GC system. The analysis of the polyphenolic content of RBE was measured using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) with an Exion LC AC system for separation and a SCIEX Triple Quad 5500\u0026thinsp;+\u0026thinsp;MS/MS system equipped using electrospray ionization (ESI) for detection. The oily extract was kept in the refrigerator and warmed immediately before use to 37\u0026deg;C in a water bath.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e1.5 Diabetes induction\u003c/h2\u003e \u003cp\u003eType 1 diabetes was induced by intraperitoneal injection of multiple low doses (20 mg/kg for four consecutive days) of freshly prepared Streptozotocin (STZ) dissolved in 0.1 M citrate buffer (pH 4.5) after an overnight fast, given only a 5% glucose solution to prevent initial hypoglycaemic mortality \u003cb\u003e(\u003c/b\u003eYoussef et al., \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Diabetes was confirmed by drawing blood from the retro-orbital vein and assessing blood glucose level using a colorimetric assay kit \u003cb\u003e(Cat. No. GL 1320, Biodiagnostic, Cairo, Egypt)\u003c/b\u003e. Animals displaying fasting blood glucose levels greater than 450 mg/dl were used in the present study. Worth mentioning is that in this period (4 days), control groups received citrate buffer I.P.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e1.6 Experimental Design\u003c/h2\u003e \u003cp\u003eType 1 diabetes was induced by intraperitoneal injection of multiple low doses (20 mg/kg for four consecutive days) of freshly prepared streptozotocin (STZ) dissolved in 0.1 M citrate buffer (pH 4.5) after an overnight fast, given only a 5% glucose solution to prevent initial hypoglycemic mortality \u003cb\u003e(\u003c/b\u003eYoussef et al., \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Diabetes was confirmed by drawing blood from the retro-orbital vein and assessing blood glucose level using a colorimetric assay kit \u003cb\u003e(Cat. No. GL 1320, Biodiagnostic, Cairo, Egypt)\u003c/b\u003e. Animals displaying fasting blood glucose levels greater than 450 mg/dl were used in the present study. Worth mentioning is that in this period (4 days), control groups received citrate buffer I.P.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e1.7 Biochemical analysis\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.7.1 Estimation of glucose level in blood\u003c/h2\u003e \u003cp\u003eThe glucose level in the blood was determined using a colorimetric assay kit (\u003cb\u003eCat. No. GL 1320, Biodiagnostic, Cairo, Egypt)\u003c/b\u003e according to the method of \u003cb\u003eTrinder et al. (1969)\u003c/b\u003e. Following the manufacturer's instructions, the amount of glucose present was estimated as absorbance O.D. and measured at 405 nm using a single-beam spectrophotometer \u003cb\u003e(Shimadzu UV-2401PC).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e2.7.2 Estimation of Calcium level in pancreatic tissue\u003c/h2\u003e \u003cp\u003ePancreatic calcium level content was determined by a colorimetric assay kit \u003cb\u003e(Cat. No. GL 13 20, Biodiagnostic, Cairo, Egypt)\u003c/b\u003e according to the Gindler and King method \u003cb\u003e(\u003c/b\u003eGindler and King \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e1972\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The manufacturer's instructions were followed to detect calcium quantity existing at absorbance O.D. and measured at 585 nm using a single-beam spectrophotometer \u003cb\u003e{Shimadzu UV-2401PC}.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e2.7.3 Estimation of insulin level (INS) in blood/pancreatic tissue\u003c/h2\u003e \u003cp\u003eQuantitative measurements of INS levels in blood samples and pancreatic tissue were assayed using an INS rat ELISA kit \u003cb\u003e(Sunlong, SL0373Ra)\u003c/b\u003e. Appropriate assay procedures were followed according to the manufacturer's instructions. Insulin levels were estimated as absorbance O.D. within 15 minutes and measured at 450 nm using a titer plate reader \u003cb\u003e(BioTek/SN 263732).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e2.7.4 Estimation of Glucose Transporter 2 level (GLUT 2) in pancreatic tissue.\u003c/h2\u003e \u003cp\u003eQuantitative measurement of the GLUT 2 level was assayed using a GLUT 2 rat ELISA kit \u003cb\u003e(Bioassay Technology Laboratory, E1058Ra)\u003c/b\u003e. The manufacturer's instructions for appropriate assay procedures had been followed. Pancreatic GLUT 2 levels were assessed as absorbance O.D. within 10 minutes and measured at 450 nm using a titer plate reader \u003cb\u003e{BioTek/SN 263732}.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e2.7.5 Homeostasis model assessment of β-cell function (HOMA-β)\u003c/h2\u003e \u003cp\u003eHOMA-β, an index of insulin secretory function, was calculated based upon the measurement of blood glucose and blood insulin concentrations according to the following equation: HOMA-beta = [blood insulin concentration (\u0026micro;U/ml) \u0026times; 20] / [blood glucose (mmol/L) \u0026minus;\u0026thinsp;3.5] \u003cb\u003e(\u003c/b\u003eReaven \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e2009\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e1.8 Quantitative real-time PCR gene expression of PPARγ, SERCA, PrKC, and PDX1 genes in pancreatic tissue\u003c/h2\u003e \u003cp\u003eTotal RNA was extracted from 60 rats' pancreatic tissues using the RNeasy Mini kit \u003cb\u003e(Cat. No. 74101, Qiagen, Germany)\u003c/b\u003e following the manufacturer's instructions. The concentration and purity of the extracted RNA were determined using a nanodrop spectrophotometer \u003cb\u003e(2000 c, Thermoscientific, USA).\u003c/b\u003e For purification of the RNA, 1500 ng/\u0026micro;l of the sample was added to 2 \u0026micro;l of wipe-out buffer (7x) and nuclease-free water to make a final volume of 14 \u0026micro;l. Incubate for 2 minutes at 42\u0026ordm;C in a thermocycler \u003cb\u003e(BIO-RAD T100, USA)\u003c/b\u003e. A mixture was prepared for cDNA synthesis using a QuantiTect reverse transcription kit with a 1:4:1 ratio of RT primer mix, Quantiscript RT buffer, and Quantiscript reverse transcriptase, and then added to the extracted RNA (14 \u0026micro;l). The samples were incubated in a thermocycler for 30 minutes at 42\u0026deg;C and 95\u0026deg;C and then stored at -80\u0026deg;C until analyzed. For each sample, four genes were measured (PPARγ, SERCA, PrKC, and PDX1) using the RT2 Syber Green kit \u003cb\u003e(Cat. No. 330524, Qiagen, Germany).