Role of linagliptin in preventing the pathological progression of hepatic fibrosis in high fat diet and streptozotocin-induced diabetic obese rats

Abstract

Liver fibrosis is a common complication of diabetes mellitus, with a major global public health concern. Linagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4), is classically used to treat type 2 diabetes mellitus and improves insulin resistance. Additional potential influences of linagliptin on liver fibrosis are still unclear. The present study was undertaken to investigate the therapeutic credit of linagliptin in hepatic fibrosis induced by a high-fat diet (HFD) and streptozotocin (STZ) in rats. Moreover, the mechanisms underline its anti-fibrotic effect were explored. To induce liver fibrosis with T2DM; male Sprague-Dawley albino rats were fed on a high-fat high-sucrose diet for 28 days then exposed to a single dose of STZ (30 mg/kg, IP). After two days of STZ injection, a diabetes confirmation test was done and all diabetic rats were constantly fed on HFD for thirty days with or without treatment with linagliptin (6 mg/kg). Hepatotoxicity markers, lipid profile screening, insulin signaling, inflammatory cytokines (TNF-α, IL-6, NF-κB p65), fibrosis markers (Collagen, α-SMA, TGF-β1) and histopathological studies including hematoxylin and eosin (H&E) as well Masson's trichrome stains were performed. In our preliminary study, linagliptin at a dose of 6 mg/kg was chosen as the optimum anti-diabetic dose in rats challenged with STZ. Linagliptin significantly improved insulin sensitivity and lipid profile and reduced inflammatory mediators, and collagen depositions in rats with liver fibrosis and T2DM. In conclusion, above and beyond its anti-diabetic effect, this study introduced linagliptin as a promising option for preventing the pathological progression of liver fibrosis associated with T2DM.

Keywords: Inflammation; Insulin resistance; Linagliptin; Liver fibrosis.