{"id":54071,"date":"2023-12-31T11:20:35","date_gmt":"2023-12-31T11:20:35","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=54071"},"modified":"2024-01-05T06:22:39","modified_gmt":"2024-01-05T06:22:39","slug":"empagliflozin-potential-protective-effects-on-hepatocytes-and-liver-outcomes-in-streptozotocin-diabetic-rats","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no4\/empagliflozin-potential-protective-effects-on-hepatocytes-and-liver-outcomes-in-streptozotocin-diabetic-rats\/","title":{"rendered":"Empagliflozin: Potential Protective Effects on Hepatocytes and Liver Outcomes in Streptozotocin -Diabetic Rats."},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Diabetes is a chronic disease that\nis characterized by hyperglycemia (blood glucose: > 126 mg\/dL) due to\ninsufficient insulin production, insulin resistance, or increased glucagon\nproduction 1,<\/sup>2<\/sup> Diabetes mellitus (DM) is a\nsignificant worldwide problem; in 2019, 9.3% of the world’s population was\naffected. The percentage is presumed to rise to 10.2% by 2045 3<\/sup>.\nUncontrolled DM leads to nephropathy, retinopathy, neuropathy, and\ncardiovascular complications 4-7<\/sup> pathogenesis of these complications\ninvolves several proposed mechanisms, with oxidative stress being one of the\nmost widely accepted factors. When there is an imbalance between the production\nof reactive oxygen species (ROS) and the body’s defense mechanisms against\nantioxidants8<\/sup>, it is known as oxidative stress. Research has\nindicated that oxidative stress plays a crucial role in the onset and\nprogression of complications associated with diabetes 9, 10<\/sup>.<\/p>\n\n\n\n

EMPA is an inhibitor of (SGLT2) sodium-glucose cotransporter 2 11-14<\/sup> and is a novel therapeutic approach agent for managing type 2 DM 10-13. It reduces glucose reabsorption in the kidney tubules, lowering blood glucose levels 15-18<\/sup>. Clinical studies have demonstrated that EMPA improves clinical outcomes and reduces mortality in diabetic patients with cardiovascular and chronic kidney diseases 19, 20<\/sup>. Studies have demonstrated that EMPA can reduce oxidative stress in the heart and kidneys of diabetic animal models. It has also been observed to decrease lipid peroxidation in patients with diabetes.21, 22<\/sup>. The effects of EMPA interconnected mechanisms and outcomes associated with different factors, such as Histone Deacetylases (HDACs) in deacetylases, mediate the effects of EMPA and SGLT2 inhibition in the context of DPN.23,24<\/sup> Assess HDACs modulate gene expression and epigenetic changes related to neuroprotection and nerve regeneration in diabetic conditions and glycerophospholipids in modulating neuronal membrane structure and function, their role in the DPN context, and their potential interaction with EMPA and SGLT2 inhibition. The combined influence of EMPA, SGLT2 inhibition, histone deacetylases, and glycerophospholipids contributes to the amelioration of DPN in rats. The impact on nerve conduction, pain perception, and neuroinflammatory processes, considering central and peripheral nerve function. Role of miR-21, TRAF3IP2, and RECK in mediating the effects of EMPA and SGLT2 inhibition on DPN. These factors influence neuroinflammation, extracellular matrix remodeling, and neuronal survival in diabetic neuropathy.23, 24<\/sup><\/p>\n\n\n\n

Various research studies have shown\nthe beneficial effects of EMPA on liver health. For instance, EMPA treatment\nsignificantly improved liver outcomes in hereditary hypertriglyceridemic rats\nby reducing cell senescence markers and attenuating oxidative stress 25<\/sup>.\nClinical trials in patients with non-alcoholic fatty liver disease (NAFLD)\nwithout diabetes demonstrated that EMPA treatment significantly improved liver\nsteatosis and fibrosis compared to placebo 26, 27<\/sup> Another study\nindicated that the treatment with EMPA showed improvement in markers of\nfibrosis and liver steatosis. Suggesting its potential benefit in managing\nliver-related conditions 28<\/sup>. Additionally, EMPA exhibited hepatoprotective\neffects in rats with bile duct ligation-induced liver injury, highlighting its\nefficacy in protecting the liver against injury 29<\/sup> A recent study showed that\nursodeoxycholic acid leads to more reduction in insulin resistance and liver\nfibrosis scores in NAFLD patients with type 2 diabetes compared with EMPA\ntreatment. However, both treatments managed the liver steatosis and achieved a\nsignificant regression in non-alcoholic fatty liver score30<\/sup>. <\/p>\n\n\n\n