\u003c/b\u003e The RT-PCR was performed using Design \u0026amp; Analysis Software (DA2) version 2.6.0 for Applied Biosystems QuantStudio 5 DX, involving adding 1 \u0026micro;l cDNA of each sample, 12.5 \u0026micro;l RT2 Syber Green, and 10.5 \u0026micro;l nuclease-free water. \u003cb\u003e(Thermo Fisher Scientific, USA).\u003c/b\u003e Relative quantification for gene expression (RQ) was calculated by the 2-ΔΔCT equation according to Livak and Schmittgen (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2001\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e using the β-actin reference gene for the normalizer as follows:\u003c/p\u003e \u003cp\u003eΔCt control\u0026thinsp;=\u0026thinsp;CTtarget-CT endogenous β-actin\u003c/p\u003e \u003cp\u003eΔCt sample\u0026thinsp;=\u0026thinsp;CTtarget-CT endogenous β-actin\u003c/p\u003e \u003cp\u003eΔΔCt\u0026thinsp;=\u0026thinsp;ΔCt sample - ΔCt control\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e1.9 Histopathological examination of pancreatic tissue\u003c/h2\u003e \u003cp\u003eAutopsy samples were taken from the pancreas of rats in all groups and fixed in 10% neutral buffer formalin for 12 hours. Washing was done with tap water, and then serial dilutions of methyl alcohol (70%, 80%, 90%, 95%, and 100% consecutively) were used for dehydration. Samples were cleared in xylene for 1 hour twice and embedded in soft paraffin, then hard paraffin, each for 1 hr. Finally, paraffin blocks were prepared for sectioning by microtome 2\u0026ndash;4 \u0026micro;. For pancreas routine examination using a light electron microscope, the obtained tissue sections were collected on glass slides, deparaffinized, and stained with hematoxylin and eosin stain \u003cb\u003e(\u003c/b\u003eBancroft and Stevens, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e1996\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e Congo red staining was performed for the brains of rats in all groups using the established protocol. Formalin-fixed and paraffin-embedded tissue was cut into 6-\u0026micro;m-thick sections, deparaffinized, and dyed with 2.5 g of Congo red \u003cb\u003e(Merck Millipore, Darmstadt, Germany)\u003c/b\u003e and 1 g potassium hydroxide (Merck Millipore) dissolved into 500 ml.\u003c/p\u003e \u003cp\u003eof 80% ethanol \u003cb\u003e(\u003c/b\u003eMenter et al., \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e1.10 Behavioral assessment\u003c/h2\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e2.10.1 Y-maze test:\u003c/h2\u003e \u003cp\u003eThis test evaluates short-term spatial memory. A three-armed, opaque wooden Y-shaped apparatus measuring 32 mm in length, 10 mm in height, and 5 cm in width and angled at a 120\u0026deg; angle from one another was utilized. Following an introduction to the center of the maze, the rat was given eight minutes to freely investigate each of the three arms, and the order in which it entered each arm was recorded. When its working memory is intact, the rat would prefer to explore a new section of the maze than go back to a previously explored one. The percent alternation is calculated as:\u003c/p\u003e \u003cp\u003e(Number of alternations/number of entries-2)\u0026times;100.\u003c/p\u003e \u003cp\u003eWhere the number of alternations is any three successive choices of three different arms that are counted as a correct choice and the number of entries are the total possible alternations \u003cb\u003e(\u003c/b\u003eArai et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2001\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e2.10.2 Novel Object Recognition Test:\u003c/h2\u003e \u003cp\u003eThis test assesses different interspecies aspects of non-spatial recognition memory. The main arena was a wooden, white, opaque chamber (around 40 cm x 40 cm x 60 cm). On the first day, for habituation, each rat was allowed to freely explore the arena without any objects for 10 min. On the following day, each rat goes through a training session for visual exploration of two identical objects for 10 min, then, after a 2-h retention interval, a testing session where one of the previously explored objects is substituted with a novel object, and the animal is left 5 min to explore. In the testing session, a video was recorded of the rats' behavior. Since rodents have an innate preference for novelty, the rat with intact memory will spend more time exploring the novel object. In all sessions, each rat was removed from its home cage and placed in the middle of the open arena, and at the end, the rat was removed and placed in a holding cage. Between each rat, the apparatus was cleaned using 70% ethanol. Objects were different enough to be easily discriminated by the rat but had a similar degree of complexity (texture, shape, color patterning, and brightness) to minimize any possible induced object preference. The discrimination ratio (DR) was calculated as the time spent exploring the novel object minus the time spent exploring the familiar object divided by total exploration time \u003cb\u003e(\u003c/b\u003eAntunes and Biala, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Lueptow, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2017\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"3 Statistical analysis","content":"\u003cp\u003eAll results were expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.E.M. (standard error of the mean). Data were analyzed with a one-way analysis of variance (ANOVA) followed by a Tukey-Kramer post-test for one-variable multiple-group comparison. Only blood glucose and blood insulin were analyzed with a two-way analysis of variance (ANOVA) followed by the Bonferroni post-test for two-variable multiple-group comparisons. In all cases, a p-value less than 0.05 was considered statistically significant. Statistical analysis was performed using instant automated software \u003cb\u003e(GraphPad Prism Software version 5.01).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe F distribution formed by the variance ratios according to the degree of freedom combinations was represented by the F value to serve as a reference for the P value location in the data distribution \u003cb\u003e(\u003c/b\u003eKim, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2017\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The winsorization (weight modification method) approach was used for treating the outliers \u003cb\u003e(\u003c/b\u003eKwak and Kim, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2017\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHistopathological score values were considered non-parametric values, so data were analyzed by the Kruskal-Wallis test followed by a Dunn's post-test.