Endocrine Abstracts

Introduction: Metabolic disorders characterized by insulin resistance/hyperinsulinemia, such as metabolic syndrome and T2DM, are associated with Non-Alcoholic Fatty Liver Disease (NAFLD). SGLT-2i reduce reabsorption of glucose from the kidneys thereby promoting glucosuria, while their beneficial effects on insulin resistance have been recently recognized. In this study, we aimed to investigate the effect of Empagliflozin, in de novo triglyceride synthesis and beta-oxidation as well as high-fat diet (HFD)-induced inflammation in the liver and kidneys of ApoE (−/−) male mice.

Methods: At the age of 5 weeks, mice were switched from normal to HFD. After 5 weeks, they were divided into Control-group (9 mice) and Empa-group (9 mice: empagliflozin 10 mg/kg per day). After 10 weeks, animals were culled and liver and kidneys were harvested. Biochemical markers were measured at the onset and at the end of the intervention. The mRNA levels of enzymes contributing in de novo triglyceride synthesis including GPAT1, GPAT3, GPAT4, AGPAT2, DGAT1, DGAT2 and beta oxidation (AMPKa 1 and 2) were measured by qPCR. Liver and kidney sections were stained with H&E and histomorphometric analysis was performed. Immunohistochemical staining with anti-MCP-1 and anti-CD-68 was also conducted to assess inflammation.

Results: Empa-group mice had lower glucose and HDL-cholesterol levels (P≤0.01), while total-cholesterol, LDL and triglycerides did not change significantly compared to control group. Histomorphometry indicated that Empagliflozin significantly induced lipid accumulation and infammation in both liver and kidney, compared to Control-group. Immunohistochemistry staining revealed an increase in CD68 and MCP-1 expression in the Empa-group compared to Control-group in both kidney and liver. GPAT3, AGPAT2 mRNA levels were increased in Empa-group compared to Control-group in both kidney and liver (P<0.05). Empagliflozin also increased GPAT4, DGAT1 and DGAT2 mRNA levels in both kidney and liver approaching statistical significance (P≤0.09). AMPKa2 expression was up-regulated in the kidney of the Empa-group compared to the Control-group (P≤0.01) while no significant difference was observed in AMPKa 1 and 2 expression in the liver.

Conclusions: Our study revealed that long-term administration of Empagliflozin in ApoE (−/−) atherosclerosis mouse model, promotes NAFLD and induces lipid accumulation and inflammation in the kidney, at least partially via inducing the expression of enzymes involved in de novo synthesis of triglycerides and inflammatory process.