Protective effects of Suberoylanilide hydroxamic acid and Dapagliflozin administration on liver of diabetic rats

Protective effects of Suberoylanilide hydroxamic acid and Dapagliflozin administration on liver of diabetic rats | 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 Protective effects of Suberoylanilide hydroxamic acid and Dapagliflozin administration on liver of diabetic rats Zaenah Zuhair Alamri, Sahar J. Melebary This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5015447/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Type 2 diabetes mellitus (T2DM) is common metabolic disorders. T2DM patients had 2-fold increase to get liver disorders. Evidence that some antidiabetic substances treated liver disorders in T2DM patients is evolving. Current study aimed to investigate hepatoprotective actions of Suberoylanilide hydroxamic acid (SAHA) and dapagliflozin (DAPA) in T2DM rats. Methods T2DM occured by high fat diet (HFD) and single Streptozotocin (STZ) injection (35 mg/kg i.p.). Forty rats sorted into 4 groups: NC (negative control), T2DM, T2DM + SAHA (5 mg/kg/i.p. for 8 weeks) and T2DM + DAPA (1mg/kg/p.o. for 8 weeks). At experimental end, levels of fasting blood glucose (FBG), fasting insulin, hepatic function tests [gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, albumin, total protein], lipid profiles [total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG)] measured in serum. Hepatic tissue homogenization prepared for estimating oxidative stress biomarkers [glutathione (GSH), malonaldehyde (MDA), superoxide dismutase (SOD)]. Hepatic histopathological examination made under light microscope. Results Diabetic rats had significant rise in liver weights and hepatic enzymes (AST, ALT, GGT, total bilirubin), lipid profile [TG, TC, LDL-C) in serum, and elevation in MDA in liver homogenate, but significant decline in total proteins, albumin, HDL-C) in serum and SOD, GSH in liver homogenate. These changes associated with histopathological changes in liver tissue as degeneration, vacuolation of hepatocytes, dilatation, and congestion of portal veins with lymphocytic infiltration. SAHA and DAPA treatment decreased liver weights, FBG, insulin, insulin resistance (IR), AST, ALT, GGT, bilirubin, TG, TC, LDL-C. SAHA and DAPA increased antioxidant enzymes (GSH, SOD) levels, serum total protein, albumin and HDL-C. Interestingly, DAPA was better that SAHA in improving liver enzymes, lipid profile, decreased FBG but SAHA was better in improving antioxidants as SOD, insulin levels and IR. Also, there were marked improvements in liver histopathological changes in SAHA and DAPA groups that were better in SAHA group. Conclusions Suberoylanilide hydroxamic acid and dapagliflozin represent an approach to protect liver versus DM-induced disorders via suppression oxidative stress, improve lipid profile, hyperglycemia and IR progression thus conserving liver functions and structure. Dapagliflozin liver protective effects rats Suberoylanilide hydroxamic acid type 2 diabetes mellitus Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction By 2045, there will likely be 700 million more diabetes mellitus (DM) patients worldwide than 463 million currently cases [ 1 ]. More than 90% of all people with diabetes are diagnosed with type 2 diabetes mellitus (T2DM), a complicated metabolic condition linked to insulin resistance (IR) and pancreatic dysfunction [ 2 ]. Chronic hyperglycemia with various causes and disorders in metabolism of fats, proteins, and carbohydrates are T2DM hallmarks. There is a strong correlation between chronic hyperglycemia and a high rate of complications, including liver disorders as cirrhosis, hepatocellular cancer, nonalcoholic fatty liver disease (NAFLD), acute liver cell failure and abnormal liver enzymes [ 3 ]. A number of microvascular and macrovascular problems may result from improper T2DM therapy and control [ 4 ]. Even with the abundance of antidiabetic drugs available, T2DM is still linked to a high rate of morbidity and death. Histone deacetylases (HDAC) and histone acetyltransferases (HAT) have drawn a lot of interest as crucial molecules involved in controlling a range of cellular responses and altering pathological situations [ 5 ]. Transcriptional activation and nucleosome relaxation follow chromatin structural alteration brought about by histone acetylation mediated by histone acetylation transferase (HAT). It follows that a crucial mechanism for epigenetic gene expression regulation is provided via nucleosome histone tails acetylation. Transcriptional repression, chromatin condensation, and de-acetylation are brought about by the opposite process that HDACs mediate [ 6 ]. Histone deacetylase enzymes have been the subject of several investigations throughout the last ten years because they have a pathogenic role in DM [ 6 ]. HDACs can epigenetically regulate carbohydrates and fatty acids metabolism by regulating many genes transcription. Classical HDACs could affect non-histone protein deacetylation, signal transducer, transcription 3 (STAT3) activation that leads to inhibition of gluconeogenesis enzymes expression. There is evidence linking diabetes mellitus (DM) to HDAC inhibitors (HDACi), which have been demonstrated to have positive actions on β-cell formation, differentiation, proliferation, and functions in addition to signaling of insulin [ 7 ]. Furthermore, in vivo and in vitro models of cytokine-induced β-cell destruction are prevented by HDACi [ 8 , 9 ]. Suberoylanilide hydroxamic acid (SAHA), commonly referred to as Vorinostat or Vorino, is an HDAC inhibitor with anti-inflammatory and antioxidant activities that primarily suppress Class II, I, and IV HDACs. It approved in 2006 for cutaneous T-cell lymphoma treatment [ 10 ]. SAHA had antidiabetic benefits in type 1 diabetes mellitus (T1DM) animal model [ 11 ]. SAHA prevents liver fibrosis in LX2 cells by blocking HDAC2, HDAC6, and HDAC8 proteins [ 6 ]. Sodium–glucose cotransporter-2 inhibitors (SGLT2is) were promising pharmaceuticals class for T2DM therapy because they improve insulin sensitivity, suppress gluconeogenesis, and reduce glucose reabsorption by blocking SGLT2 protein that included in 90% of glucose reabsorption [ 12 ]. The FDA originally authorized canagliflozin in 2013 and dapagliflozin (DAPA) in 2014 as SGLT2i [ 13 ]. In addition to their anti-hyperglycemic action, SGLT2i has been associated in several trials to improve hepatic function in individuals with T2DM [ 14 ]. Preclinical studies showed that SGLT2i decrease liver lipid accumulations [ 15 ] and decrease fat mass and body weights by enhancing fatty acids utilization instead of glucose as source of energy for metabolism [ 16 ]. Due to the insulin-independent mechanism of SGLT2i, individuals with insulin resistance or reduced pancreatic function may benefit from this family of drugs as an additional treatment. So, SGLT2is may be appropriate in treatment of T2DM [ 17 ]. This experimental research was conducted to study possible protective effects of histone deacetylase inhibitors (Suberoylanilide hydroxamic acid) and Sodium–glucose cotransporter-2 inhibitor (dapagliflozin) in vivo administration on liver of T2DM rat’s model and examine the underlying mechanism of their effects. Material and method Animals Forty adult male Albino rats weighing 250–300 gm and aged 8 weeks obtained from Animal house at Faculty of Pharmacy, King Abdulaziz University (KAU), Jeddah, Saudi Arabia. Rats kept in suitable laboratory status of light (12h light/dark cycle), temperature (25 ± 1°C), and humidity 60% with ad libitum access to distilled water and a rodent rat’s diet for one week before experiment start for acclimatization to laboratory condition. The experimental procedure made according to ARRIVE (Animal Research Reporting of In Vivo Experiments) and approved by Ethical Committee of King Abdulaziz University, Jeddah, Saudi Arabia. Chemicals and drugs Streptozotocin (STZ) bought from Sigma‑Aldrich (Sigma-Aldrich Co. St. Louis, Missouri, USA). STZ mixed in 0.1M citrate buffer (pH 4.4) and administered to rats intraperitoneally (i.p.). Suberoylanilide hydroxamic acid bought from Selleck Chemicals (Sigma-Aldrich Co. St. Louis, Missouri, USA), and mixed in vehicle of 10% dimethyl sulfoxide (DMSO), 45% polyethylene glycol 400 (PEG-400), 45% saline & administered i.p. Dapagliflozin bought from AstraZeneca Pharmaceutical Company (Cairo, Egypt), and put in 0.5% aqueous solution of carboxymethyl cellulose (CMC) and ingested oral via gastric lavage. Experimental design and induction of T2DM Forty rats randomly sorted equally into 4 groups as follows: first group was negative control (NC) that fed by regular chow diet (23% protein, 53% carbohydrate, and 5% fat) for 12 weeks. From week 4, NC group rats took 1 ml/kg daily i.p. injections of 10% DMSO, 45% PEG-400, 45% saline (vehicle of SAHA) and 1 ml/kg daily orally of CMC (vehicle of DAPA). All other rats (n = 30) were fed high fat diet (HFD) (normal diet + 2.5% cholesterol + 20% saccharose + 15% lard stearin) for 11 weeks and received at 3rd week a once STZ injection (35 mg/kg i.p.) for T2DM induction [ 18 ]. Three days followed STZ intake, fasting blood glucose (FBG) levels evaluated and animals showed FBG ≥ 250 mg/dl considered diabetic and included into research [ 19 ]. For more 8 weeks, HFD gave with the following therapy. Second group was T2DM and took saline [ 20 ]. Third group (T2DM + SAHA) received daily SAHA injection (5 mg/kg /i.p. for 8 weeks) [ 21 ]. Fourth group (T2DM + DAPA) received daily dapagliflozin (1mg/kg/p.o. for 8 weeks) [ 22 ]. Body weights of rats estimated at beginning of experiment and weekly using digital scale. Weight gain (%) calculated as final body weight – initial body weight divided by initial body weight then multiplied by 100. Food intake was calculated weekly and food efficiency ratio (FER) (%) calculated as weight gain (g/week) divided by intake of food (g/week) X 100. At experimental end, rats were fasted for 12 hours. Thiopental sodium (50 mg/kg) was used to anesthetize rats. Retro-orbital plexus, the orbital sinus, was the site of blood sample collection. Blood collected into plain tubes then left to coagulate for 20 minutes. Sera were obtained by centrifuging the blood for 15 minutes at 4000 rpm. The separated sera were stored frozen at -20°C in aliquots till used. Rats were died by cervical dislocation and livers isolated, washed with cold saline and weighed. Hepatic index (%) calculated as weight of liver divided by final body weight X 100. Liver was dissected into two halves. One liver half fixed in 10% formalin for histopathological evaluation under light microscopy. Other liver half washed with saline, frozen in liquid nitrogen, and kept at – 80°C till preparation of hepatic homogenates. Hepatic tissue homogenate preparation Half of liver homogenized in phosphate-buffered saline (PBS) to made 10% (w/v) homogenate utilized homogenizer (Omni International, Kennesaw, GA, USA). Homogenates further spun at 5,000g at 4°C for 15 min. Supernatants collected, aliquoted and storage at -20° for further measurement of oxidative stress biomarkers. Biochemical Measurements FBG was measured using colorimetric kit (catalog# ab282922) from Abcam (United Kingdom). Fasting serum insulin concentrations estimated by rat insulin enzyme-linked immunosorbent assay (ELISA) kit (catalog# MBS281388) from My BioSource (San Diego, USA) based upon manufacturer’s protocol. Assessment of IR carried out using homeostatic model assessment of insulin resistance (HOMA-IR) index. HOMA-IR = [fasting insulin (µU/ml) × fasting plasma glucose (mg/dl)]/405 [ 23 ]. Liver functions as alanine aminotransferase (ALT), total bilirubin, gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), total protein and albumin estimated by colorimetric method by available kits (Teco diagnostics, Cairo, Egypt). Serum levels of lipid profile as total cholesterol (TC), triglycerides (TG), high-density lipoprotein concentration (HDL-C) estimated by kits (Spectrum diagnostics, Cairo, Egypt) based upon manufacturer’s protocol. Low density lipoprotein concentration (LDL-C) calculated according to Friedewald formula: LDL-C = TC – [HDL-C + TG/5)] [ 24 ]. Values of malondialdehyde (MDA) (catalog# MBS268427), lipid peroxidation marker, and superoxide dismutase (SOD) (catalog# MBS036924) and glutathione (GSH) (catalog# MBS265966), markers of antioxidants estimated in hepatic homogenates by commercially available kits from MyBioSource, Inc. (San Diego, CA 92195 − 3308, USA) based upon manufacturer’s protocols. Histological examination The livers were examined closely for any noticeable alterations. Portions of left liver lobes prepped for light microscopy so that a liver histological assessment may be carried out. After being first preserved in a 10% neutral formalin solution, sample progressively dried out in 50% – 100% ethanol, cleaned in xylene, and then embedded into paraffin. Hematoxylin and eosin (HX&E) staining made after sections cut into 5 m thick portions. Slices of liver were analyzed by a skilled histopathologist using light microscopy to assess tissue alterations. Statistical Analysis Results presented as mean ± standard deviation (SD). Value analysis made using IBM Corporation's SPSS version 22 (Armonk, NY, USA). Shapiro-Wilk test employed to determine the normality of value distributions. Tukey's test is utilized to compare groups of normally distributed values after One-Way ANOVA has been used to analyze the data. Kruskal Wallis and Mann Whitney tests utilized to compare groups when values are abnormally distributed (weight increase, weight index, FER, liver weights, and liver indices). Statistical significance defined as a p < 0.050. Results Biological results Compared to NC group, there were significant increase in T2DM, T2DM + SAHA and T2DM + DAPA groups of final body weight ( p < 0.001, p < 0.001 and p < 0.010, respectively), Weight gain ( p < 0.001, p < 0.010 and p < 0.050, respectively) and weight gain percentage ( p < 0.001, p < 0.050 and p < 0.050, respectively). Food Efficiency Ratio (FER) significantly decreased in T2DM, T2DM + SAHA and T2DM + DAPA groups versus NC group ( p < 0.001, p < 0.010 and p < 0.050, respectively). The liver weight significantly decreased in T2DM + DAPA versus negative control ( p < 0.010). The hepatic index significantly increased in T2DM compared with NC and T2DM + DAPA groups ( p < 0.001 and p < 0.010) (Table 1 ). Table 1 Comparison of initial, final body