\u003c/p\u003e"},{"header":"4 Results","content":"\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Effect of Rice bran extract and Insulin on biochemical parameters\u003c/h2\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e4.1.1 blood glucose levels in STZ diabetic rat\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, blood glucose levels differed greatly between the CON groups and the diabetic groups in all weeks of the experiment (F (220, 4)\u0026thinsp;=\u0026thinsp;2481.55, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Just after induction, before treatment, the diabetic groups showed a significant increase in blood glucose levels compared with the CON group of 189.8%. At week 3, compared to the diabetic group, blood glucose levels in the INS-treated group decreased by 21.36% significantly, and blood glucose levels in the RB-treated groups decreased by 10.62% non-significantly. There was also a significant difference between weeks within each group (F (220, 3)\u0026thinsp;=\u0026thinsp;80.86, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). There was a significant decrease in blood glucose levels in both treated groups at week 3 compared to week 1 in each individual treated group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section3\"\u003e \u003ch2\u003e4.1.2 blood insulin levels in STZ diabetic rat\u003c/h2\u003e \u003cp\u003eThroughout all weeks of the experiment, as presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the blood insulin level was highly significantly different between the various groups (F (100, 4)\u0026thinsp;=\u0026thinsp;35.68). All diabetic groups displayed a significant increase in blood insulin levels after the induction by 74.119% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At weeks 2 and 3, the diabetic group's blood insulin level decreased, showing significantly lower levels than the CON group by 26.079% (P\u0026thinsp;=\u0026thinsp;0.0061) and 33.567% (P\u0026thinsp;=\u0026thinsp;0.004). On the other hand, in week 3, in the treated groups, the diabetic\u0026thinsp;+\u0026thinsp;INS group and diabetic\u0026thinsp;+\u0026thinsp;RB group, insulin blood levels increased significantly by 62.15% and 122.62%, respectively, compared to the diabetic group. Interestingly, at week 3, in the CON\u0026thinsp;+\u0026thinsp;RB group, blood insulin level increased by 47.89%, a P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 significant increase from the untreated diabetic group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAs well, within each group revealed in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef, there was a significant difference among weeks (F (220, 3)\u0026thinsp;=\u0026thinsp;38.86, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At week 3, In the INS diabetic-treated group, insulin blood level showed no significant difference compared to its level in the same group at week 2. Where, in the RB diabetic treated group, there was a significant rise in insulin blood level compared to its level in the same group at week 2. Interestingly, the CON\u0026thinsp;+\u0026thinsp;RB group insulin blood level increased significantly at week 3 compared with week 2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003e4.1.3 Effect of Rice bran extract and Insulin on β-cell insulin secretory function (HOMA-β)\u003c/h2\u003e \u003cp\u003eIn Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea, all diabetic rats, after induction, displayed a significant decline in β-cell capacity in insulin secretion compared to control groups. However, in both diabetic-treated groups there was a continuous decline through weeks 1 and 2, whereas at week 3, the RB diabetic-treated group showed a numerically insignificant increase in the HOMA-β index compared to the diabetic group. Interestingly, the CON\u0026thinsp;+\u0026thinsp;RB group showed a higher, non-significant increase in the HOMA-β index compared to the CON group at the end of the experiment. Using a correlation matrix in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb, we could evaluate the RB-treated diabetic group strong relationship with CON and CON-RB groups (P\u0026thinsp;=\u0026thinsp;0.592, 0.472 respectively), with a weaker relationship in relevance to the untreated diabetic group (P\u0026thinsp;=\u0026thinsp;0.441), in contrast with the diabetic INS-treated group that holds a week relationship with CON and CON-RB groups (P\u0026thinsp;=\u0026thinsp;0.821, 0.935 respectively) and a stronger relationship in relevance to the untreated diabetic group (P\u0026thinsp;=\u0026thinsp;0.285). Where the P-value represents the probability of finding the correlation coefficient\u0026rsquo;s value indicating a greater correlation degree, given that the two variables are not actually correlated (null hypothesis).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003e4.1.4 Pancreatic insulin level in STZ diabetic rat\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea, rats' pancreatic insulin levels vary between different groups (F (25, 4)\u0026thinsp;=\u0026thinsp;19.47). Results presented a significant decline in pancreatic insulin levels in the diabetic group by 73.57 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to the CON group and 73.77% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to the CON\u0026thinsp;+\u0026thinsp;RB group. INS-treated diabetic group insulin level decreased with no significant difference from the diabetic rats. While surprisingly, in the RB-treated diabetic group, insulin levels returned to normal levels, with a significant difference from the diabetic rats by 149.13%. (P\u0026thinsp;=\u0026thinsp;0.024).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003e4.1.5 Pancreatic Glut2 Level in STZ diabetic rat\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb reflects the variation in rats' pancreatic Glut2 levels between different groups (F (25, 4)\u0026thinsp;=\u0026thinsp;251.8, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The diabetic group displayed a significant decrease in pancreatic Glut2 level from the CON group by 80.937% and from the CON\u0026thinsp;+\u0026thinsp;RB group by 80.887%. When compared to the diabetic group, the diabetic INS-treated group's pancreatic Glut2 level remained unchanged. In contrast, the diabetic RB-treated group's pancreatic Glut2 levels increased significantly by 126.495%. Noteworthy, there is still a significant difference between diabetic RB-treated group pancreatic Glut2 levels related to the CON group. Remarkably, in the CON\u0026thinsp;+\u0026thinsp;RB group, pancreatic Glut2 levels increased significantly compared to the CON group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section3\"\u003e \u003ch2\u003e4.1.6 Pancreatic Calcium Levels in STZ diabetic rat\u003c/h2\u003e \u003cp\u003eThe disparity in pancreatic calcium levels among groups is revealed in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec (F (25, 4)\u0026thinsp;=\u0026thinsp;498.2, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Diabetic group pancreatic calcium level significantly dropped by 76.168% from CON and 76.339% from CON\u0026thinsp;+\u0026thinsp;RB. The INS-treated group's pancreatic calcium levels do not differ from those of the diabetic group. In contrast, the diabetic group treated with RB had a significant increase in pancreatic calcium levels of 54.589% when compared to the diabetic group. However, it is important to note that the pancreatic calcium level of the diabetic RB-treated group differs significantly from that of the CON group.