Canagliflozin protects against non-alcoholic steatohepatitis in type-2 diabetic rats through zinc alpha-2 glycoprotein up-regulation

Elevated blood glucose and insulin resistance are triggering factors for non-alcoholic steatohepatitis (NASH). We investigated the effects of the Sodium Glucose co-Transporter 2 (SGLT2) inhibitor canagliflozin on NASH development in rats with type 2 diabetes mellitus as well as the possible underlying mechanisms and for the first time the effect of canagliflozin on the hepatic zinc-alpha 2-glycoprotein (ZAG) levels.& para;& para;Rats were treated with nicotinamide and streptozotocin to reduce the insulin secretory capacity then fed high fat diet for 8 weeks. The diabetic high fat diet rats were divided into three groups; untreated group, canagliflozin 10 mg/kg treated group and canagliflozin 20 mg/kg treated group during this period. The elevated blood glucose and glycated haemoglobin (HbA1c) levels in the diabetic high fat diet rats were significantly reduced by canagliflozin. Moreover, the diabetic high fat diet induced NASH development as evidenced by liver weight gain, hepatic lipid accumulation and low hepatic ZAG expression as well as increased serum alanine aminotransferase; all these changes were reversed in rats treated with canagliflozin. Additionally, canagliflozin succeeded to upregulate the hepatic ZAG levels in both normal and diabetic high fat fed rats, lower the serum and hepatic inflammatory cytokines levels as well as lower the serum caspase-3 levels and enhanced hepatic Bcl-2 expression. Also, canagliflozin attenuated hepatic oxidative stress and elevated the antioxidant enzymes activity as well as the total antioxidant capacity. All these effects of canagliflozin were dose dependant. Conclusion: SGLT2 inhibitor-canagliflozin- has beneficial effects in treatment of NASH associated with diabetes mellitus.