weight, weight gain, Food Efficiency Ratio, liver weight and liver index in various studied groups. Variables NC group (n = 10) T2DM group (n = 10) T2DM + SAHA group (n = 10) T2DM + DAPA group (n = 10) Initial body weight (grams) 272.70 ± 45.97 232.80 ± 35.37 235.90 ± 29.12 252.10 ± 14.04 Final body weight (grams) 404.50 ± 50.31 248.40 ± 41.30 *** 287.40 ± 56.90 *** 308.20 ± 72.21 ** Weight gain (grams) 131.80 ± 55.23 15.60 ± 36.44 *** 51.50 ± 64.40 ** 56.10 ± 67.21 * Weight gain (%) 32.07 ± 11.69 5.32 ± 12.74 *** 15.35 ± 18.79 * 14.84 ± 17.05 * Food Efficiency Ratio (FER) (%) 0.051 ± 0.022 0.006 ± 0.014 *** 0.020 ± 0.024 ** 0.021 ± 0.026 * Liver weight (grams) 9.76 ± 1.16 8.75 ± 1.09 8.67 ± 1.33 6.98 ± 2.18 ** Liver index (%) 2.42 ± 0.16 3.62 ± 0.82 *** 3.17 ± 0.90 2.35 ± 0.77 ## Data expressed as mean +/- standard deviation. * : significance versus NC group; # : significance versus T2DM. *: P < 0.050, **: P < 0.010, ***: P < 0.001. Food intake at different weeks among different studied groups is shown in Fig. 1 . Glycemic control results At the 3rd week, FBG level was significantly increased in T2DM, T2DM + SAHA and T2DM + DAPA groups versus negative control ( p < 0.0001 for all). At the 11th week, blood glucose level significantly declined in T2DM + DAPA group versus T2DM and T2DM + SAHA groups (p < 0.001 for both) and in T2DM + SAHA versus T2DM (p = 0.029). Fasting insulin levels and HOMA-IR significantly elevated in T2DM, T2DM + SAHA and T2DM + DAPA groups versus negative control ( p < 0.0001 for all) but were significantly decreased in T2DM + SAHA and T2DM + DAPA groups versus T2DM group ( p < 0.0001 for all) and in T2DM + DAPA groups versus T2DM + SAHA ( p < 0.0001 for both) (Table 2 ). Table 2 Comparison of glycemic control in various studied groups. Variables NC group (n = 10) T2DM group (n = 10) T2DM + SAHA group (n = 10) T2DM + DAPA group (n = 10) Blood glucose (mg/dl) 3rd week 75.70 ± 7.60 395.20 ± 31.95 *** 403.70 ± 48.87 *** 410.90 ± 57.36 *** 11th week 78.90 ± 9.98 354.90 ± 22.57 *** 333.20 ± 7.50 ***,# 263.70 ± 20.82 ***,###,&&& Insulin (uIU/ml) 26.80 ± 2.30 85.40 ± 3.06 *** 42.50 ± 1.84 ***,### 75.30 ± 2.11 ***,###,&&& HOMA-IR 5.22 ± 0.76 74.94 ± 6.90 *** 34.97 ± 1.85 ***,### 49.01 ± 3.80 ***,###,&&& Data expressed as mean +/- standard deviation. * : significance versus NC group; # : significance versus T2DM, & : significance versus T2DM + SAHA group. *: P < 0.050, ***: P < 0.001. Liver function test results At experimental end, AST, ALT and GGT values were significantly increased in T2DM, T2DM + DAPA and T2DM + SAHA groups versus NC (p < 0.001 for all) and in T2DM versus T2DM + DAPA and T2DM + SAHA groups (p < 0.001 for all). Meanwhile, AST and ALT values were significantly decreased in T2DM + DAPA than T2DM + SAHA group (p < 0.001). Total bilirubin was significantly elevated in T2DM versus negative control, T2DM + SAHA and T2DM + DAPA (p < 0.001 for all) and in T2DM + DAPA versus negative control (p < 0.050). Total proteins levels declined in T2DM, T2DM + SAHA and T2DM + DAPA compared to NC (p < 0.001 for all); decreased in T2DM versus T2DM + SAHA and T2DM + DAPA (p < 0.001), declined in T2DM + DAPA versus T2DM + SAHA (p < 0.001). Albumin levels significantly decreased in T2DM and T2DM + DAPA versus NC (p < 0.001 for all); decreased in T2DM versus T2DM + SAHA and T2DM + DAPA (p < 0.001), declined in T2DM + DAPA than T2DM + SAHA (p < 0.001) (Table 3 ). Table 3 Comparison of liver function tests and lipid profile in various studied groups. Parameters NC group (n = 10) T2DM group (n = 10) T2DM + SAHA group (n = 10) T2DM + DAPA group (n = 10) AST (U/L) 116.10 ± 4.06 248.80 ± 4.32 *** 171.60 ± 8.58 ***,### 151.50 ± 6.77 ***,###,&&& ALT (U/L) 80.70 ± 2.31 150.60 ± 4.27 *** 127.50 ± 5.08 ***,### 115.40 ± 4.86 ***,###,&&& GGT (U/L) 5.98 ± 1.58 23.30 ± 2.41 *** 13.00 ± 1.83 ***,### 13.90 ± 1.29 ***,### Total bilirubin (µmol/L) 5.58 ± 0.56 8.36 ± 0.80 *** 5.94 ± 0.39 ### 6.38 ± 0.41 *,### Total protein (mg/dl) 72.16 ± 2.36 32.30 ± 2.50 *** 48.60 ± 2.91 ***,### 43.90 ± 2.42 ***,###,&&& Albumin (mg/dl) 45.20 ± 2.65 23.50 ± 1.78 *** 42.50 ± 3.44 ### 33.90 ± 2.42 ***,###,&&& Triglyceride (mg/dl) 132.90 ± 2.96 375.00 ± 9.13 *** 314.00 ± 12.65 ***,### 265.00 ± 15.81 ***,###,&&& Total cholesterol (mg/dl) 93.70 ± 3.06 258.70 ± 7.67 *** 191.00 ± 13.29 ***,### 136.50 ± 9.73 ***,###,&&& LDL-C (mg/dl) 44.70 ± 3.20 151.10 ± 7.81 *** 74.90 ± 7.17 ***,### 77.80 ± 4.21 ***,### HDL-C (mg/dl) 72.30 ± 2.71 32.60 ± 3.95 *** 36.10 ± 4.12 *** 36.00 ± 4.62 *** Data expressed as mean +/- standard deviation. * : significance versus NC group; # : significance versus T2DM, & : significance versus T2DM + SAHA group. *: P < 0.050, ***: P < 0.001. Lipid profile results At experimental end, Triglyceride, total cholesterol, LDL-C values significantly elevated in T2DM, T2DM + DAPA and T2DM + SAHA groups versus NC (p < 0.001) and in T2DM versus T2DM + DAPA and T2DM + SAHA groups (p < 0.001 for all). Triglyceride and total cholesterol serum values were significantly increased in T2DM + SAHA versus T2DM + DAPA (p < 0.001). HDL-C values were significantly declined in T2DM, T2DM + DAPA and T2DM + SAHA groups versus NC (p < 0.001 for all) (Table 3 ). Oxidative stress results At experimental end, MDA liver homogenate levels were significantly elevated in T2DM, T2DM + DAPA and T2DM + SAHA groups versus NC (p < 0.001 for all) and in T2DM versus T2DM + DAPA and T2DM + SAHA groups (p < 0.001 for both). SOD and GSH liver homogenate values were significantly declined in T2DM, T2DM + DAPA and T2DM + SAHA groups versus NC (p < 0.001 for all); decreased in T2DM versus T2DM + DAPA and T2DM + SAHA groups (p < 0.001 and p < 0.050). Meanwhile, SOD value was significantly increased in T2DM + SAHA versus T2DM + DAPA (p < 0.001) (Table 4 ). Table 4 Comparison of oxidative stress markers in various studied groups. Parameters NC group (n = 10) T2DM group (n = 10) T2DM + SAHA group (n = 10) T2DM + DAPA group (n = 10) MDA (nmol/ml) 9.67 ± 3.33 23.54 ± 2.38 *** 15.31 ± 2.14 ***,### 17.55 ± 1.82 ***,### SOD (U/ml) 17.93 ± 2.11 9.11 ± 1.37 *** 14.40 ± 0.71 ***,### 10.93 ± 1.15 ***,#,&&& GSH (U/L) 315.99 ± 13.04 225.01 ± 11.60 *** 267.27 ± 7.25 ***,### 277.01 ± 10.72 ***,### Data expressed as mean +/- standard deviation. * : significance versus NC group; # : significance versus T2DM, & : significance versus T2DM + SAHA group. *: P < 0.050, ***: P < 0.001. Histology results The livers of healthy control rats were examined using HX and E staining, and the results showed a typical hepatic shape with the liver split into classic hepatic lobules. Hepatocyte cords that extend outward from central vein to lobule's perimeter make up the classic lobule. Loose stromal connective tissue envelops portal triads, also known as tracts, which are dispersed at the corners of lobules. The polyhedral hepatocytes had one or two conspicuous nucleoli, a clear vesicular spherical nucleus, and a highly eosinophilic cytoplasm speckled with basophilic granules. Binucleation of hepatocytes occurs often. Flat endothelial cells line central vein, and statistically significant hepatic blood sinusoids found between endothelial cell-lined hepatic cell cords and von Kupffer cells with ovoid nuclei (Fig. 2 a). Peripherally each lobule has three to six portal areas with more fibrous connective tissue, each of which has three interlobular structures that comprise portal triad or portal tracts, portal vein, hepatic artery and one or two small branches of bile ducts lined with cuboidal epithelium (Fig. 2 .b). Rats of diabetic group showed severe damage in rat liver. The most significant alterations were disorderly hepatocyte, inflammatory, degenerative, necrotic, nucleus karyolysis and hyperplastic changes. Liver showed degenerations and vacuolation of hepatocytes and some of them exhibited one large cytoplasmic vacuole. Severe infiltrative fatty changes in form of more well-defined fat droplets occupying hepatocytes cytoplasm, pushing nucleus to periphery (Fig. 3 a). Also, multiple inflammatory cells appeared. Hydropic degeneration of hepatocytes was observed around dilated central vein. Central vein showed dilatation and congestion with leukocytic infiltrations around it (Fig. 3 b). There were many localized necrotic regions with extensively vacuolated hepatocyte cytoplasm and strongly stained pyknotic nuclei, together with a noticeable infiltration of mononuclear cells or widespread hepatic coagulative necrosis (Figs. 3 a,b). Portal tract showed congested and dilated portal vein and mononuclear leucocytic cell infiltrations around portal vein (Fig. 3 c). Treated diabetic groups with SAHA showed improvement in hepatic histological structure. Amelioration of hepatocytes, and alleviate inflammation, leucocytic cell infiltration, necrotizing hepatocytes, which is produced by STZ. Liver tissue kept its normal hepatic shape with radiating hepatic cell cords and central veins to some extent similar to negative control group (Fig. 4 a). Most of hepatocytes appeared polyhedral with strongly eosinophilic cytoplasm dotted with basophilic granules, and distinct vesicular rounded nuclei and one or two prominent nucleoli. Central vein is lined with flat endothelial cells and hepatic blood sinusoids were noticed between hepatic cell cords lined with endothelial cells and von Kupffer cells. Portal tract showed normal bile duct, hepatic artery and portal vein (Fig. 4 b). Regarding diabetic rat treated with DAPA showed moderate improvement in liver histological structure. Liver tissue preserved to some extent its normal hepatic shape with central veins and radiating hepatic cell cords to some extent as negative control group. Most of hepatocytes appeared polyhedral with eosinophilic cytoplasm dotted with basophilic granules, and vesicular rounded nuclei. Central vein is lined with flat endothelial cells and hepatic blood sinusoids noticed between hepatic cell cords lined with endothelial cells. Portal tracts showed normal histological structure as that of control group (Figs. 5 a,b). Some specimens still showed moderate fatty infiltrative changes where smaller well-defined fat droplets occupying hepatic cytoplasm with loss of normal architecture of liver tissue and mononuclear cell infiltration's (Figs. 5 c,d). Discussion T2DM-related metabolic abnormalities may cause liver damage, which may ultimately lead to a number of liver illnesses, including cirrhosis, hepatocellular carcinoma, and fatty liver [ 25 ]. Numerous variables, including hyperglycemia, insulin resistance, dyslipidemia, oxidative stress, and inflammations, can lead to diabetic liver damage [ 25 ]. In this study, HFD/STZ utilized to induce a T2DM liver damage rat model [ 26 ]. The results of this research revealed that, final body weight, weight gain, weight gain percentage and FER declined in T2DM group compared to negative control group. In this respect, According to Zhu et al., T2DM rat group's body weight dramatically dropped while their intake of food, water, and urine volume were significantly elevated [ 26 ]. Lower body weight in T2DM is due to catabolic state of poorly controlled glycaemia. Under these conditions, lipolysis, metabolic processes, and oxidative degradation of amino acids elevated; they degrade greatest energy and tissue reserves in animal, so decreasing body weights [ 27 ]. In this study, body weights in diabetic rats were not improved by administration of SAHA or DAPA to diabetic rats, which may be caused by continuous catabolic condition. SAHA appears to have complex effects on body weight. While some metabolic alterations and adverse consequences, such as anorexia, were noted in preclinical and clinical trials, significant weight changes were not always recorded [ 28 , 29 ]. This suggests that not all circumstances and dose ranges will result in a consistent or direct effect of SAHA on body weight. In the meantime, osmotic drainage brought on by the glycosuria brought on by DAPA alters body composition, resulting in a decrease in body fat and body weight loss. According to Phrueksotsai et al., DAPA prescription resulted in significant decline in body weight and body fats after 12 weeks of therapy, with a mean 3% decrease in baseline body weights. Furthermore, correlation analysis showed a significant positive relationship between weight loss and decrease in liver fat content [ 30 ]. Ahmed et al. found that total body weight was declined in three groups of rats that received three different DAPA doses (0.75, 1.5 and 3 mg/kg, p.o.) than negative and diabetic control groups [ 31 ]. Liver index in this research was significantly increased in T2DM versus negative control and T2DM + DAPA groups. Zhu et al. reported that the liver indices were significantly increased in T2DM rat’s model [ 26 ]. In this study, the liver weight significantly decline in T2DM + DAPA versus negative control. DAPA medication significantly reduces total liver fat content in T2DM patients [ 32 ]. In addition to decreased body weight, metabolic substrate shift from glucose to fatty acids and likely higher hepatic oxidation of fatty acids are other theories explaining the loss of liver fat [ 33 ]. This study showed that at experimental end FBG level, fasting insulin level and HOMA-IR significantly elevated in T2DM group versus negative control as previously reported [ 26 , 34 ]. In rats, HFD causes IR [ 26 ]. The results of this research showed that FBG, fasting insulin, HOMA-IR was significantly decreased T2DM + SAHA versus T2DM but were still significantly elevated than negative control group. Bocchi et al. reported that injection of SAHA (25 mg/kg i.p.) for 23 days into mice leads to improved sensitivity to insulin [ 35 ]. Silva et al. reported that injection of SAHA (25–50 mg/kg i.p.) for 8 weeks into HFD fed mice with leads to ameliorate insulin sensitivity [ 36 ]. In the mesenchymal stem cell model MG63, SAHA was shown to affect the formation of β-cells and improve insulin production by upregulating transcription factor PDX1 expression. Additionally, pretreatment with SAHA increased β-cell markers in response to high glucose challenges, indicating that it may improve stem cells' ability to develop into β-cells that produce insulin [ 37 ]. Histones, other regulatory proteins and different transcription factors that either indirectly or directly included in metabolism of glucose are deacetylated by HDACs. Furthermore, histone acetylation regulates the glucose-mediated regulation of insulin gene transcription, indicating HDACs