\u003c/p\u003e \u003cp\u003e \u003cb\u003e4.2 Effect of Rice bran extract and Insulin on pancreatic mRNA expression level of PPARℽ, SERCA, PrKc, and PDX1 genes involved in the regulation of insulin secretion in STZ diabetic rats.\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section3\"\u003e \u003ch2\u003e4.2.1 PPARℽ Expression Levels\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea, unexpectedly, the PPARℽ expression level in the diabetic group slightly decreased from the control groups (CON and CON\u0026thinsp;+\u0026thinsp;RB) with no significant difference. The INS-treated group showed no significant difference between the related control groups and the diabetic group. On the contrary, the RB-treated diabetic group demonstrated significant up-regulation (F (25, 4)\u0026thinsp;=\u0026thinsp;83.09, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) in PPARℽ expression levels higher than the CON group by 1646.1% and higher than the diabetic group by 3303.797%. Also, there is no significant difference between the insulin-treated group related to the CON group or the diabetic group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec30\" class=\"Section3\"\u003e \u003ch2\u003e4.2.2 SERCA Expression Levels\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eb showed a minor increase in SERCA expression levels in diabetic rats with no significant difference compared to control groups (CON and CON\u0026thinsp;+\u0026thinsp;RB). In addition, SERCA expression level up-regulation in the INS-treated diabetic group has no significance related to the diabetic group or control group. While SERCA Expression level significantly up-regulated in RB-diabetic-treated rats 3 times compared to the diabetic group, and 18 times compared to the CON group (F (25, 4)\u0026thinsp;=\u0026thinsp;6.42, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec31\" class=\"Section3\"\u003e \u003ch2\u003e4.2.3 Prkc Expression Levels\u003c/h2\u003e \u003cp\u003eIt was noticed in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC a slight rise in Prkc expression levels in the diabetic group with no significant difference related to the control group. As well, in the INS-treated diabetic group, Prkc expression level up-regulation showed no significant change compared to the CON and diabetic groups. However, in the RB-treated diabetic group, significant up-regulation in Prkc expression levels was 15 times compared to the diabetic group and 126 times compared to the CON group (F (25, 4)\u0026thinsp;=\u0026thinsp;12.40, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section3\"\u003e \u003ch2\u003e4.2.4 PDX1 Expression Levels\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ed presented an unanticipated, non-significant rise in PDX1 expression levels in diabetic rats related to the control group. INS-treated rats revealed significant PDX1 expression up-regulation (F (25, 4)\u0026thinsp;=\u0026thinsp;5.824, P\u0026thinsp;\u0026lt;\u0026thinsp;0.005) by 316.262% related to the diabetic group. Rather unexpectedly, in the RB-treated diabetic group, PDX1 expression levels displayed no significant difference compared to the diabetic group.\u003c/p\u003e \u003cp\u003e\u003cb\u003e4.3 Effect of Rice bran extract and Insulin on STZ-induced histological alteration in STZ diabetic rat\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003e4.3.1 Pancreatic tissue (H\u0026amp;E stain)\u003c/h2\u003e \u003cp\u003eIn Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e, the CON group displayed normal pancreatic architecture. The acinar cells that make up the exocrine (EX) portion of the pancreas are arranged into tiny lobules and tightly packed. The CON\u0026thinsp;+\u0026thinsp;RB group revealed the pancreas' distinct lobules and external secretory units involving several pyramidal cells. Furthermore, internal secretory units (IL) represented several hormone-secreting cells next to the blood vessel.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn diabetic rats, the overall structure is deformed. Most exocrine acini displayed cell atrophy as a sign of acinar damage. Acini demonstrated a degree of decline. Degeneration, vacuolation, necrosis, and a significant decline in the number of beta cells lead the islets of Langerhans (IL) to decrease. Most of the areas showed thickly walled, dilated, and congested blood arteries.\u003c/p\u003e \u003cp\u003eIn Both treated groups Mononuclear cells (ICI) infiltrated and clogged up some blood vessels (BV) still present, however, both showed some progress whereas vacuolation is mild in both groups. Besides, in insulin-treated rats, minor acinar cell aging was exhibited. As well, it is worth taking a look at RB-treated rats' pancreas which revealed slight improvement in which Some IL inside the acinar cells has several beta cells and a regular shape and size.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003e4.3.2 Brain tissue (Congo red stain)\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e, Congo red staining of brain sections from the CON group and CON\u0026thinsp;+\u0026thinsp;RB group revealed normal faint staining with the absence of any dark-stained plaques. On the contrary, the diabetic group showed numerous red-stained plaques scattered within the brain tissue. The insulin-treated rats showed sporadic red-stained plaques in a few sections, whereas the RB-treated rats showed fewer red-stained plaques.