In addition, EMPA has an advantageous\neffect on the hematological system by restoring\nneutrophil function and count and allows the termination of G-CSF treatment, thereby improving patients\u2019\nquality of life by removing painful injections31<\/sup>. Moreover, the AMPK\/SIRT-1\npathway regulates metabolism, apoptosis, inflammation, and mitochondrial\nfunction during oxidative stress. In thioacetamide-induced Liver\nfibrosis in Rats, EMPA showed an ant-fibrotic effect <\/em>by inhibiting\nHypoxia-inducible factor 1-alpha (HIF-1\u03b1) and stimulation AMP-activated protein\nkinase (AMPK)\/Sirtuin-1 (SIRT-1) activity. EMPA is an SGLT-2 inhibitor that activates\nthe AMP-activated protein kinase (AMPK)\/mammalian target of the rapamycin\n(mTOR) signaling pathway, thus controlling the autophagy and oxidative stress\nin NAFLD32<\/sup>. <\/strong><\/p>\n\n\n\n

The effects of empagliflozin on the liver in conjunction with metallothionein and quercetin, and considering various related pathways and outcomes in the context of streptozotocin-induced diabetes mellitus in rats including Modulation of NF-\u03baB\/Nrf-2\/PPAR-\u03b3 Interplay within the liver, the potential regulatory effects on inflammation, oxidative stress, and metabolic regulation, Normalized Pin1 Expression Level and AMPK Activation Assess how these changes affect cellular proliferation, apoptosis, and energy metabolism in the diabetic liver. SGLT2 Inhibitors and Lipotoxicity its influence on lipid metabolism, hepatic steatosis, and lipid-induced cellular stress responses, particularly in the diabetic condition.33, 34, 35<\/sup><\/p>\n\n\n\n

Despite existing studies\nsupporting the positive impact of EMPA on liver outcomes, the present study investigates\nthe potential protective effects of EMPA on hepatocytes and liver function in\nstreptozotocin-induced diabetes in rats. This study’s results could enhance our\ncomprehension of how EMPA acts as a hepatoprotective agent against\ndiabetes-related complications.<\/p>\n\n\n\n

Material and methods<\/strong><\/p>\n\n\n\n

Animals<\/strong><\/p>\n\n\n\n

58 male Wister rats aged 9-10\nweeks were selected for this study. The Animal Care and Use Committee at Jordan\nUniversity of Science and Technology approved the animal protocol. The rats\nwere housed in a controlled environment with a 12-hour light\/dark cycle at room\ntemperature and provided ad libitum access to food and water. The rats were randomly\nassigned to one of four groups: Control (n=15), DM (n=13), DM+EMPA (Diabetic\nrats treated with EMPA, n=15), and EMPA (Control rats treated with EMPA, n=15).\n<\/p>\n\n\n\n

Diabetes induction and\nempagliflozin treatment<\/strong><\/p>\n\n\n\n

Diabetic rats were included in the\nstudy. To reduce early death, the drinking water after STZ injection was\nsupplemented with sucrose (15g\/l) for 48 hours (205). However, two rats in the DM\ngroup died. The fasting blood glucose was monitored weekly using a glucose\nanalyzer (Accu-check Guide Blood Glucose Meter, Germany). Rats in groups 2 and\n3 were treated with  (10 mg\/kg) EMPA dissolved\nin 5% hydroxyethylcellulose by oral gavage using a 2.25 mm metallic gauge for 8\nweeks after DM induction. Diabetes was induced by administering a single\nintraperitoneal injection of streptozotocin (STZ) (40 mg\/kg) dissolved in\nsodium citrate buffer (pH 4.5). The fasting plasma glucose level was measured\none day after STZ injection, and\nrats with fasting blood glucose levels >150 mg\/dl (204). To prevent early mortality, the\ndrinking water of diabetic rats was supplemented with sucrose (15 g\/L) for 48\nhours (205). EMPA treatment was initiated\nafter 7 days of STZ injection at a dose of 10 mg\/kg, administered orally using\na 5% hydroxyethyl cellulose solution, and continued for 8 weeks.<\/p>\n\n\n\n