involvement in manufacture and function of insulin [ 38 ]. The results of this research revealed that therapy of diabetic rats with DAPA led to decline in FBG, fasting insulin, HOMA-IR versus T2DM but were still significantly higher than negative control group. In DAPA treated diabetic rats, FBG was significantly decline, but fasting insulin and HOMA-IR were increased versus SAHA treated diabetic group. Tang et al. reported that after four weeks of therapy, there was decline in blood glucose values and an increase in urine glucose excretion with DAPA [ 39 ]. Joannides et al. reported that DAPA administration for 45 days into PEPCK transgenic rats caused reduced plasma glucose and insulin values due to improve IR, elevated fat and muscle glucose uptake and GLUT4 protein values, and decreased size of adipocyte and elevated number of adipocyte, but not elevated secretion of insulin [ 40 ]. HFD/STZ -induced diabetic mice treated with DAPA showed improved glucose tolerance, IR and insulin secretion, with a significant elevation in insulin content of pancrease [ 41 ]. Liver was affected in T2DM rat models in this study as revealed by increased ALT, AST, GGT, total bilirubin, and decline in total protein and albumin versus negative control group. Zhu et al. reported ALT and AST values were significantly elevated in T2DM rats model [ 26 ]. SAHA administration to diabetic rats had protective effect on liver as revealed in this study by decreased AST, ALT, GGT, total bilirubin and significant increase in total protein and albumin. SAHA has protective effect on liver damage produced by lethal hemorrhagic shock in rats that was associated with elevated H3K9 acetylation and suppression of JNK/caspase-3 apoptotic pathway [ 42 ]. SAHA administration significantly reduced serum values of AST, ALT, and lactate dehydrogenate, increased the survival rate and decreased apoptotic markers expression in liver tissues, suggesting its protective role in early hemorrhagic shock conditions [ 43 ]. Wang et al. found that in rats carbon tetrachloride (CCl4) significantly made liver fibrosis and elevated serum values of transforming growth factor (TGF)-β1, total bilirubin, ALT, AST, laminin, and procollagen type III; liver HDAC2, p-Smad2/3, HDAC6, HDAC8, α-SMA and connective tissue growth factor (CTGF) proteins; whereas Smad7 mRNA and AH3 protein levels were notably suppressed. SAHA treatment significantly downregulated, these liver chemistries, cytokines and liver fibrosis-related genes and mitigated hepatic fibrosis [ 44 ]. Alhaddad et al. reported that SAHA administration (15 mg/kg/day p.o.) for 8 weeks to rat model of autoimmune hepatitis made by Concanavalin A led to decreased in AST and ALT liver enzymes [ 45 ]. DAPA administration to diabetic rats had protective effect on liver as revealed in this study by decreased ALT, AST, GGT, total bilirubin and significant increase in albumin and total protein. Dapagliflozin therapy protected the liver in db/db mice, as revealed by markedly lower levels of oxidative stress and inflammatory indicators, hepatic lipid buildup, and plasma ALT activity and TG levels [ 39 ]. DAPA markedly reduced ALT and AST serum levels and protected liver from pathologic damages in diabetic mice [ 46 ]. A clinical trial utilizing DAPA in T2DM patients revealed reduced values of liver damage biomarkers, as ALT, AST, and GGT; combining carboxylic acids (OM-3CA) resulted in a significant decline in hepatic fat content [ 32 ]. DAPA led to ALT-lowering effect by decrease liver fat deposition by making hyperglucagonemia [ 47 ] and ameliorate IR caused by decreased ectopic steatosis [ 48 ]. Dyslipidemia is considered a major cardiovascular disorders risk factor resulting in myocardial infarction, sudden cardiac arrest, and death. In this study, significant increase in serum TC, TG and LDL-C values accompanied by decline in serum HDL-C value were demonstrated in T2DM rats versus control group as reported by others [ 26 , 34 ]. IR and dyslipidemia are important risk factors of diabetic hepatic damage [ 25 ]. In this study, treatment of diabetic rats with SAHA led to a significant decreased in serum TG, TC and LDL-C values compared to T2DM rats but were still significantly elevated versus control group. SAHA intake did not improve levels of HDL-C. SAHA exhibits significant anti-inflammatory effects by reducing pro-inflammatory cytokines production as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon gamma. These cytokines are known to influence metabolic processes, including lipid metabolism [ 49 ]. HDACs inhibition by SAHA affects various signaling pathways and gene expressions related to lipid biosynthesis and metabolism as lipoxygenases [ 50 ]. The induction of 15-lipoxygenase-1 by SAHA, for example, correlates with significant changes in lipid metabolism [ 51 ]. However, direct studies specifically focusing on serum lipid profiles post-SAHA treatment are limited, indicating a need for more targeted research in this area. In this study, treatment of diabetic rats with DAPA led to a significant decreased in serum TG, TC and LDL-C values versus T2DM rats but were still significantly elevated than control group. Decline in TG and TC levels were more effective that SAHA administration. Meanwhile, DAPA administration did not improve HDL-C levels. Leng et al. found that DAPA decreased the values of TG and free fatty acids (FFAs) in liver and serum, which correlated with decreased lipotoxicity in diabetic mice [ 46 ]. Hazem et al. reported lower liver weights and decreased serum values of TG and TC in rats received DAPA [ 52 ]. Ahmed et al. reported that TC and TG were decreased in three groups that received three different DAPA doses (0.75, 1.5 and 3 mg/kg, p.o.) for 6 weeks more than negative and diabetic control groups [ 31 ]. This reduction in TC and TG may be attributed to the total reduction in body weight or may be explained by shift of metabolic substrate from glucose to fatty acids [ 53 ]. The development of T2DM and its consequences, as well as IR, are significantly affected by oxidative stress. Reactive oxygen species (ROS) produced by dyslipidemia and hyperglycemia may damage live cells and certain cell membrane receptors, which may lead to damage to organs including liver [ 54 ]. The results of this research showed elevation of MDA and decrease in SOD and GSH in diabetic rats versus negative control group. Researches revealed that tissue homogenate GSH concentrations in STZ-induced diabetic rats significantly decline versus negative control rats [ 55 , 56 ]. Decline GSH and SOD values in diabetic rats caused by its increased consumption that is required to relieve oxidative stress. Zhu et al. revealed that oxidative stress and inflammation significantly elevated in hepatic homogenates of T2DM rats [ 26 ]. Hazem et al. revealed that diabetic group had much lower values of GSH, SOD, and catalase and significantly greater amounts of MDA [ 52 ]. By further reducing tissue oxidative stress, tight glycemic control or add-on techniques which block oxidative stress to antihyperglycemic medications might improve capacity to prevent disease development in organ damage due to diabetes [ 39 ]. In this study, diabetic rats that received SAHA showed significant decrease in MDA but elevation of SOD and GSH hepatic homogenate levels versus T2DM rats. Bakhdar et al. reported that SAHA administration to Wistar rats (15 mg/kg/day i.p.) for 28 days led to pancreatic protection via anti-inflammatory and antioxidant actions [ 57 ]. SAHA was shown to reduce hepatic cellular injury and ROS production in lipopolysaccharide (LPS)-induced liver damage. It enhanced the antioxidant enzyme GSH and inhibited apoptotic signaling pathways, suggesting its potential in alleviating inflammatory liver conditions [ 43 ]. In this study, diabetic rats that received DAPA showed significant decrease in MDA but elevation of SOD and GSH hepatic homogenate levels versus T2DM rats. The effect of SAHA in elevation of SOD hepatic homogenate level was better than DAPA. Hazem et al. provides evidence for hepatoprotective effects of DAPA, as seen by the dose-dependent increases in antioxidant enzymes SOD, catalase activity, and GSH and decline in MDA levels [ 52 ]. In Kashiwagi study, the SOD activity was significantly improved after 8 weeks of diabetic group treatment with insulin in addition to dapagliflozin [ 58 ]. The results of this research suggest that dapagliflozin significantly improved antioxidant status in diabetic rats. The treatment's antihyperglycemic impact, which lessens the load of oxidative stress, might be the cause of this improvement. In this study, diabetic rats showed severe liver damage. The most significant alterations in diabetic control rat liver were disorderly hepatocyte, inflammatory, degenerative, necrotic, nucleus karyolysis and hyperplastic changes. These findings are in accord with those of Ahmed et al. who found that in diabetic, liver severe infiltrative fatty changes in form of more well-defined fat droplets occupying cytoplasm of hepatocytes, pushing nucleus to periphery. Also, multiple inflammatory cells appear with loss of normal architecture of hepatocytes [ 31 ]. Also, Salih et al. [ 59 ] observed that in STZ-diabetic mice showed more progressive changes, sever congestion, necrotic foci, hydropic changes, fatty changes in hepatocytes and aggregation of lymphocytes between the hepatocytes. Furthermore, additional research has documented damage to the liver cells, sinusoidal dilatation in the central venous region, elevated cell apoptosis, and elevated lipid droplets in the liver cells of diabetic mice [ 60 ]. By activating NF-B that stimulates pro-apoptotic genes activity in liver cells and increases the creation of ROS, hyperglycemia circumstances will aggravate the process of liver damage by inducing oxidative stress and inflammatory conditions [ 61 ]. Our results showed that treated diabetic groups with SAHA showed improvement in liver histological structure. Amelioration of hepatocytes, and alleviate inflammation, leucocytic cell infiltration, necrotizing hepatocytes, which is produced by STZ. So, hepatic tissue maintained its normal hepatic lobular shape with central veins and radiating hepatic cell cords to some extent similar to negative control group. Zhao et al. [ 62 ] evaluate SAHA-mediated protection against LPS-induced hepatic damage using histological examination. As predicted, the 24-hour LPS exposure significantly increased the inflammatory response in the murine liver. This was demonstrated by the inflammatory cells' growing penetration into parenchyma, where necrotic and apoptotic hepatocyte cell death were noted. Compared to LPS alone group, liver architecture was better conserved in the mice treated with SAHA following an LPS injection. SAHA prevented ROS from being produced by LPS and stopped the antioxidant enzyme glutathione from declining due to STZ. Additionally, SAHA reduced the hepatic apoptosis caused by STZ. Additionally, SAHA prevented the activation of mitogen-activated protein kinases p38 and Jun N-terminal kinase, as well as redox-sensitive kinase and apoptosis signal-regulating kinase-1 [ 62 ]. Our findings demonstrate that SAHA can mitigate the hepatotoxicity caused by STZ and imply that a novel therapeutic approach for treating STZ-induced inflammatory conditions could involve blocking the upstream processes necessary for the function of apoptotic signal-regulating kinase-1. Also, Bocchi, et al. [ 63 ] discovered that by lowering cell oxidative damage, SAHA therapy might reverse the initial functional aberration in cardiomyocytes. After being exposed to SAHA, diabetic cardiomyocytes (CMs) showed a simultaneous reduction in metabolic status, namely NAD(P)H dehydrogenase activities and ROS values. This finding raises the possibility of a mechanistic relationship between changed ROS generation and cell metabolism. In diabetic cells, SAHA aids in the restoration of proper redox signaling, which is necessary for maintaining homeostasis of cardiomyocyte and is implicated in heart's action to stress [ 64 ]. The present research showed that diabetic rat reveived DAPA showed in some specimens, moderate improvement in liver histological structure. On the other hand, some specimens still showed moderate fatty infiltrative changes with droplets of fats occupying hepatocytes cytoplasm and loss of normal architecture of liver tissue accompanying mononuclear cell infiltrations. Our data agree with the results of Ahmed et al. [ 31 ] who noticed that diabetics on DAPA (0.75 mg/kg), section of rat liver tissue showed mild to moderate fatty infiltrative changes where smaller well-defined fat droplets occupying hepatic cytoplasm with loss of liver tissue normal architecture. Diabetic rats on DAPA 1.5 and 3 mg/kg groups: section of rat hepatic tissue revealed improvement of fatty infiltrative alteration with normal hepatocytes around central vein and normal liver tissue architecture. Hazem et al. [ 52 ] observed that DAPA represent a viable approach to protect liver versus diabetes-induced steatohepatitis via suppressing oxidative stress, fibrosis progression and inflammation thus conserving hepatic functions and structure. Conclusions In conclusion, this research confirms that SGLT2 inhibition via DAPA and HDAC inhibition by SAHA decrease blood glucose level and protective in slowing the progression of liver damage in T2DM rats by improve IR and lipid profile and reduced tissue oxidative stress. The effect of DAPA was better than SAHA in decreasing fasting blood glucose level and improving lipid profile; while SAHA was better than DAPA in improving insulin secretion and IR and increased antioxidant and improvement of hepatic tissue damage. These findings suggest that selective SGLT2i and HDACi could be utilized in combination with other oral anti-diabetes drugs and insulin to further improve glycemic control and reverse organ damage in T2DM. Declarations Authorship contribution ZZA Resources, Conceptualization, Methodology, Writing – original draft, Preparation– review & editing. SIM Methodology, Resources, Writing – original draft, and editing. Both authors approved manuscript for publication. Conflict of interest Authors state that none of known financial conflicts or interpersonal ties that may have looked to have an impact on work described in this article. Funding This is a self-funded research. Declarations Ethics approval Research made after getting ethical approval from Ethical Committee of King Abdulaziz University, Jeddah, Saudi Arabia. Consent for publication Not applicable. Competing interests Authors declare that they had no competing interests. References Teo ZL, Tham Y-C, Yu M, Chee ML, Rim TH, Cheung N, et al. (2021) Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. 