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec35\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Effect of Rice bran extract and Insulin on rats' behavioral alterations\u003c/h2\u003e \u003cdiv id=\"Sec36\" class=\"Section3\"\u003e \u003ch2\u003e4.4.1 Y-maze Test in STZ-diabetic rats\u003c/h2\u003e \u003cp\u003eAs displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003ea, rats\u0026rsquo; spatial memory performance differs significantly within the 5 groups (F (25, 4)\u0026thinsp;=\u0026thinsp;13.69, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The diabetic group showed an inability to opt for the correct choice, showing a significant decrease in the percentage of alteration compared to the CON group and CON\u0026thinsp;+\u0026thinsp;RB group by 56.99% and 50.05% respectively. RBE and INS-treated groups improved rats' spatial memory and displayed a significant increase in the percentage of alteration by 123.66% and 100%, respectively, from the diabetic group. Remarkably, both treated groups revealed no significant difference in the percentage of alteration from the normal CON group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec37\" class=\"Section3\"\u003e \u003ch2\u003e4.4.2 Novel object recognition Test in STZ-diabetic rats\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eb demonstrates rats' recognition behavior altered among groups (F (25, 4)\u0026thinsp;=\u0026thinsp;18.64). Results showed a significant decline in the discrimination ratio in the diabetic group (156%, P\u0026thinsp;\u0026lt;\u0026thinsp;0. 001) compared to CON. Diabetic groups treated with RB and INS restored the ability to explore new objects and showed a significant increase by 217% (P\u0026thinsp;=\u0026thinsp;0. 001) and 226% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), respectively, from the diabetic group. Remarkably, both treated groups revealed no significant difference in discrimination ratio from the normal CON group.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"5 Discussion","content":"\u003cp\u003eIn the present experiment, administration of STZ for four sequential days induced T1D, which displayed an acute rise in blood glucose \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea\u003cb\u003e)\u003c/b\u003e, reflecting a significant drop in β-cell insulin secretory function as indicated by the HOMA-β index \u003cb\u003e(\u003c/b\u003eFigs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e With sustained hyperglycemia \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e at the end of the experiment, the diabetic group showed a decline in pancreatic Ca\u003csup\u003e2+\u003c/sup\u003e levels as a result of the decrease in pancreatic GLUT2 levels \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea, b \u003cb\u003eand c)\u003c/b\u003e. The reduction in pancreatic GLUT2 levels is consistent with published research, which links GLUT2 expression decline to an increase in free fatty acids and triglycerides in the blood as a result of β-cell dysfunction \u003cb\u003e(\u003c/b\u003eThorens, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e2001\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e GLUT2 levels decline, reducing glucose uptake by β-cells and impairing glucose-6-phosphate phosphorylation and the production of ATP in the glycolysis process. This hinders glucose-inducing intracellular ATP levels from increasing the cytoplasmic ATP/ADP ratio for K+-ATP channel shutting and voltage-dependent Ca\u003csup\u003e2+\u003c/sup\u003e channel opening. This reduces Ca\u003csup\u003e2+\u003c/sup\u003e release, ultimately leading to inhibition of exocytotic insulin release from insulin-containing granules \u003cb\u003e(\u003c/b\u003eSun et al., \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). The observed fall in pancreatic GLUT2 and Ca\u003csup\u003e2+\u003c/sup\u003e levels in the diabetic group was also reflected in a drop in blood insulin levels \u003cb\u003e(\u003c/b\u003eKlec et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; \u003cb\u003eTrexler and Taraska et al., 2017)\u003c/b\u003e, highlighting the role of glucose transport in β-cells in glucose-stimulating insulin secretion (GSIS) \u003cb\u003e(\u003c/b\u003eSaji et al., \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRB treatment had an inverse effect on insulin levels, showing a significant increase in blood insulin levels compared to the insulin-treated group, as shown at the end of the experiment \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed\u003cb\u003e).\u003c/b\u003e Moreover, in pancreatic tissue, only RBE significantly increased pancreatic insulin levels compared to untreated and insulin-treated groups \u003cb\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, p\u0026thinsp;\u0026lt;\u0026thinsp;0. 1) (\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003cb\u003eA).\u003c/b\u003e This effect was corroborated by the strong correlation of the HOMA-β index between the RB-treated group and control groups rather than with the insulin-treated group \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. On the contrary, for blood glucose levels, only insulin therapy showed a significant reduction in diabetic rats, while RBE showed a slow, non-significant decline until the end of the experiment. Interestingly, the same finding regarding blood glucose levels was reported \u003cb\u003eby\u003c/b\u003e Kaup et al. (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) when examining the RBE administration for glucose-treated rats (2 g/kg BW) and abruptly elevated plasma insulin. The author argued that the organism requires tight glucose regulation in the long term and suggested prolonged RBE treatment to adjust blood glucose levels. This assumption is supported by the reported effect of tocotrienol, the rice bran oil fraction, on reducing fasting blood glucose and HbA1C in a T1D rat model after 8 weeks of diabetes induction \u003cb\u003e(Siddiqui et al., 2010).\u003c/b\u003e It is well known that the antidiabetic effect of tocotrienols is a long-term PPAR-mediated activity \u003cb\u003e(\u003c/b\u003eFang et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Like other stabilized RB supplements, they reduced HbA1C in T2D patients after 12 weeks \u003cb\u003e(\u003c/b\u003eCheng et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2010\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDiabetic rats treated with RBE showed a significant rise in pancreatic GLUT2 levels compared to those treated with insulin \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003cb\u003eB).\u003c/b\u003e This is the first study to report such an effect of RBE on GLUT2 levels in the pancreas. Nevertheless, it's worth noting that RBE vitamin E components, tocotrienols (δ- and γ-T3), have a dose-dependent effect on increasing GLUT2 expression in rat pancreatic islets \u003cb\u003e(\u003c/b\u003eChia et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). The RBE control group showed an intriguingly significant increase in GLUT2 levels compared to the untreated control group \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb\u003cb\u003e)\u003c/b\u003e, suggesting a possible effect of RBE on GLUT2 basal levels at normal conditions\u0026mdash;an observation that needs further investigation.