COMPARATIVE GLUCOSE-LOWERING AND RENOPROTECTIVE EFFECTS OF SITAGLIPTIN AND INSULIN AND THEIR COMBINED THERAPY ON TYPE-2 DIABETES MELLITUS WITH NEPHROPATHY IN RATS

Abstract

The study compared the glucose-lowering and renoprotective effects of sitagliptin, insulin and their combination on high-fat, high-sugar diet, streptozotocin (STZ)-induced type-2 diabetes mellitus (T2DM) with nephropathy in rats. Methods: In addition to the normal control group (n= 8), diabetes was induced in adult male Spurge-Dawley rats by 6-week high-fat, high-sugar diet followed by a single intraperitoneal injection of streptozotocin 30 mg/kg BW. For four weeks thereafter, diabetic rats (n= 32) were divided into 4 equal groups (n
= 8) and received daily: vehicle (untreated diabetic group), insulin 10 IU/kg SC, sitagliptin 30 mg/kg PO, or combined sitagliptin-insulin, and continued on the same diet. We assessed a group of blood/serum measures of glucose metabolism and kidney functions and histopathology. Results: Compared to control group, the untreated diabetic rats developed significant decreases in body weight (BW) and serum insulin, increases in kidney weight (KW), KW/BW ratio, blood glucose and AGEs levels, increases in blood urea, creatinine, urine output, albuminuria and renal tissue TGF-β1 levels, and decrease in the creatinine clearance and showed variable glomerular, tubule-interstitial and vascular kidney lesions. Sitagliptin monotherapy stabilized the BW, KW and KW/BW ratio, reduced the blood glucose, AGEs, urea, creatinine, urine output, albuminuria and renal tissue TGF-β1 levels and increased the serum insulin and creatinine clearance, with greater improving the biochemical parameters (and not blood glucose), and ameliorating kidney histopathological lesions more than insulin alone. In contrast, insulin produced better effects on BW and KW/BW ratio. Importantly, sitagliptin-insulin co-treatment highly and greatly improved measures of glucose metabolism and kidney functions, and highly ameliorated kidney lesions when compared to treatment with insulin or sitagliptin alone. Conclusion: Combined sitagliptin-insulin therapy, in rats with T2DM and nephropathy, produced greater glycemic control and renoprotective effects more than treatment with sitagliptin or insulin alone. This combined therapy could have clinical unique application in the management of T2DM with nephropathy.
Keywords: Sitagliptin; insulin; diabetes mellitus; nephropathy; rats
Abbreviations: DM: Diabetes mellitus, T1DM: Type-1 diabetes mellitus, T2DM: Type-2 diabetes mellitus, IP: Intraperitoneal, STZ: Streptozotocin, FBG: Fasting blood glucose, 2hBG: 2-hour blood glucose postload, AGEs: Advanced glycation end-products, GIP: Glucose-dependent insulinotropic peptide, DPP-IV: Dipeptidyl peptidase-IV, GLP-1: Glucagon-like peptide-1, GLP-1R: GLP-1 receptor, TGF-𝛽1: Transforming growth factor-𝛽1, TNF-𝛼: Tumor necrosis factor-𝛼, IL-1β: Interleukin-1β