Blood collection and biochemical analysis<\/strong><\/p>\n\n\n\n

Following the euthanization of the rats, blood samples were obtained.\nThese blood samples were subsequently subjected to centrifugation, separating\nserum from other blood components for further biochemical analysis. The levels\nof lactate dehydrogenase (LDH) (AGAPPE, India), alanine aminotransferase (ALT),\naspartate aminotransferase (AST) (Teco Diagnostics, Annaheim, CA, USA), total\nand direct bilirubin (BioLabo, France), and total protein (TP) (Abcam, USA),\nwere evaluated using commercially available kits. The activity or concentration\nof each parameter was measured spectrophotometrically by UV\/VIS single beam\nspectrophotometer (EMC-11D-V; EMCLAB instruments, Duisburg, Germany).<\/p>\n\n\n\n

Histological examination<\/strong><\/p>\n\n\n\n

Liver tissues were harvested after\nsacrificing the rats. Liver tissues were washed with phosphate buffered saline to\nremove excess blood and then fixed in 10% formaldehyde for 48 hours. The\ntissues were dehydrated, cleared, infiltrated with paraffin wax, and embedded\nin paraffin blocks. Subsequently, thin sections (3-5 \u00b5m) were cut using a\nmicrotome, deparaffinized with xylene, stained with H and E and mounted with\nDPX for light microscopic (Leica inverted light mi-croscopy, Leica\nMicrosystems, Wetzlar, Germany) examination.<\/p>\n\n\n\n

Data analysis<\/strong><\/p>\n\n\n\n

To perform the statistical tests,\nwe utilized GraphPad Prism 5.01 Computer Software from GraphPad Software Inc.\nSpecifically, we employed the D’Agostino & Pearson omnibus and Shapiro-Wilk\nnormality tests. To compare the different groups, either One Way ANOVA or\nKruskal-Wallis tests were utilized. The data were presented as means \u00b1 standard\nerror of the mean (SEM). At a ‘p<\/em>‘ value of 0.05, the results were\naccepted as statistically significant.<\/p>\n\n\n\n

Results and Discussion<\/strong><\/p>\n\n\n\n

Figure (1) demonstrates the levels\nof aspartate aminotransferase (a), alanine aminotransferase (b), Lactate\ndehydrogenase (c), and alkaline phosphatase (d) in the four experimental\ngroups.  All liver enzymes were measured\nin U\/L. As shown in Figure (1a), AST concentration was significantly increased\n(p<\/em> < 0.05) in rats treated with EMPA compared to control rats.\nHowever, when we compared the levels of the same enzyme between DM and rats\ntreated with EMPA, the former group showed a statistically significant decline\n(p<\/em> = 0.05). Figure (1b) shows that DM rats with and without treatment ha EMPA\nd a significant increase in ALT concentration (p<\/em> < 00.5) when\ncompared to control rats. Figure (1c) shows that LDH levels were significantly\nlower in DM rats treated with (p<\/em> < 0.0001, p <\/em>< 0.005) or\nwithout (p<\/em> < 0.05, p<\/em> < 0.005) EMPA compared to control\ngroups treated with or without EMPA. As can be seen in Figure (1d), the levels\nof ALP were significantly higher in both DM rats (p<\/em> < 0.0001) and DM+\nEMPA (p<\/em> < 0.005) versus control rats. In addition, the DM group\nshowed higher levels of ALP (p<\/em> < 0005) versus normal rats treated\nwith EMPA. <\/p>\n\n\n\n

Figure (2) illustrates the levels\nof total protein (g\/dL) in the four tested groups; DM rats without treatment,\nDM+ EMPA, rats treated with EMPA, and control rats. As reflected in the figure,\nthere were no significant differences (p<\/em> = 0.1037) in the total protein\nconcentrations between all groups. <\/p>\n\n\n\n

Levels of bilirubin (mg\/dL) in DM\nrats, DM+ EMPA rats, EMPA rats, and control rats are illustrated in Figure (3).\nAs can be seen in the figure, even though there was an increase in the\nbilirubin levels in the tested groups versus the control group, this elevation\nwas not statistically significant (p<\/em> = 0.1165).<\/p>\n\n\n\n