\u003c/p\u003e \u003cp\u003eThis, in turn, was consistent with a significant increase in intracellular Ca\u003csup\u003e2+\u003c/sup\u003e ion levels in the RBE-treated group compared to insulin \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec\u003cb\u003e)\u003c/b\u003e. This infers an increase in glucose transport inside β-cells \u003cb\u003e(\u003c/b\u003eSaji et al., \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), leading to an increase in Ca\u003csup\u003e2+\u003c/sup\u003e ion influx through ATP-induced Ca\u003csup\u003e2+\u003c/sup\u003e channel opening \u003cb\u003e(\u003c/b\u003eSun et al., \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Vanillic acid, one of the phenolic compounds of the RBE phenolic fraction (\u003cb\u003esupplementary data S1-S4)\u003c/b\u003e, has been reported to increase Ca\u003csup\u003e2+\u003c/sup\u003e influx through a voltage-dependent calcium channel \u003cb\u003e(\u003c/b\u003eMahendra et al., \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Additionally, another phenolic compound, ferulic acid, a main active metabolite of RBE γ-oryzanol \u003cb\u003e(\u003c/b\u003eArumsari et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Kokumai et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), stimulated Ca\u003csup\u003e2+\u003c/sup\u003e influx in INS-1 cells, supporting RBE active components in their role in GSIS \u003cb\u003e(\u003c/b\u003eRuamyod et al., \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). On the contrary, levels of pancreatic GLUT2 and Ca\u003csup\u003e2+\u003c/sup\u003e were not altered in the insulin-treated group in relation to the untreated diabetic group (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB\u003cb\u003e\u0026amp;C\u003c/b\u003e). This indicates no impact of insulin treatment on GSIS, in agreement with Persaud et al.'s (\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2001\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e, where the study disclosed the insulin-inhibitory effect of its own secretion in human islet cells. Other insulin therapy studies showed an acute decrease in β-cell GLUT2 in STZ-induced diabetic rats \u003cb\u003e(\u003c/b\u003eThulesen et al., \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e1997\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo reveal the molecular mechanism underlying the influence of RBE administration on insulin secretion signaling pathways, we analyzed the gene expression levels of PPARγ, SERCA, PKC, and PDX1. Interestingly, RBE showed a highly significant increase in PPARγ pancreatic gene expression in comparison to the untreated diabetic group \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003cb\u003eA, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/b\u003e. This finding supports our previously reported RBE-PPARγ agonist activity \u003cb\u003e(\u003c/b\u003eAbd El Fattah et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; El-Din SS et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Mostafa et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). The potential of RBE in regulating molecules in the insulin signaling cascade is also evidenced by the reported effect of tocotrienols on increasing PPARγ expression in glucose-stimulated pancreatic β-islet cells \u003cb\u003e(\u003c/b\u003eChia et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). On the contrary, although insulin is a PPARγ receptor regulator \u003cb\u003e(\u003c/b\u003eRieusset et al., \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e1999\u003c/span\u003e), insulin treatment in the present study showed an insignificant effect on PPARγ gene expression compared to the untreated diabetic group. The precise impact of insulin on PPARγ expression is not well comprehended. However, the ERK proteins and activated signaling molecules provided a plausible explanation for PPARγ-insulin interaction through ERK-1/2-Junk phosphorylation of the PPARγ-insulin signaling cascade in adipose tissue. Studies have found that PPARγ phosphorylation decreased PPARγ ligand's transcriptional activity as proteasomal degradation increased, leading to the suppression of PPARγ expression \u003cb\u003e(\u003c/b\u003eLeonardini et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; \u003cb\u003eFloyd and Stephens et al., 2002).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eRBE administration resulted in a significant increase in SERCA2 gene expression \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eb\u003cb\u003e)\u003c/b\u003e, surpassing both diabetic and control groups. This finding supports the link between PPARγ and SERCA2 gene expression, which is regulated by PPARγ interaction with the PPAR-responsive element in the human SERCA2 promoter \u003cb\u003e(\u003c/b\u003eKono et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). The increase in SERCA2 expression aligns with the observed rise in Ca\u003csup\u003e2+\u003c/sup\u003e levels \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea\u003cb\u003e)\u003c/b\u003e in the RBE-treated group, indicating that SERCA2 maintains high intracellular Ca\u003csup\u003e2+\u003c/sup\u003e levels (\u003cb\u003eTrexler and Taraska et al., 2017)\u003c/b\u003e. The use of RBE resulted in a notable increase in PrkC levels in the diabetes-treated groups compared to insulin \u003cb\u003e(p\u0026thinsp;\u0026gt;\u0026thinsp;0.001) (\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003cb\u003eC)\u003c/b\u003e. This finding suggests that the rise in Ca\u003csup\u003e2+\u003c/sup\u003e influx activates PrKC βII \u003cb\u003e(\u003c/b\u003eShimabukuro et al., \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e1998\u003c/span\u003e), which in turn stimulates Na+-permeable channels, leading to membrane depolarization and insulin secretion \u003cb\u003e(\u003c/b\u003eFleming and Storz, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2017\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e Moreover, the increase in PrKC βII is expected to redistribute GLUT2 to transport glucose molecules inside the β-cell \u003cb\u003e(\u003c/b\u003eCohen et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). This condition was obviously detected in our current results, as illustrated before \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003cb\u003eB).