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(2013) Antioxidant status and organ function in streptozotocin-induced diabetic rats treated with aqueous, methanolic and petroleum ether extracts of Ocimum basilicum leaf. Journal of Applied Pharmaceutical Science. 3(4):S75. Chen Y, Du J, Zhao YT, Zhang L, Lv G, Zhuang S, et al. (2015) Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovascular diabetology. 14:1–13. Bocchi L, Motta BM, Savi M, Vilella R, Meraviglia V, Rizzi F, et al. (2019) The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Restores Cardiomyocyte Contractility in a Rat Model of Early Diabetes. International journal of molecular sciences. 20(8). https://doi.org/10.3390/ijms20081873 Santos CX, Anilkumar N, Zhang M, Brewer AC, Shah AM (2011) Redox signaling in cardiac myocytes. Free radical biology & medicine. 50(7):777–93. https://doi.org/10.1016/j.freeradbiomed.2011.01.003 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5015447","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":351933441,"identity":"3d4c711d-6807-45d0-bcfd-600cc09fdabb","order_by":0,"name":"Zaenah Zuhair Alamri","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIie3OvQrCMBSG4RMKdUlxraDmFgIFFwdv5Ti5OAiCcye7KFl7Gy6dUwK6iHMniRcgOOogeNrJqT+bYN7hTHn4AuBy/WZM0+F9AATwW5qKDOKuBGR12xChjNWv5XUYFWjhsTEgEl1PWHyU+T5b80mByNKLAXnGeuKxWOogw4p4wZYINBDf6z3yN5EoJfImIpStJ9zn0pQrMiTCiEDRsBJyvjIjIuHZYr67LLgsGlaEOh1u9wxn/WQ5t8/NdCxUw8r3H1GXt/V7qqe7vHa5XK4/6gPCbkRh++LjrgAAAABJRU5ErkJggg==","orcid":"","institution":"University of Jeddah","correspondingAuthor":true,"prefix":"","firstName":"Zaenah","middleName":"Zuhair","lastName":"Alamri","suffix":""},{"id":351933444,"identity":"cc134044-4495-4fba-af4e-f32ce749180f","order_by":1,"name":"Sahar J. Melebary","email":"","orcid":"","institution":"University of Jeddah","correspondingAuthor":false,"prefix":"","firstName":"Sahar","middleName":"J.","lastName":"Melebary","suffix":""}],"badges":[],"createdAt":"2024-09-02 05:00:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5015447/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5015447/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66942604,"identity":"1a1728ea-1d18-46c7-aa91-3b1e9f463c6b","added_by":"auto","created_at":"2024-10-18 09:10:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23562,"visible":true,"origin":"","legend":"\u003cp\u003eFood intake in different studied groups at different weeks.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-5015447/v1/1a8d381155d4ca0c0614ba2b.png"},{"id":66942605,"identity":"a2aa485f-7007-4637-abb5-13f075850c1a","added_by":"auto","created_at":"2024-10-18 09:10:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":758497,"visible":true,"origin":"","legend":"\u003cp\u003eA photomicrograph in the control rat liver (NC) stained with HX\u0026amp;E stain showing;\u003c/p\u003e\n\u003cp\u003e(a) Thin walled central vein (CV) lined with flat endothelial cells (white arrow) and normal hepatocytes (H) with rounded vesicular nuclei (N) and eosinophilic cytoplasm with basophilic granules. Some cells are binucleated. Note: thin walled blood sinusoids (S) between hepatocyte cell cords lined with endothelial cells (black arrows) and von Kupffer cells(blue arrows). (X400 HX\u0026amp;E). Scale Bar 30 um.\u003c/p\u003e\n\u003cp\u003e(b) Portal tract (PT) contained branch of hepatic artery (HA), branch of portal vein (PV) and bile duct (BD). Hepatocytes with eosinophilic cytoplasm (H) and rounded vesicular nuclei (N) were observed. (X400 HX\u0026amp;E). Scale Bar 30 um.\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-5015447/v1/941a0bc36d101c2d214a6fab.png"},{"id":66943037,"identity":"d7f3cac2-ec3b-4dd6-b257-004757a11f77","added_by":"auto","created_at":"2024-10-18 09:18:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1048412,"visible":true,"origin":"","legend":"\u003cp\u003ePhotomicrograph of T2DM group liver stained HX\u0026amp;E stain showing;\u003c/p\u003e\n\u003cp\u003e(a) Degeneration and vacuolation of hepatocytes (H) with deeply stained pyknotic nuclei (red arrows) and appearance of large one vacuole inside most hepatocytes (*) (severe infiltrative fatty changes). Note: blood sinusoids (S) with lining endothelial cells (black arrows) and central vein (CV). (HX\u0026amp;E – X400). Scale Bar 30 um.\u003c/p\u003e\n\u003cp\u003e(b) Dilatation and congestion of central vein (CV) with mononuclear cellular infiltrations around central vein (blue arrow). Note: degeneration and vacuolation of hepatocytes (H) (Fatty changes) with deeply stained pyknotic nuclei (black arrows). (HX\u0026amp;E – X400). Scale Bar 30 um.\u003c/p\u003e\n\u003cp\u003e(c) Dilatation and congestion of portal vein (PV) associated with lymphocytic infiltrations (blue arrow) around portal vein. Degeneration and vacuolation of hepatocytes (H) with deeply stained pyknotic nuclei (black arrows) were observed. Note: hepatic artery (HA) and bile duct (BD) (HX\u0026amp;E – X400). Scale Bar 30 um.\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-5015447/v1/1d6691ac8db0fbcd547fbb09.png"},{"id":66942606,"identity":"c9d8a69c-7210-44aa-a3a7-852bf40eb087","added_by":"auto","created_at":"2024-10-18 09:10:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":693536,"visible":true,"origin":"","legend":"\u003cp\u003eA photomicrograph in T2DM+SAHA group liver stained with HX\u0026amp;E stain showing;\u003c/p\u003e\n\u003cp\u003e(a) Improvement in liver histological structure with normal hepatocytes (H) exhibited eosinophilic cytoplasm and rounded vesicular nuclei (black arrows) radiating from central vein (CV). Note: blood sinusoids (S) lined with flat endothelial cells (blue arrows) (X400 HX\u0026amp;E).Scale Bar 30 um.\u003c/p\u003e\n\u003cp\u003e(b) Normal portal vein (PV), bile duct (BD) and hepatic artery (HA). Improvement in liver histological structure with normal hepatocytes (H) exhibited eosinophilic cytoplasm and rounded vesicular nuclei (black arrows). Note: blood sinusoids (S) lined with flat endothelial cells (blue arrows) (X400 HX\u0026amp;E).Scale Bar 30 um.\u003c/p\u003e","description":"","filename":"Slide4.png","url":"https://assets-eu.researchsquare.com/files/rs-5015447/v1/9e6e3c5868ff3402e7b185ab.png"},{"id":66942609,"identity":"1061dddb-f812-4d32-bec1-2dcf08c50f97","added_by":"auto","created_at":"2024-10-18 09:10:33","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1412786,"visible":true,"origin":"","legend":"\u003cp\u003eA photomicrograph in T2DM+DAPA liver stained with HX\u0026amp;E stain showing;\u003c/p\u003e\n\u003cp\u003e(a) Improvement in hepatic histological structure with normal hepatocytes (H) exhibited eosinophilic cytoplasm and rounded vesicular nuclei (black arrows) radiating from central vein (CV). Note: normal blood sinusoids (S) lined with flat endothelial cells (HX\u0026amp;E – X400). Scale Bar 30 um.\u003c/p\u003e\n\u003cp\u003e(b) Normal portal vein (PV), bile duct (BD) and hepatic artery (HA). Improvement in liver histological structure with normal hepatocytes (H) exhibited eosinophilic cytoplasm and rounded vesicular nuclei (black arrows). Note: normal blood sinusoids (S) lined with flat endothelial cells (blue arrows) (HX\u0026amp;E – X400). Scale Bar 30 um.\u003c/p\u003e\n\u003cp\u003e(c) Some hepatocytes (H) showed moderate fatty infiltration in their cytoplasm (*) and mononuclear cell infiltration's (white arrow) between hepatocytes (HX\u0026amp;E – X400). Scale Bar 30 um.\u003c/p\u003e\n\u003cp\u003e(d) \u0026nbsp;In some specimens, hepatocytes (H) around central vein (CV) showed fatty infiltration in their cytoplasm (*) with deeply stained pyknotic nuclei (black arrows) and mononuclear cell infiltration's (blue arrows) (HX\u0026amp;E – X400). Scale Bar 30 um.\u003c/p\u003e","description":"","filename":"Slide5.png","url":"https://assets-eu.researchsquare.com/files/rs-5015447/v1/b2f02b6582a3834d4a09ff91.png"},{"id":76872990,"identity":"ff7d0896-65f6-49cb-b3b8-a5df7a116bb4","added_by":"auto","created_at":"2025-02-21 15:38:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5195791,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5015447/v1/29a81c7f-1811-4838-9f57-de8043b95b54.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Protective effects of Suberoylanilide hydroxamic acid and Dapagliflozin administration on liver of diabetic rats","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBy 2045, there will likely be 700\u0026nbsp;million more diabetes mellitus (DM) patients worldwide than 463\u0026nbsp;million currently cases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. More than 90% of all people with diabetes are diagnosed with type 2 diabetes mellitus (T2DM), a complicated metabolic condition linked to insulin resistance (IR) and pancreatic dysfunction [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Chronic hyperglycemia with various causes and disorders in metabolism of fats, proteins, and carbohydrates are T2DM hallmarks. There is a strong correlation between chronic hyperglycemia and a high rate of complications, including liver disorders as cirrhosis, hepatocellular cancer, nonalcoholic fatty liver disease (NAFLD), acute liver cell failure and abnormal liver enzymes [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A number of microvascular and macrovascular problems may result from improper T2DM therapy and control [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Even with the abundance of antidiabetic drugs available, T2DM is still linked to a high rate of morbidity and death.\u003c/p\u003e \u003cp\u003eHistone deacetylases (HDAC) and histone acetyltransferases (HAT) have drawn a lot of interest as crucial molecules involved in controlling a range of cellular responses and altering pathological situations [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Transcriptional activation and nucleosome relaxation follow chromatin structural alteration brought about by histone acetylation mediated by histone acetylation transferase (HAT). It follows that a crucial mechanism for epigenetic gene expression regulation is provided via nucleosome histone tails acetylation. Transcriptional repression, chromatin condensation, and de-acetylation are brought about by the opposite process that HDACs mediate [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Histone deacetylase enzymes have been the subject of several investigations throughout the last ten years because they have a pathogenic role in DM [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. HDACs can epigenetically regulate carbohydrates and fatty acids metabolism by regulating many genes transcription. Classical HDACs could affect non-histone protein deacetylation, signal transducer, transcription 3 (STAT3) activation that leads to inhibition of gluconeogenesis enzymes expression. There is evidence linking diabetes mellitus (DM) to HDAC inhibitors (HDACi), which have been demonstrated to have positive actions on β-cell formation, differentiation, proliferation, and functions in addition to signaling of insulin [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Furthermore, \u003cem\u003ein vivo\u003c/em\u003e and \u003cem\u003ein vitro\u003c/em\u003e models of cytokine-induced β-cell destruction are prevented by HDACi [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Suberoylanilide hydroxamic acid (SAHA), commonly referred to as Vorinostat or Vorino, is an HDAC inhibitor with anti-inflammatory and antioxidant activities that primarily suppress Class II, I, and IV HDACs. It approved in 2006 for cutaneous T-cell lymphoma treatment [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. SAHA had antidiabetic benefits in type 1 diabetes mellitus (T1DM) animal model [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. SAHA prevents liver fibrosis in LX2 cells by blocking HDAC2, HDAC6, and HDAC8 proteins [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSodium\u0026ndash;glucose cotransporter-2 inhibitors (SGLT2is) were promising pharmaceuticals class for T2DM therapy because they improve insulin sensitivity, suppress gluconeogenesis, and reduce glucose reabsorption by blocking SGLT2 protein that included in 90% of glucose reabsorption [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The FDA originally authorized canagliflozin in 2013 and dapagliflozin (DAPA) in 2014 as SGLT2i [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition to their anti-hyperglycemic action, SGLT2i has been associated in several trials to improve hepatic function in individuals with T2DM [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Preclinical studies showed that SGLT2i decrease liver lipid accumulations [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and decrease fat mass and body weights by enhancing fatty acids utilization instead of glucose as source of energy for metabolism [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Due to the insulin-independent mechanism of SGLT2i, individuals with insulin resistance or reduced pancreatic function may benefit from this family of drugs as an additional treatment. So, SGLT2is may be appropriate in treatment of T2DM [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis experimental research was conducted to study possible protective effects of histone deacetylase inhibitors (Suberoylanilide hydroxamic acid) and Sodium\u0026ndash;glucose cotransporter-2 inhibitor (dapagliflozin) \u003cem\u003ein vivo\u003c/em\u003e administration on liver of T2DM rat\u0026rsquo;s model and examine the underlying mechanism of their effects.\u003c/p\u003e"},{"header":"Material and method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAnimals\u003c/h2\u003e \u003cp\u003eForty adult male Albino rats weighing 250\u0026ndash;300 gm and aged 8 weeks obtained from Animal house at Faculty of Pharmacy, King Abdulaziz University (KAU), Jeddah, Saudi Arabia. Rats kept in suitable laboratory status of light (12h light/dark cycle), temperature (25\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026deg;C), and humidity 60% with \u003cem\u003ead libitum\u003c/em\u003e access to distilled water and a rodent rat\u0026rsquo;s diet for one week before experiment start for acclimatization to laboratory condition. The experimental procedure made according to ARRIVE (Animal Research Reporting of \u003cem\u003eIn Vivo\u003c/em\u003e Experiments) and approved by Ethical Committee of King Abdulaziz University, Jeddah, Saudi Arabia.