Figure (4) represents the\nhistological examination of liver tissues harvested from the study groups using\nmicroscopy. In figure (4a), the liver section from the control group exhibited\na normal liver structure, including a central vein, portal vein, sinusoids, and\nhepatocytes forming hepatic lobules. In figure (4b), the liver section from the\nDM rat group demonstrated dilated sinusoids and infiltration of inflammatory\ncells, along with congestion of blood within the sinusoids. However, in figure\n(4c), the liver section from the DM+ EMPA showed a normal arrangement of\nhepatocytes with slight dilation of sinusoids.<\/p>\n\n\n\n

Figure (1)<\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 1: Levels of liver enzymes in U\/L [Aspartate amino transferase (a), Alanine amino transferase (b), Lactate dehydrogenase (c), alkaline phosphatase (d)] in diabetic rats without treatment, diabetic rats treated with EMPA, and normal rats treated with EMPA compared to the control rats. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\nFigure 2: Levels of total protein (g\/dL) in four tested groups; diabetic rats
without treatment, diabetic rats treated with , normal rats treated with EMPA, and control rats. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\nFigure 3: Levels of total bilirubin (mg\/dL) in four tested groups; diabetic rats without treatment, diabetic rats treated with , normal rats treated with EMPA, and control rats. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\n\n

Figure 4: Histological examination of liver tissues harvested from (a) the control rats,(b) untreated diabetic rats, (c) diabetic rats treated with EMPA, Bar = 50 \u00b5m, H & E.<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The impact of diabetes on various organ systems is a pressing concern in light of the escalating global prevalence of this metabolic disorder36<\/sup>. While much attention has been given to the renal and cardiovascular complications of diabetes, the effect on liver is highly important. The liver’s functions are essential for metabolic regulation, detoxification, and nutrient storage. Unfortunately, diabetes can have a harmful impact on this vital organ. Liver complications, including hepatic steatosis, inflammation, fibrosis, and impaired liver function, can significantly contribute to the overall burden of diabetes-related complications. <\/p>\n\n\n\n

In terms of liver enzyme levels, analyzed data showed that\nempagliflozin treated diabetic rats had lower AST and LDH levels when compared\nto the diabetic group. These enzymes are commonly used as biochemical markers\nfor liver damage 37, 38<\/sup>. This decrease in AST and LDH levels\nsuggests that empagliflozin has beneficial for liver health. The observed\nreduction in AST and LDH levels may be attributable to empagliflozin’s ability\nto improve hepatic cellular function and energetic status 39<\/sup>,\nenhance glucose utilization 40<\/sup>, and reduce inflammation 41<\/sup>.<\/p>\n\n\n\n

The observed increase in ALT levels in diabetic rats treated with\nempagliflozin may be influenced by the drug’s effects on hepatic metabolism.\nEmpagliflozin is known to modulate gluconeogenesis and hepatic glucose output 25<\/sup>,\nwhich can impact alanine levels and subsequently affect ALT concentrations 42<\/sup>.\nAdditionally, empagliflozin’s ability to increase fatty acid oxidation 43<\/sup>\nand decrease hepatic steatosis may also contribute to changes in ALT levels 44<\/sup>,\nreflecting alterations in hepatic lipid turnover. <\/p>\n\n\n\n

Diabetes disrupts the balance of calcium and phosphate 45, 46<\/sup>,\nwhich can influence ALP levels 47<\/sup>. Furthermore, the presence of\nhepatic inflammation and hepatocyte damage associated with diabetes can\ncontribute to the release of ALP into the bloodstream. Although empagliflozin’s\neffects on glucose metabolism and hepatic function may help mitigate these\ndisturbances, they may not fully normalize ALP levels in the diabetic\ncondition. Another point, it is important to note that ALP is not a specific\nindicator of liver damage and can be elevated in various clinical conditions,\nincluding active bone formation 48<\/sup>, disorders affecting blood\ncalcium levels 49<\/sup>, and vitamin D deficiency 38<\/sup>. Given\nthat, factors other than liver damage may contribute to the observed elevation\nin ALP levels in both diabetic rats and diabetic rats treated with\nempagliflozin. Empagliflozin\ncauses a reduction in liver fat in type 2 diabetes patients compared with\ncontrol group50<\/sup>.Also, it lowers the blood glucose level. Of note,\nEMPA treated-rats showed a significant smaller Atherosclerotic plaque area in\nthe aortic valve51<\/sup>. The beneficial effect of EMPA through inhibiting\nthe p38 MAPK\u03b1 and ERK1\/2 activities causes an enhancement of the anti-fibrotic\naction of metformin52<\/sup>.<\/p>\n\n\n\n