\u003c/b\u003e It is worth noting that ferulic acid can be reported to activate pathways like PKA, CaMKII, MAPK/ERK, and PI3K to influence PrkC expression \u003cb\u003e(\u003c/b\u003eZeni et al., \u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e2012\u003c/span\u003e), which may promote efficient GSIS.\u003c/p\u003e \u003cp\u003eRBE Improving cognitive abilities was examined by evaluating the performance of diabetic rats in Y-maze and NOR behavioral tests. The findings of RBE administration demonstrated a significant improvement in cognitive functions, with no notable disparity observed between the treated groups \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eA, B\u003cb\u003e)\u003c/b\u003e compared to the diabetic group. The outcomes align with our earlier findings that Egyptian RBE enhances rats\u0026rsquo; cognitive function in an LPS-induced neuroinflammatory animal model \u003cb\u003e(\u003c/b\u003eMostafa et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). In a corresponding manner, Hagl et al. (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) conducted a study that demonstrated the efficacy of RBE in restoring cognitive abilities in aged rats. This restoration was achieved through the activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which directly regulates PPARγ. Regarding insulin treatment, \u003cb\u003eStrachan's (2005)\u003c/b\u003e findings reported the effectiveness of intranasal insulin therapy in improving declarative memory. Insulin, whether generated internally or externally, has been found to potentially promote synaptic remodeling and synaptogenesis, which are crucial for memory consolidation \u003cb\u003e(\u003c/b\u003eCholerton et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Skeberdis et al., \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). Additionally, it induces the expression of neurotransmitters like acetylcholine and norepinephrine, regulating cognitive functions through the coordination of cholinergic and adrenergic pathways \u003cb\u003e(\u003c/b\u003eCholerton et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; De Leo et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Thus, the study suggests that RBE may enhance memory and cognition by increasing peripheral insulin secretion through PPARγ regulator activity, potentially acting in the central nervous system. Furthermore, Congo-red staining brain sections showed fewer red Aβ plaques in the brain tissue of the treated groups compared to untreated diabetic rats \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. This observation indicates a decline in the formation of amyloid plaques, as demonstrated in our previous study on the neuroprotective mechanism of RBE in mice with LPS-induced neuroinflammation. \u003cb\u003e(\u003c/b\u003eAbd El Fattah et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Insulin impacts tau phosphorylation and amyloid-β peptide clearance, which are Alzheimer's disease pathological features \u003cb\u003e(\u003c/b\u003eBoccardi et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). This lends credence to the association between diabetes and dementia. Histological examination results supported the RBE effect on restoring pancreatic structure more effectively than insulin treatment, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. Untreated diabetics showed distortion in pancreatic structure, atrophy in exocrine glands, and decreased β-cells and IL numbers, which corresponds to the acute rise in blood glucose \u003cb\u003e(\u003c/b\u003eFigs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e Interestingly, rats treated with RBE showed several normal β-cells with regular shape and size, disclosing upgraded IL structure inside the acinar cell compared to insulin treatment. A result in alignment with the reported effect of red RBE on enhancing pancreatic structure in n mice treated with a high-fat diet \u003cb\u003e(\u003c/b\u003eMunkong et al., \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) and reinforced by the role of pioglitazone PPARγ agonistic effect in shielding pancreatic β-cells from the effects of hyperglycemia, deficiencies in insulin secretion, and the impact of cell death. This protective mechanism is achieved by activation of the SERCA2b pump via direct enhancement of; SERCA2b gene expression. This supports our present results on the effect of RBE on SERCA2b gene expression.\u003c/p\u003e"},{"header":"6 Conclusion","content":"\u003cp\u003eIn conclusion, our RBE treatment enhanced insulin secretion, obviously with little influence on glucose levels, which we suggest it should be reversed by longer-term supplementation. This finding suggests that RBE's beneficial effect on cognitive performance may be related to an increase in insulin levels in the brain. The RBE effect on enhancing β cell insulin secretion provides further insights into the RBE mechanism of action by targeting the PPARγ/PDX1 signaling pathway. This is evidence-based action by RBE components.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eT1D\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eType 1 diabetes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePPAR-γ\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePeroxisome proliferator-activated receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTZDs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eThiazolidinediones\u003c/span\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eGSIS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlucose-stimulating insulin secretion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePDX1\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePancreatic and duodenal homeobox 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eGLUT2\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlucose transport 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eSERCA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSarcoendoplasmic reticulum calcium ATPase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePrKC\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProtein Kinase C\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePDX1\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePancreatic and duodenal homeobox 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eDCVs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDense core vesicles\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRBE\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRice bran Extract\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePGC1α\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eproliferator-activated receptor gamma coactivator 1-alpha\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eThe Research Ethics Committee at Cairo University (Cairo, Egypt, PT 3080) approved this research methodology. The guidelines for the care and use of laboratory animals, issued by the United States National Institute of Health (NI.