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eChemicals and drugs\u003c/h2\u003e \u003cp\u003eStreptozotocin (STZ) bought from Sigma‑Aldrich (Sigma-Aldrich Co. St. Louis, Missouri, USA). STZ mixed in 0.1M citrate buffer (pH 4.4) and administered to rats intraperitoneally (i.p.). Suberoylanilide hydroxamic acid bought from Selleck Chemicals (Sigma-Aldrich Co. St. Louis, Missouri, USA), and mixed in vehicle of 10% dimethyl sulfoxide (DMSO), 45% polyethylene glycol 400 (PEG-400), 45% saline \u0026amp; administered i.p. Dapagliflozin bought from AstraZeneca Pharmaceutical Company (Cairo, Egypt), and put in 0.5% aqueous solution of carboxymethyl cellulose (CMC) and ingested oral via gastric lavage.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eExperimental design and induction of T2DM\u003c/h2\u003e \u003cp\u003eForty rats randomly sorted equally into 4 groups as follows: first group was negative control (NC) that fed by regular chow diet (23% protein, 53% carbohydrate, and 5% fat) for 12 weeks. From week 4, NC group rats took 1 ml/kg daily i.p. injections of 10% DMSO, 45% PEG-400, 45% saline (vehicle of SAHA) and 1 ml/kg daily orally of CMC (vehicle of DAPA). All other rats (n\u0026thinsp;=\u0026thinsp;30) were fed high fat diet (HFD) (normal diet\u0026thinsp;+\u0026thinsp;2.5% cholesterol\u0026thinsp;+\u0026thinsp;20% saccharose\u0026thinsp;+\u0026thinsp;15% lard stearin) for 11 weeks and received at 3rd week a once STZ injection (35 mg/kg i.p.) for T2DM induction [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Three days followed STZ intake, fasting blood glucose (FBG) levels evaluated and animals showed FBG\u0026thinsp;\u0026ge;\u0026thinsp;250 mg/dl considered diabetic and included into research [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. For more 8 weeks, HFD gave with the following therapy. Second group was T2DM and took saline [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Third group (T2DM\u0026thinsp;+\u0026thinsp;SAHA) received daily SAHA injection (5 mg/kg /i.p. for 8 weeks) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Fourth group (T2DM\u0026thinsp;+\u0026thinsp;DAPA) received daily dapagliflozin (1mg/kg/p.o. for 8 weeks) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBody weights of rats estimated at beginning of experiment and weekly using digital scale. Weight gain (%) calculated as final body weight \u0026ndash; initial body weight divided by initial body weight then multiplied by 100. Food intake was calculated weekly and food efficiency ratio (FER) (%) calculated as weight gain (g/week) divided by intake of food (g/week) X 100.\u003c/p\u003e \u003cp\u003eAt experimental end, rats were fasted for 12 hours. Thiopental sodium (50 mg/kg) was used to anesthetize rats. Retro-orbital plexus, the orbital sinus, was the site of blood sample collection. Blood collected into plain tubes then left to coagulate for 20 minutes. Sera were obtained by centrifuging the blood for 15 minutes at 4000 rpm. The separated sera were stored frozen at -20\u0026deg;C in aliquots till used.\u003c/p\u003e \u003cp\u003eRats were died by cervical dislocation and livers isolated, washed with cold saline and weighed. Hepatic index (%) calculated as weight of liver divided by final body weight X 100. Liver was dissected into two halves. One liver half fixed in 10% formalin for histopathological evaluation under light microscopy. Other liver half washed with saline, frozen in liquid nitrogen, and kept at \u0026ndash; 80\u0026deg;C till preparation of hepatic homogenates.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eHepatic tissue homogenate preparation\u003c/h2\u003e \u003cp\u003eHalf of liver homogenized in phosphate-buffered saline (PBS) to made 10% (w/v) homogenate utilized homogenizer (Omni International, Kennesaw, GA, USA). Homogenates further spun at 5,000g at 4\u0026deg;C for 15 min. Supernatants collected, aliquoted and storage at -20\u0026deg; for further measurement of oxidative stress biomarkers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical Measurements\u003c/h2\u003e \u003cp\u003eFBG was measured using colorimetric kit (catalog# ab282922) from Abcam (United Kingdom). Fasting serum insulin concentrations estimated by rat insulin enzyme-linked immunosorbent assay (ELISA) kit (catalog# MBS281388) from My BioSource (San Diego, USA) based upon manufacturer\u0026rsquo;s protocol. Assessment of IR carried out using homeostatic model assessment of insulin resistance (HOMA-IR) index. HOMA-IR = [fasting insulin (\u0026micro;U/ml) \u0026times; fasting plasma glucose (mg/dl)]/405 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Liver functions as alanine aminotransferase (ALT), total bilirubin, gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), total protein and albumin estimated by colorimetric method by available kits (Teco diagnostics, Cairo, Egypt). Serum levels of lipid profile as total cholesterol (TC), triglycerides (TG), high-density lipoprotein concentration (HDL-C) estimated by kits (Spectrum diagnostics, Cairo, Egypt) based upon manufacturer\u0026rsquo;s protocol. Low density lipoprotein concentration (LDL-C) calculated according to Friedewald formula: LDL-C\u0026thinsp;=\u0026thinsp;TC \u0026ndash; [HDL-C\u0026thinsp;+\u0026thinsp;TG/5)] [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Values of malondialdehyde (MDA) (catalog# MBS268427), lipid peroxidation marker, and superoxide dismutase (SOD) (catalog# MBS036924) and glutathione (GSH) (catalog# MBS265966), markers of antioxidants estimated in hepatic homogenates by commercially available kits from MyBioSource, Inc. (San Diego, CA 92195\u0026thinsp;\u0026minus;\u0026thinsp;3308, USA) based upon manufacturer\u0026rsquo;s protocols.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eHistological examination\u003c/h2\u003e \u003cp\u003eThe livers were examined closely for any noticeable alterations. Portions of left liver lobes prepped for light microscopy so that a liver histological assessment may be carried out. After being first preserved in a 10% neutral formalin solution, sample progressively dried out in 50% \u0026ndash; 100% ethanol, cleaned in xylene, and then embedded into paraffin. Hematoxylin and eosin (HX\u0026amp;E) staining made after sections cut into 5 m thick portions. Slices of liver were analyzed by a skilled histopathologist using light microscopy to assess tissue alterations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eResults presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Value analysis made using IBM Corporation's SPSS version 22 (Armonk, NY, USA). Shapiro-Wilk test employed to determine the normality of value distributions. Tukey's test is utilized to compare groups of normally distributed values after One-Way ANOVA has been used to analyze the data. Kruskal Wallis and Mann Whitney tests utilized to compare groups when values are abnormally distributed (weight increase, weight index, FER, liver weights, and liver indices). Statistical significance defined as a \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eBiological results\u003c/h2\u003e \u003cp\u003eCompared to NC group, there were significant increase in T2DM, T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA groups of final body weight (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.010, respectively), Weight gain (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.010 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050, respectively) and weight gain percentage (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050, respectively). Food Efficiency Ratio (FER) significantly decreased in T2DM, T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA groups versus NC group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.010 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050, respectively). The liver weight significantly decreased in T2DM\u0026thinsp;+\u0026thinsp;DAPA versus negative control (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.010). The hepatic index significantly increased in T2DM compared with NC and T2DM\u0026thinsp;+\u0026thinsp;DAPA groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.010) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of initial, final body weight, weight gain, Food Efficiency Ratio, liver weight and liver index in various studied groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNC group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT2DM group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT2DM\u0026thinsp;+\u0026thinsp;SAHA group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT2DM\u0026thinsp;+\u0026thinsp;DAPA group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInitial body weight\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(grams)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e272.70\u0026thinsp;\u0026plusmn;\u0026thinsp;45.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e232.80\u0026thinsp;\u0026plusmn;\u0026thinsp;35.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e235.90\u0026thinsp;\u0026plusmn;\u0026thinsp;29.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e252.10\u0026thinsp;\u0026plusmn;\u0026thinsp;14.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFinal body weight\u003c/b\u003e (grams)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e404.50\u0026thinsp;\u0026plusmn;\u0026thinsp;50.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e248.40\u0026thinsp;\u0026plusmn;\u0026thinsp;41.30\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e287.40\u0026thinsp;\u0026plusmn;\u0026thinsp;56.90\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e308.20\u0026thinsp;\u0026plusmn;\u0026thinsp;72.21\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight gain\u003c/b\u003e (grams)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e131.80\u0026thinsp;\u0026plusmn;\u0026thinsp;55.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.60\u0026thinsp;\u0026plusmn;\u0026thinsp;36.44\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e51.50\u0026thinsp;\u0026plusmn;\u0026thinsp;64.40\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e56.10\u0026thinsp;\u0026plusmn;\u0026thinsp;67.21\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight gain\u003c/b\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e32.07\u0026thinsp;\u0026plusmn;\u0026thinsp;11.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5.32\u0026thinsp;\u0026plusmn;\u0026thinsp;12.74\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e15.35\u0026thinsp;\u0026plusmn;\u0026thinsp;18.79 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e14.84\u0026thinsp;\u0026plusmn;\u0026thinsp;17.05\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFood Efficiency Ratio\u003c/b\u003e (FER) (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.051\u0026thinsp;\u0026plusmn;\u0026thinsp;0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.006\u0026thinsp;\u0026plusmn;\u0026thinsp;0.014\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e0.020\u0026thinsp;\u0026plusmn;\u0026thinsp;0.024\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e0.021\u0026thinsp;\u0026plusmn;\u0026thinsp;0.026\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver weight\u003c/b\u003e (grams)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.76\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e8.75\u0026thinsp;\u0026plusmn;\u0026thinsp;1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e8.67\u0026thinsp;\u0026plusmn;\u0026thinsp;1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e6.98\u0026thinsp;\u0026plusmn;\u0026thinsp;2.18 \u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver index\u003c/b\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.82\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e3.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e2.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003csup\u003e##\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData expressed as mean +/- standard deviation. \u003csup\u003e*\u003c/sup\u003e: significance versus NC group; \u003csup\u003e#\u003c/sup\u003e: significance versus T2DM. *: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050, **: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.010, ***: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFood intake at different weeks among different studied groups is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eGlycemic control results\u003c/h2\u003e \u003cp\u003eAt the 3rd week, FBG level was significantly increased in T2DM, T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA groups versus negative control (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for all). At the 11th week, blood glucose level significantly declined in T2DM\u0026thinsp;+\u0026thinsp;DAPA group versus T2DM and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both) and in T2DM\u0026thinsp;+\u0026thinsp;SAHA versus T2DM (p\u0026thinsp;=\u0026thinsp;0.029). Fasting insulin levels and HOMA-IR significantly elevated in T2DM, T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA groups versus negative control (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for all) but were significantly decreased in T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA groups versus T2DM group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for all) and in T2DM\u0026thinsp;+\u0026thinsp;DAPA groups versus T2DM\u0026thinsp;+\u0026thinsp;SAHA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for both) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of glycemic control in various studied groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNC group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT2DM group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT2DM\u0026thinsp;+\u0026thinsp;SAHA group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT2DM\u0026thinsp;+\u0026thinsp;DAPA group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood glucose (mg/dl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3rd week\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e75.70\u0026thinsp;\u0026plusmn;\u0026thinsp;7.