In regard of the effect of\nEMPA in the digestive system, it has been found to reduce the uric acid level\nin type 2 diabetic patients and thus eliminates the need for antigout therapy53<\/sup>.Additionally,\nempagliflozin reduces gluconeogenesis and increasing glycogenesis by stimulation\nrenal mRNA expression of phosphoenolpyruvate carboxykinase, gluconeogenic\nenzyme54<\/sup>.<\/p>\n\n\n\n

Despite the lack of significance in some statistical tests, clear\ntrends indicate improved liver parameters in diabetic mice treated with\nempagliflozin compared to untreated diabetic mice. Further studies are needed\nfor a longer duration of empagliflozin treatment to draw better conclusions. <\/p>\n\n\n\n

Drawing attention to an intriguing comparison, this study compared\nliver functional tests in control rats (non-diabetic) treated with the drug\nversus control rat. Interestingly, the control rats receiving the drug showed\nhigher liver parameter values in comparison to the normal rats, indicating\npotential complications associated with empagliflozin administration. However,\nin diabetic rats, the drug appeared to alleviate the negative effects of\ndiabetes on liver outcomes. This contrast highlights the importance of\nconsidering the diabetes context when assessing the drug’s impact on liver\nfunction. <\/p>\n\n\n\n

In a previous study\nconducted in bile duct ligation-induced liver injury in rat,EMPA\ntreatment reduced TNF-\u03b1, IL-6 and liver enzymes and increased Superoxide\ndismutase and glutathione peroxidase enzymes, therefore this shows the\nanti-inflammtory ,hepatoprotective, and antioxidant role of EMPA sequentially.\nAlso, bile duct proliferation and fibrosis of liver are both reduced55<\/sup>.\nAnother study showed that EMPA minimizes the lipid accumulation and oxidative\nstress in the liver and accordingly ameliorates the NAFLD condition. The mechanism\nof action of EMPA on hepatic lipid metabolism could be summarized in four\npoints as following: (1) a reduction in accumulation of lipotoxic\ndiacylglycerol and ectopic triacylglycerol56<\/sup> (2) a decrease in the\nmRNA expression of lipogenic enzymes including fatty acid synthetase (fas) and\nstearoyl-CoA desaturase 1 (scd1). (3) Lowering the expression of sterol\nregulatory element-binding protein 1 (srebp1) and peroxisome\nproliferator-activated receptor-\u03b1 (PPAR-\u03b1), and thus suppressing\nhepatic lipogenesis57<\/sup>.(4) The EMPA treatment in Type 2 diabetes\nmellitus patients causes a significant reduction in liver fat content 58<\/sup>.Another\nresearch showed that EMPA lowers the concentration of intrahepatic\nlactosylceramide and increases the unsaturated triglycerides in normal mice59<\/sup><\/strong><\/p>\n\n\n\n

Several limitations are evident in this study that should be\nacknowledged. One limitation of this study is the use of an animal model, which\nmay not fully represent the complexities of human diabetes and liver\ncomplications. The focus on biochemical parameters and histological examination\nprovides valuable insights but may not capture the complete spectrum of liver\nfunction. Additionally, this study solely examined empagliflozin without\ncomparing it to other treatments, limiting the assessment of its relative\nefficacy. Further investigations using diverse techniques, longer-term studies,\nand comparative analyses are needed to enhance the understanding of\nempagliflozin’s effects on diabetes-related liver complications.<\/p>\n\n\n\n

A research study was conducted to observe the impact of Wattakaka\nvolubilis leaf extract, a traditional Indian herb, on male Wistar rats.\nDiabetic rats exhibited necrosis of hepatocytes, congestion of blood in\nsinusoids, and infiltration of inflammatory cells with dilation of sinusoids 60<\/sup>.\nThese pathological changes are indicative of liver damage and inflammation\nassociated with diabetes. In light of this, exploring novel therapeutic\ninterventions that can effectively manage diabetes-related liver complications\nis of utmost importance. <\/p>\n\n\n\n