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eGraphical abstract:\u003c/h2\u003e \u003cp\u003e(Legend): Schematic pathway for insulin secretion via PPAR-γ dependent pathway in type 1 diabetes\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research was funded by the strategic program for Biotechnology and Genetic Engineering\u0026mdash;Science and Technological Cooperation Center\u0026mdash;Academic of Scientific Research and Technology (ASRT).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eThe study conception and design. Material preparation, data collection: Madonna Magdy Youssef, Mohammed Farrag Elyamny, Ola Ahmed Heikal. Statistical analysis and interpretation of the data: Madonna Magdy Youssef, Mohammed Farrag Elyamny, Ola Ahmed Heikal. Reham Mahmoud Abdelkader. The first draft of the manuscript was written by: Madonna Magdy Youssef, Ola Ahmed Heikal and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors express their gratitude for the funding support provided by the Strategic Program for Biotechnology and Genetic Engineering, Science and Technological Cooperation Center (STC) - Academy of Scientific Research and Technology (ASRT). Additionally, the authors thank Health Tec Company (Health Tech\u0026reg;) for supplying the research with RBE.Regarding histopathological examination, Assistant Professor Dr. Heba Ali Abd Elrahman from the Faculty of Science at Cairo University provided valuable assistance. The authors are also thankful to Omnia Samir Hosni, MSc in Genetics, Histology, and Cell Biology from the Zoology Department at Cairo University, who is a Senior Technical Support and Molecular Genetics Specialist, for her help in Quantitative Real Time PCR analysis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAbd El Fattah MA, Abdelhamid YA, Elyamany MF, Badary OA, Heikal OA (2020) Rice Bran Extract Protected against LPS-Induced Neuroinflammation in Mice through Targeting PPAR-γ Nuclear Receptor. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fphys.2014.00226\u003c/span\u003e\u003cspan address=\"10.3389/fphys.2014.00226\" targettype=\"DOI\" 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":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"metabolic-brain-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mebr","sideBox":"Learn more about [Metabolic Brain Disease](https://www.springer.com/journal/11011)","snPcode":"11011","submissionUrl":"https://submission.nature.com/new-submission/11011/3","title":"Metabolic Brain Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"insulin, diabetes, rice bran extract, PPARγ, and cognition","lastPublishedDoi":"10.21203/rs.3.rs-5702421/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5702421/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eType I diabetes (T1D), also known as juvenile diabetes, is an autoimmune disease that causes gradual destruction of pancreatic cells and leads to intellectual disability, neuropathy, cognitive impairment, and impaired learning ability in children. Despite standard treatment with synthetic human insulin, T1D patients can maintain up to 40% of their insulin-producing islets. PPARγ receptor activation research that aims to restore β-cell biology could help reverse the loss of pancreatic mass that comes with getting older and improve β-cell function. Egyptian RB ethanol extract (RBE), previously reported with PPARγ agonist activity, showed an increase in insulin secretion both in vivo and in INS-1 cells. The exact antidiabetic RBE mechanism is still unclear. The present study aims to investigate the molecular RBE mechanism in glucose-stimulating insulin secretion and restoration of β cell function. A diabetic rat streptozotocin (STZ) model was used; five groups were designed. The STZ-diabetic rats were treated with RBE daily for 21 days compared to an insulin-treated group. Biochemical parameters and quantitative RT-PCR of β-cell genes related to the PPAR/PDX1 signaling pathway were performed, and the influence on cognitive ability was confirmed by behavioral testing (Y-maze and NOR) and histological examination. The RBE-treated group reversed blood glucose, Glut2, Ca2+, and insulin levels in diabetic rats, with pancreatic insulin levels significantly increasing compared to the insulin group. With the exception of PDX1, RBE boosted PPARγ, SERCA, and PrKC gene expression. RBE also restored cognitive functions. This study suggests that RBE may enhance memory and cognition by increasing peripheral insulin secretion through PPARγ regulator activity.\u003c/p\u003e","manuscriptTitle":"Rice Bran Extract attenuates cognitive impairment by enhancing pancreatic β-cell insulin secretion in STZ-induced diabetic rats targeting the PPARγ/PDX1 pathway","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-10 18:03:41","doi":"10.21203/rs.3.rs-5702421/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-09T05:31:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-08T17:17:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-08T17:16:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Metabolic Brain Disease","date":"2024-12-23T23:38:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"metabolic-brain-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mebr","sideBox":"Learn more about [Metabolic Brain Disease](https://www.springer.com/journal/11011)","snPcode":"11011","submissionUrl":"https://submission.nature.com/new-submission/11011/3","title":"Metabolic Brain Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bd339a22-2046-4372-9062-bca6250b6f3d","owner":[],"postedDate":"January 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-23T16:01:07+00:00","versionOfRecord":{"articleIdentity":"rs-5702421","link":"https://doi.org/10.1007/s11011-025-01639-1","journal":{"identity":"metabolic-brain-disease","isVorOnly":false,"title":"Metabolic Brain Disease"},"publishedOn":"2025-06-19 15:57:32","publishedOnDateReadable":"June 19th, 2025"},"versionCreatedAt":"2025-01-10 18:03:41","video":"","vorDoi":"10.1007/s11011-025-01639-1","vorDoiUrl":"https://doi.org/10.1007/s11011-025-01639-1","workflowStages":[]},"version":"v1","identity":"rs-5702421","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5702421","identity":"rs-5702421","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}