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e395.20\u0026thinsp;\u0026plusmn;\u0026thinsp;31.95\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e403.70\u0026thinsp;\u0026plusmn;\u0026thinsp;48.87\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e410.90\u0026thinsp;\u0026plusmn;\u0026thinsp;57.36\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e11th week\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e78.90\u0026thinsp;\u0026plusmn;\u0026thinsp;9.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e354.90\u0026thinsp;\u0026plusmn;\u0026thinsp;22.57\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e333.20\u0026thinsp;\u0026plusmn;\u0026thinsp;7.50\u003csup\u003e***,#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e263.70\u0026thinsp;\u0026plusmn;\u0026thinsp;20.82\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInsulin (uIU/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e26.80\u0026thinsp;\u0026plusmn;\u0026thinsp;2.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e85.40\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e42.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.84\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e75.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHOMA-IR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e74.94\u0026thinsp;\u0026plusmn;\u0026thinsp;6.90\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e34.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.85\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e49.01\u0026thinsp;\u0026plusmn;\u0026thinsp;3.80\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData expressed as mean +/- standard deviation. \u003csup\u003e*\u003c/sup\u003e: significance versus NC group; \u003csup\u003e#\u003c/sup\u003e: significance versus T2DM, \u003csup\u003e\u0026amp;\u003c/sup\u003e: significance versus T2DM\u0026thinsp;+\u0026thinsp;SAHA group. *: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050, ***: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eLiver function test results\u003c/h2\u003e \u003cp\u003eAt experimental end, AST, ALT and GGT values were significantly increased in T2DM, T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups versus NC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all) and in T2DM versus T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all). Meanwhile, AST and ALT values were significantly decreased in T2DM\u0026thinsp;+\u0026thinsp;DAPA than T2DM\u0026thinsp;+\u0026thinsp;SAHA group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Total bilirubin was significantly elevated in T2DM versus negative control, T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all) and in T2DM\u0026thinsp;+\u0026thinsp;DAPA versus negative control (p\u0026thinsp;\u0026lt;\u0026thinsp;0.050). Total proteins levels declined in T2DM, T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA compared to NC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all); decreased in T2DM versus T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), declined in T2DM\u0026thinsp;+\u0026thinsp;DAPA versus T2DM\u0026thinsp;+\u0026thinsp;SAHA (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Albumin levels significantly decreased in T2DM and T2DM\u0026thinsp;+\u0026thinsp;DAPA versus NC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all); decreased in T2DM versus T2DM\u0026thinsp;+\u0026thinsp;SAHA and T2DM\u0026thinsp;+\u0026thinsp;DAPA (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), declined in T2DM\u0026thinsp;+\u0026thinsp;DAPA than T2DM\u0026thinsp;+\u0026thinsp;SAHA (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of liver function tests and lipid profile in various studied groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNC group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT2DM group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT2DM\u0026thinsp;+\u0026thinsp;SAHA group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT2DM\u0026thinsp;+\u0026thinsp;DAPA group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAST (U/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e116.10\u0026thinsp;\u0026plusmn;\u0026thinsp;4.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e248.80\u0026thinsp;\u0026plusmn;\u0026thinsp;4.32\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e171.60\u0026thinsp;\u0026plusmn;\u0026thinsp;8.58\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e151.50\u0026thinsp;\u0026plusmn;\u0026thinsp;6.77\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eALT (U/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e80.70\u0026thinsp;\u0026plusmn;\u0026thinsp;2.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e150.60\u0026thinsp;\u0026plusmn;\u0026thinsp;4.27\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e127.50\u0026thinsp;\u0026plusmn;\u0026thinsp;5.08\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e115.40\u0026thinsp;\u0026plusmn;\u0026thinsp;4.86\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGGT (U/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e23.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.41\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e13.00\u0026thinsp;\u0026plusmn;\u0026thinsp;1.83\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e13.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.29\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal bilirubin (\u0026micro;mol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e8.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e5.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e6.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003csup\u003e*,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal protein (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e72.16\u0026thinsp;\u0026plusmn;\u0026thinsp;2.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e32.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.50\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e48.60\u0026thinsp;\u0026plusmn;\u0026thinsp;2.91\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e43.90\u0026thinsp;\u0026plusmn;\u0026thinsp;2.42\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlbumin (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e45.20\u0026thinsp;\u0026plusmn;\u0026thinsp;2.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e23.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.78\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e42.50\u0026thinsp;\u0026plusmn;\u0026thinsp;3.44\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e33.90\u0026thinsp;\u0026plusmn;\u0026thinsp;2.42\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTriglyceride (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e132.90\u0026thinsp;\u0026plusmn;\u0026thinsp;2.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e375.00\u0026thinsp;\u0026plusmn;\u0026thinsp;9.13\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e314.00\u0026thinsp;\u0026plusmn;\u0026thinsp;12.65\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e265.00\u0026thinsp;\u0026plusmn;\u0026thinsp;15.81\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal cholesterol (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e93.70\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e258.70\u0026thinsp;\u0026plusmn;\u0026thinsp;7.67\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e191.00\u0026thinsp;\u0026plusmn;\u0026thinsp;13.29\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e136.50\u0026thinsp;\u0026plusmn;\u0026thinsp;9.73\u003csup\u003e***,###,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDL-C (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e44.70\u0026thinsp;\u0026plusmn;\u0026thinsp;3.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e151.10\u0026thinsp;\u0026plusmn;\u0026thinsp;7.81\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e74.90\u0026thinsp;\u0026plusmn;\u0026thinsp;7.17\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e77.80\u0026thinsp;\u0026plusmn;\u0026thinsp;4.21\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHDL-C (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e72.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e32.60\u0026thinsp;\u0026plusmn;\u0026thinsp;3.95\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e36.10\u0026thinsp;\u0026plusmn;\u0026thinsp;4.12\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e36.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.62\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData expressed as mean +/- standard deviation. \u003csup\u003e*\u003c/sup\u003e: significance versus NC group; \u003csup\u003e#\u003c/sup\u003e: significance versus T2DM, \u003csup\u003e\u0026amp;\u003c/sup\u003e: significance versus T2DM\u0026thinsp;+\u0026thinsp;SAHA group. *: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050, ***: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLipid profile results\u003c/h2\u003e \u003cp\u003eAt experimental end, Triglyceride, total cholesterol, LDL-C values significantly elevated in T2DM, T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups versus NC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and in T2DM versus T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all). Triglyceride and total cholesterol serum values were significantly increased in T2DM\u0026thinsp;+\u0026thinsp;SAHA versus T2DM\u0026thinsp;+\u0026thinsp;DAPA (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). HDL-C values were significantly declined in T2DM, T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups versus NC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eOxidative stress results\u003c/h2\u003e \u003cp\u003eAt experimental end, MDA liver homogenate levels were significantly elevated in T2DM, T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups versus NC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all) and in T2DM versus T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both). SOD and GSH liver homogenate values were significantly declined in T2DM, T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups versus NC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all); decreased in T2DM versus T2DM\u0026thinsp;+\u0026thinsp;DAPA and T2DM\u0026thinsp;+\u0026thinsp;SAHA groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.050). Meanwhile, SOD value was significantly increased in T2DM\u0026thinsp;+\u0026thinsp;SAHA versus T2DM\u0026thinsp;+\u0026thinsp;DAPA (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of oxidative stress markers in various studied groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNC group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT2DM group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT2DM\u0026thinsp;+\u0026thinsp;SAHA group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT2DM\u0026thinsp;+\u0026thinsp;DAPA group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMDA\u003c/b\u003e (nmol/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.67\u0026thinsp;\u0026plusmn;\u0026thinsp;3.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e23.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.38\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e15.31\u0026thinsp;\u0026plusmn;\u0026thinsp;2.14\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e17.55\u0026thinsp;\u0026plusmn;\u0026thinsp;1.82\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSOD\u003c/b\u003e (U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e17.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9.11\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e14.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e10.93\u0026thinsp;\u0026plusmn;\u0026thinsp;1.15\u003csup\u003e***,#,\u0026amp;\u0026amp;\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGSH\u003c/b\u003e (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e315.99\u0026thinsp;\u0026plusmn;\u0026thinsp;13.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e225.01\u0026thinsp;\u0026plusmn;\u0026thinsp;11.60\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e267.27\u0026thinsp;\u0026plusmn;\u0026thinsp;7.25\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e277.01\u0026thinsp;\u0026plusmn;\u0026thinsp;10.72\u003csup\u003e***,###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData expressed as mean +/- standard deviation. \u003csup\u003e*\u003c/sup\u003e: significance versus NC group; \u003csup\u003e#\u003c/sup\u003e: significance versus T2DM, \u003csup\u003e\u0026amp;\u003c/sup\u003e: significance versus T2DM\u0026thinsp;+\u0026thinsp;SAHA group. *: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.050, ***: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eHistology results\u003c/h2\u003e \u003cp\u003eThe livers of healthy control rats were examined using HX and E staining, and the results showed a typical hepatic shape with the liver split into classic hepatic lobules. Hepatocyte cords that extend outward from central vein to lobule's perimeter make up the classic lobule. Loose stromal connective tissue envelops portal triads, also known as tracts, which are dispersed at the corners of lobules. The polyhedral hepatocytes had one or two conspicuous nucleoli, a clear vesicular spherical nucleus, and a highly eosinophilic cytoplasm speckled with basophilic granules. Binucleation of hepatocytes occurs often. Flat endothelial cells line central vein, and statistically significant hepatic blood sinusoids found between endothelial cell-lined hepatic cell cords and von Kupffer cells with ovoid nuclei (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Peripherally each lobule has three to six portal areas with more fibrous connective tissue, each of which has three interlobular structures that comprise portal triad or portal tracts, portal vein, hepatic artery and one or two small branches of bile ducts lined with cuboidal epithelium (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.b).