The present study investigated the potential influence of empagliflozin\nis an inhibitor of sodium-glucose cotransporter 2 (SGLT2). On liver outcomes in\ndiabetic rats. The results revealed intriguing trends; indicating improvements\nin liver functional tests among diabetic rats treated with empagliflozin. In\naddition, histological examination revealed a restoration of the normal\narrangement of hepatocytes and reduced sinusoidal dilation in the\nempagliflozin-treated diabetic group. Altogether, these findings offer valuable\ninsights into the potential hepatoprotective effects of empagliflozin in the\ncontext of diabetes. These findings contribute to the existing body of\nknowledge and stimulate further exploration of the mechanisms underlying\nempagliflozin’s impact on liver outcomes.<\/p>\n\n\n\n

According to the literature, few research studies have demonstrated\nthe impact of empagliflozin on liver outcomes. For instance, a study by\nTrnovska and colleagues showed that empagliflozin treatment significantly\nimproved liver outcomes in hereditary hypertriglyceridemic rats 25<\/sup>.\nThese improvements are associated with reduced biomarkers of cell senescence,\nwhich refers to the deterioration and loss of cellular function over time.\nAdditionally, empagliflozin attenuated oxidative stress biomarkers in the liver\ntissues 25<\/sup>. A research team conducted a study using randomized,\ndouble-blind, and placebo-controlled methods to examine how empagliflozin\naffects liver steatosis and fibrosis in patients with NAFLD but no diabetes.\nAccording to the study, empagliflozin treatment resulted in notable\nenhancements in liver steatosis and fibrosis when compared to the placebo group\n26, 27 <\/sup>.The researchers also explored the possible protective\neffects of empagliflozin on liver injury induced by bile duct ligation in rats.\n29<\/sup>. Through a combination of molecular docking analysis and in vivo\nexperiments, the study revealed that empagliflozin demonstrated promising\nefficacy in protecting the liver against injury 29<\/sup>. These studies\nare in line with the findings of our current study.<\/p>\n\n\n\n

Several explanations have been addressed and discussed here to\nelucidate the observed findings in the current study. For example, one possible\nexplanation for restoration of the normal arrangement of hepatocytes and the\nreduction in sinusoidal dilation observed in diabetic mice following\nempagliflozin administration is its impact on hepatic inflammation, fibrosis,\nand oxidative stress. Empagliflozin has demonstrated anti-inflammatory effects 22,\n40<\/sup>, attenuated hepatic fibrosis 24<\/sup>, and exhibited antioxidant\nproperties in various models 20, 23<\/sup>. Hence, empagliflozin may contribute to the restoration of\nhepatocyte structure and improved sinusoidal dilation, and Hallmarks of Aging\nin the Liver which includes hepatocyte growth factor (HGF), Kupffer cells,\nendothelial cell dysfunction, hepatic stellate cells, and liver sinusoidal\nfunction61<\/sup>. Empagliflozin’s potential to inhibit inflammatory and\napoptotic signaling pathways within the liver may contribute to the attenuation\nof liver damage and aging. Investigating the combined effects of empagliflozin\nwith other agents, such as MET and JTXK, in enhancing antioxidant capacity and restoring\nliver cell activities can provide a comprehensive understanding of its\nsynergistic actions in promoting liver health62, 63<\/sup>. Additionally,\nits effects on glucose and lipid metabolism 64, 65<\/sup>, along with\nimproved insulin sensitivity, may further aid in the improvement of liver\nhistology. <\/p>\n\n\n\n

Conclusion<\/strong> <\/strong><\/p>\n\n\n\n

This study sheds light on the impact of EMPA on liver function and histological features in STZ -induced diabetic rats. Through liver functional tests, we observed significant improvements in parameters such as AST, ALT, LDH, and ALP levels among diabetic rats treated with EMPA compared to untreated diabetic rats. Moreover, histological examination revealed a restoration of the normal arrangement of hepatocytes and reduced sinusoidal dilation, infiltration of inflammatory cells, along with less congestion of blood within the sinusoids in the EMPA-treated diabetic group. Altogether, the data offer valuable insights into the potential in the context of diabetes. <\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors declare no conflict of interest.<\/p>\n\n\n\n

Funding Source<\/strong><\/p>\n\n\n\n

Financial support by Jadara University. Grant number is (R1- 122-\n13-467)<\/strong><\/p>\n\n\n\n

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