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRats of diabetic group showed severe damage in rat liver. The most significant alterations were disorderly hepatocyte, inflammatory, degenerative, necrotic, nucleus karyolysis and hyperplastic changes. Liver showed degenerations and vacuolation of hepatocytes and some of them exhibited one large cytoplasmic vacuole. Severe infiltrative fatty changes in form of more well-defined fat droplets occupying hepatocytes cytoplasm, pushing nucleus to periphery (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). Also, multiple inflammatory cells appeared. Hydropic degeneration of hepatocytes was observed around dilated central vein. Central vein showed dilatation and congestion with leukocytic infiltrations around it (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). There were many localized necrotic regions with extensively vacuolated hepatocyte cytoplasm and strongly stained pyknotic nuclei, together with a noticeable infiltration of mononuclear cells or widespread hepatic coagulative necrosis (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea,b). Portal tract showed congested and dilated portal vein and mononuclear leucocytic cell infiltrations around portal vein (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTreated diabetic groups with SAHA showed improvement in hepatic histological structure. Amelioration of hepatocytes, and alleviate inflammation, leucocytic cell infiltration, necrotizing hepatocytes, which is produced by STZ. Liver tissue kept its normal hepatic shape with radiating hepatic cell cords and central veins to some extent similar to negative control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). Most of hepatocytes appeared polyhedral with strongly eosinophilic cytoplasm dotted with basophilic granules, and distinct vesicular rounded nuclei and one or two prominent nucleoli. Central vein is lined with flat endothelial cells and hepatic blood sinusoids were noticed between hepatic cell cords lined with endothelial cells and von Kupffer cells. Portal tract showed normal bile duct, hepatic artery and portal vein (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRegarding diabetic rat treated with DAPA showed moderate improvement in liver histological structure. Liver tissue preserved to some extent its normal hepatic shape with central veins and radiating hepatic cell cords to some extent as negative control group. Most of hepatocytes appeared polyhedral with eosinophilic cytoplasm dotted with basophilic granules, and vesicular rounded nuclei. Central vein is lined with flat endothelial cells and hepatic blood sinusoids noticed between hepatic cell cords lined with endothelial cells. Portal tracts showed normal histological structure as that of control group (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea,b). Some specimens still showed moderate fatty infiltrative changes where smaller well-defined fat droplets occupying hepatic cytoplasm with loss of normal architecture of liver tissue and mononuclear cell infiltration's (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec,d).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eT2DM-related metabolic abnormalities may cause liver damage, which may ultimately lead to a number of liver illnesses, including cirrhosis, hepatocellular carcinoma, and fatty liver [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Numerous variables, including hyperglycemia, insulin resistance, dyslipidemia, oxidative stress, and inflammations, can lead to diabetic liver damage [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, HFD/STZ utilized to induce a T2DM liver damage rat model [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The results of this research revealed that, final body weight, weight gain, weight gain percentage and FER declined in T2DM group compared to negative control group. In this respect, According to Zhu et al., T2DM rat group's body weight dramatically dropped while their intake of food, water, and urine volume were significantly elevated [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Lower body weight in T2DM is due to catabolic state of poorly controlled glycaemia. Under these conditions, lipolysis, metabolic processes, and oxidative degradation of amino acids elevated; they degrade greatest energy and tissue reserves in animal, so decreasing body weights [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In this study, body weights in diabetic rats were not improved by administration of SAHA or DAPA to diabetic rats, which may be caused by continuous catabolic condition. SAHA appears to have complex effects on body weight. While some metabolic alterations and adverse consequences, such as anorexia, were noted in preclinical and clinical trials, significant weight changes were not always recorded [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. This suggests that not all circumstances and dose ranges will result in a consistent or direct effect of SAHA on body weight. In the meantime, osmotic drainage brought on by the glycosuria brought on by DAPA alters body composition, resulting in a decrease in body fat and body weight loss. According to Phrueksotsai et al., DAPA prescription resulted in significant decline in body weight and body fats after 12 weeks of therapy, with a mean 3% decrease in baseline body weights. Furthermore, correlation analysis showed a significant positive relationship between weight loss and decrease in liver fat content [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Ahmed \u003cem\u003eet al.\u003c/em\u003e found that total body weight was declined in three groups of rats that received three different DAPA doses (0.75, 1.5 and 3 mg/kg, p.o.) than negative and diabetic control groups [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLiver index in this research was significantly increased in T2DM versus negative control and T2DM\u0026thinsp;+\u0026thinsp;DAPA groups. Zhu \u003cem\u003eet al.\u003c/em\u003e reported that the liver indices were significantly increased in T2DM rat\u0026rsquo;s model [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In this study, the liver weight significantly decline in T2DM\u0026thinsp;+\u0026thinsp;DAPA versus negative control. DAPA medication significantly reduces total liver fat content in T2DM patients [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In addition to decreased body weight, metabolic substrate shift from glucose to fatty acids and likely higher hepatic oxidation of fatty acids are other theories explaining the loss of liver fat [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study showed that at experimental end FBG level, fasting insulin level and HOMA-IR significantly elevated in T2DM group versus negative control as previously reported [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In rats, HFD causes IR [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The results of this research showed that FBG, fasting insulin, HOMA-IR was significantly decreased T2DM\u0026thinsp;+\u0026thinsp;SAHA versus T2DM but were still significantly elevated than negative control group. Bocchi \u003cem\u003eet al.\u003c/em\u003e reported that injection of SAHA (25 mg/kg i.p.) for 23 days into mice leads to improved sensitivity to insulin [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Silva \u003cem\u003eet al.\u003c/em\u003e reported that injection of SAHA (25\u0026ndash;50 mg/kg i.p.) for 8 weeks into HFD fed mice with leads to ameliorate insulin sensitivity [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In the mesenchymal stem cell model MG63, SAHA was shown to affect the formation of β-cells and improve insulin production by upregulating transcription factor PDX1 expression. Additionally, pretreatment with SAHA increased β-cell markers in response to high glucose challenges, indicating that it may improve stem cells' ability to develop into β-cells that produce insulin [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Histones, other regulatory proteins and different transcription factors that either indirectly or directly included in metabolism of glucose are deacetylated by HDACs. Furthermore, histone acetylation regulates the glucose-mediated regulation of insulin gene transcription, indicating HDACs involvement in manufacture and function of insulin [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The results of this research revealed that therapy of diabetic rats with DAPA led to decline in FBG, fasting insulin, HOMA-IR versus T2DM but were still significantly higher than negative control group. In DAPA treated diabetic rats, FBG was significantly decline, but fasting insulin and HOMA-IR were increased versus SAHA treated diabetic group. Tang \u003cem\u003eet al.\u003c/em\u003e reported that after four weeks of therapy, there was decline in blood glucose values and an increase in urine glucose excretion with DAPA [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Joannides \u003cem\u003eet al.\u003c/em\u003e reported that DAPA administration for 45 days into PEPCK transgenic rats caused reduced plasma glucose and insulin values due to improve IR, elevated fat and muscle glucose uptake and GLUT4 protein values, and decreased size of adipocyte and elevated number of adipocyte, but not elevated secretion of insulin [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. HFD/STZ -induced diabetic mice treated with DAPA showed improved glucose tolerance, IR and insulin secretion, with a significant elevation in insulin content of pancrease [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLiver was affected in T2DM rat models in this study as revealed by increased ALT, AST, GGT, total bilirubin, and decline in total protein and albumin versus negative control group. Zhu \u003cem\u003eet al.\u003c/em\u003e reported ALT and AST values were significantly elevated in T2DM rats model [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. SAHA administration to diabetic rats had protective effect on liver as revealed in this study by decreased AST, ALT, GGT, total bilirubin and significant increase in total protein and albumin. SAHA has protective effect on liver damage produced by lethal hemorrhagic shock in rats that was associated with elevated H3K9 acetylation and suppression of JNK/caspase-3 apoptotic pathway [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. SAHA administration significantly reduced serum values of AST, ALT, and lactate dehydrogenate, increased the survival rate and decreased apoptotic markers expression in liver tissues, suggesting its protective role in early hemorrhagic shock conditions [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Wang \u003cem\u003eet al.\u003c/em\u003e found that in rats carbon tetrachloride (CCl4) significantly made liver fibrosis and elevated serum values of transforming growth factor (TGF)-β1, total bilirubin, ALT, AST, laminin, and procollagen type III; liver HDAC2, p-Smad2/3, HDAC6, HDAC8, α-SMA and connective tissue growth factor (CTGF) proteins; whereas Smad7 mRNA and AH3 protein levels were notably suppressed. SAHA treatment significantly downregulated, these liver chemistries, cytokines and liver fibrosis-related genes and mitigated hepatic fibrosis [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Alhaddad \u003cem\u003eet al.\u003c/em\u003e reported that SAHA administration (15 mg/kg/day p.o.) for 8 weeks to rat model of autoimmune hepatitis made by Concanavalin A led to decreased in AST and ALT liver enzymes [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. DAPA administration to diabetic rats had protective effect on liver as revealed in this study by decreased ALT, AST, GGT, total bilirubin and significant increase in albumin and total protein. Dapagliflozin therapy protected the liver in db/db mice, as revealed by markedly lower levels of oxidative stress and inflammatory indicators, hepatic lipid buildup, and plasma ALT activity and TG levels [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. DAPA markedly reduced ALT and AST serum levels and protected liver from pathologic damages in diabetic mice [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. A clinical trial utilizing DAPA in T2DM patients revealed reduced values of liver damage biomarkers, as ALT, AST, and GGT; combining carboxylic acids (OM-3CA) resulted in a significant decline in hepatic fat content [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. DAPA led to ALT-lowering effect by decrease liver fat deposition by making hyperglucagonemia [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] and ameliorate IR caused by decreased ectopic steatosis [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDyslipidemia is considered a major cardiovascular disorders risk factor resulting in myocardial infarction, sudden cardiac arrest, and death. In this study, significant increase in serum TC, TG and LDL-C values accompanied by decline in serum HDL-C value were demonstrated in T2DM rats versus control group as reported by others [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. IR and dyslipidemia are important risk factors of diabetic hepatic damage [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In this study, treatment of diabetic rats with SAHA led to a significant decreased in serum TG, TC and LDL-C values compared to T2DM rats but were still significantly elevated versus control group. SAHA intake did not improve levels of HDL-C. SAHA exhibits significant anti-inflammatory effects by reducing pro-inflammatory cytokines production as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon gamma. These cytokines are known to influence metabolic processes, including lipid metabolism [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. HDACs inhibition by SAHA affects various signaling pathways and gene expressions related to lipid biosynthesis and metabolism as lipoxygenases [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. The induction of 15-lipoxygenase-1 by SAHA, for example, correlates with significant changes in lipid metabolism [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. However, direct studies specifically focusing on serum lipid profiles post-SAHA treatment are limited, indicating a need for more targeted research in this area. In this study, treatment of diabetic rats with DAPA led to a significant decreased in serum TG, TC and LDL-C values versus T2DM rats but were still significantly elevated than control group. Decline in TG and TC levels were more effective that SAHA administration. Meanwhile, DAPA administration did not improve HDL-C levels. Leng \u003cem\u003eet al.\u003c/em\u003e found that DAPA decreased the values of TG and free fatty acids (FFAs) in liver and serum, which correlated with decreased lipotoxicity in diabetic mice [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Hazem \u003cem\u003eet al.\u003c/em\u003e reported lower liver weights and decreased serum values of TG and TC in rats received DAPA [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Ahmed \u003cem\u003eet al.\u003c/em\u003e reported that TC and TG were decreased in three groups that received three different DAPA doses (0.75, 1.5 and 3 mg/kg, p.o.) for 6 weeks more than negative and diabetic control groups [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. This reduction in TC and TG may be attributed to the total reduction in body weight or may be explained by shift of metabolic substrate from glucose to fatty acids [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe development of T2DM and its consequences, as well as IR, are significantly affected by oxidative stress. Reactive oxygen species (ROS) produced by dyslipidemia and hyperglycemia may damage live cells and certain cell membrane receptors, which may lead to damage to organs including liver [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. The results of this research showed elevation of MDA and decrease in SOD and GSH in diabetic rats versus negative control group. Researches revealed that tissue homogenate GSH concentrations in STZ-induced diabetic rats significantly decline versus negative control rats [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Decline GSH and SOD values in diabetic rats caused by its increased consumption that is required to relieve oxidative stress. Zhu \u003cem\u003eet al.\u003c/em\u003e revealed that oxidative stress and inflammation significantly elevated in hepatic homogenates of T2DM rats [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Hazem \u003cem\u003eet al.\u003c/em\u003e revealed that diabetic group had much lower values of GSH, SOD, and catalase and significantly greater amounts of MDA [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. By further reducing tissue oxidative stress, tight glycemic control or add-on techniques which block oxidative stress to antihyperglycemic medications might improve capacity to prevent disease development in organ damage due to diabetes [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In this study, diabetic rats that received SAHA showed significant decrease in MDA but elevation of SOD and GSH hepatic homogenate levels versus T2DM rats. Bakhdar \u003cem\u003eet al.\u003c/em\u003e reported that SAHA administration to Wistar rats (15 mg/kg/day i.p.) for 28 days led to pancreatic protection via anti-inflammatory and antioxidant actions [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. SAHA was shown to reduce hepatic cellular injury and ROS production in lipopolysaccharide (LPS)-induced liver damage. It enhanced the antioxidant enzyme GSH and inhibited apoptotic signaling pathways, suggesting its potential in alleviating inflammatory liver conditions [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In this study, diabetic rats that received DAPA showed significant decrease in MDA but elevation of SOD and GSH hepatic homogenate levels versus T2DM rats. The effect of SAHA in elevation of SOD hepatic homogenate level was better than DAPA. Hazem \u003cem\u003eet al.\u003c/em\u003e provides evidence for hepatoprotective effects of DAPA, as seen by the dose-dependent increases in antioxidant enzymes SOD, catalase activity, and GSH and decline in MDA levels [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. In Kashiwagi study, the SOD activity was significantly improved after 8 weeks of diabetic group treatment with insulin in addition to dapagliflozin [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. The results of this research suggest that dapagliflozin significantly improved antioxidant status in diabetic rats. The treatment's antihyperglycemic impact, which lessens the load of oxidative stress, might be the cause of this improvement.\u003c/p\u003e \u003cp\u003eIn this study, diabetic rats showed severe liver damage. The most significant alterations in diabetic control rat liver were disorderly hepatocyte, inflammatory, degenerative, necrotic, nucleus karyolysis and hyperplastic changes. These findings are in accord with those of Ahmed et al. who found that in diabetic, liver severe infiltrative fatty changes in form of more well-defined fat droplets occupying cytoplasm of hepatocytes, pushing nucleus to periphery. Also, multiple inflammatory cells appear with loss of normal architecture of hepatocytes [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Also, Salih et al. [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] observed that in STZ-diabetic mice showed more progressive changes, sever congestion, necrotic foci, hydropic changes, fatty changes in hepatocytes and aggregation of lymphocytes between the hepatocytes. Furthermore, additional research has documented damage to the liver cells, sinusoidal dilatation in the central venous region, elevated cell apoptosis, and elevated lipid droplets in the liver cells of diabetic mice [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. By activating NF-B that stimulates pro-apoptotic genes activity in liver cells and increases the creation of ROS, hyperglycemia circumstances will aggravate the process of liver damage by inducing oxidative stress and inflammatory conditions [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur results showed that treated diabetic groups with SAHA showed improvement in liver histological structure. Amelioration of hepatocytes, and alleviate inflammation, leucocytic cell infiltration, necrotizing hepatocytes, which is produced by STZ. So, hepatic tissue maintained its normal hepatic lobular shape with central veins and radiating hepatic cell cords to some extent similar to negative control group. Zhao et al. [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e] evaluate SAHA-mediated protection against LPS-induced hepatic damage using histological examination. As predicted, the 24-hour LPS exposure significantly increased the inflammatory response in the murine liver. This was demonstrated by the inflammatory cells' growing penetration into parenchyma, where necrotic and apoptotic hepatocyte cell death were noted. Compared to LPS alone group, liver architecture was better conserved in the mice treated with SAHA following an LPS injection. SAHA prevented ROS from being produced by LPS and stopped the antioxidant enzyme glutathione from declining due to STZ. Additionally, SAHA reduced the hepatic apoptosis caused by STZ. Additionally, SAHA prevented the activation of mitogen-activated protein kinases p38 and Jun N-terminal kinase, as well as redox-sensitive kinase and apoptosis signal-regulating kinase-1 [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Our findings demonstrate that SAHA can mitigate the hepatotoxicity caused by STZ and imply that a novel therapeutic approach for treating STZ-induced inflammatory conditions could involve blocking the upstream processes necessary for the function of apoptotic signal-regulating kinase-1. Also, Bocchi, et al. [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e] discovered that by lowering cell oxidative damage, SAHA therapy might reverse the initial functional aberration in cardiomyocytes. After being exposed to SAHA, diabetic cardiomyocytes (CMs) showed a simultaneous reduction in metabolic status, namely NAD(P)H dehydrogenase activities and ROS values. This finding raises the possibility of a mechanistic relationship between changed ROS generation and cell metabolism. In diabetic cells, SAHA aids in the restoration of proper redox signaling, which is necessary for maintaining homeostasis of cardiomyocyte and is implicated in heart's action to stress [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present research showed that diabetic rat reveived DAPA showed in some specimens, moderate improvement in liver histological structure. On the other hand, some specimens still showed moderate fatty infiltrative changes with droplets of fats occupying hepatocytes cytoplasm and loss of normal architecture of liver tissue accompanying mononuclear cell infiltrations. Our data agree with the results of Ahmed et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] who noticed that diabetics on DAPA (0.75 mg/kg), section of rat liver tissue showed mild to moderate fatty infiltrative changes where smaller well-defined fat droplets occupying hepatic cytoplasm with loss of liver tissue normal architecture. Diabetic rats on DAPA 1.5 and 3 mg/kg groups: section of rat hepatic tissue revealed improvement of fatty infiltrative alteration with normal hepatocytes around central vein and normal liver tissue architecture. Hazem et al. [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] observed that DAPA represent a viable approach to protect liver versus diabetes-induced steatohepatitis via suppressing oxidative stress, fibrosis progression and inflammation thus conserving hepatic functions and structure.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, this research confirms that SGLT2 inhibition via DAPA and HDAC inhibition by SAHA decrease blood glucose level and protective in slowing the progression of liver damage in T2DM rats by improve IR and lipid profile and reduced tissue oxidative stress. The effect of DAPA was better than SAHA in decreasing fasting blood glucose level and improving lipid profile; while SAHA was better than DAPA in improving insulin secretion and IR and increased antioxidant and improvement of hepatic tissue damage. These findings suggest that selective SGLT2i and HDACi could be utilized in combination with other oral anti-diabetes drugs and insulin to further improve glycemic control and reverse organ damage in T2DM.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthorship contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZZA Resources, Conceptualization, Methodology, Writing \u0026ndash; original draft, Preparation\u0026ndash; review \u0026amp; editing. \u0026nbsp;SIM Methodology, Resources, Writing \u0026ndash; original draft, and editing. Both authors approved manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors state that none of known financial conflicts or interpersonal ties that may have looked to have an impact on work described in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis is a self-funded research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations Ethics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch made after getting ethical approval from Ethical Committee of King Abdulaziz University, Jeddah, Saudi Arabia.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors declare that they had no competing interests.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTeo ZL, Tham Y-C, Yu M, Chee ML, Rim TH, Cheung N, et al. 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Free radical biology \u0026amp; medicine. 50(7):777\u0026ndash;93. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.freeradbiomed.2011.01.003\u003c/span\u003e\u003cspan address=\"10.1016/j.freeradbiomed.2011.01.003\" 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":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dapagliflozin, liver, protective effects, rats, Suberoylanilide hydroxamic acid, type 2 diabetes mellitus","lastPublishedDoi":"10.21203/rs.3.rs-5015447/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5015447/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eType 2 diabetes mellitus (T2DM) is common metabolic disorders. T2DM patients had 2-fold increase to get liver disorders. Evidence that some antidiabetic substances treated liver disorders in T2DM patients is evolving. Current study aimed to investigate hepatoprotective actions of Suberoylanilide hydroxamic acid (SAHA) and dapagliflozin (DAPA) in T2DM rats.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eT2DM occured by high fat diet (HFD) and single Streptozotocin (STZ) injection (35 mg/kg i.p.). Forty rats sorted into 4 groups: NC (negative control), T2DM, T2DM\u0026thinsp;+\u0026thinsp;SAHA (5 mg/kg/i.p. for 8 weeks) and T2DM\u0026thinsp;+\u0026thinsp;DAPA (1mg/kg/p.o. for 8 weeks). At experimental end, levels of fasting blood glucose (FBG), fasting insulin, hepatic function tests [gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, albumin, total protein], lipid profiles [total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG)] measured in serum. Hepatic tissue homogenization prepared for estimating oxidative stress biomarkers [glutathione (GSH), malonaldehyde (MDA), superoxide dismutase (SOD)]. Hepatic histopathological examination made under light microscope.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eDiabetic rats had significant rise in liver weights and hepatic enzymes (AST, ALT, GGT, total bilirubin), lipid profile [TG, TC, LDL-C) in serum, and elevation in MDA in liver homogenate, but significant decline in total proteins, albumin, HDL-C) in serum and SOD, GSH in liver homogenate. These changes associated with histopathological changes in liver tissue as degeneration, vacuolation of hepatocytes, dilatation, and congestion of portal veins with lymphocytic infiltration. SAHA and DAPA treatment decreased liver weights, FBG, insulin, insulin resistance (IR), AST, ALT, GGT, bilirubin, TG, TC, LDL-C. SAHA and DAPA increased antioxidant enzymes (GSH, SOD) levels, serum total protein, albumin and HDL-C. Interestingly, DAPA was better that SAHA in improving liver enzymes, lipid profile, decreased FBG but SAHA was better in improving antioxidants as SOD, insulin levels and IR. Also, there were marked improvements in liver histopathological changes in SAHA and DAPA groups that were better in SAHA group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSuberoylanilide hydroxamic acid and dapagliflozin represent an approach to protect liver versus DM-induced disorders via suppression oxidative stress, improve lipid profile, hyperglycemia and IR progression thus conserving liver functions and structure.\u003c/p\u003e","manuscriptTitle":"Protective effects of Suberoylanilide hydroxamic acid and Dapagliflozin administration on liver of diabetic rats","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-18 09:10:28","doi":"10.21203/rs.3.rs-5015447/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"63e895cd-f832-4aac-b903-0aa70d71c5bd","owner":[],"postedDate":"October 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-15T13:38:26+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-18 09:10:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5015447","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5015447","identity":"rs-5015447","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}