Dipeptidyl peptidase-4 inhibition prevents cell death via extrinsic and intrinsic apoptotic pathways in rat pancreas with insulin resistance

The study aims to evaluate the effect of saxagliptin, a specific inhibitor of dipeptidyl peptidase-4 enzymes, on body weight gain, lipid profiles, and cell death through apoptosis in rats with insulin resistance (IR). Male adult Sprague-Dawley rats (n=32) were divided into 4 groups: control (Ctrl), IR, saxagliptin control, and IR treated with saxagliptin(IR+S). Insulin resistance was induced by 10% fructose in the drinking water for 8weeks. Saxagliptin (10mg/kg/day) was administrated by oral gavage for 2weeks. Biochemical parameters were measured spectrophotometrically. Peptides were determined by the streptavidin-biotin-peroxidase method. Although the amount of food and liquid consumed are inversely proportional, the calories received are almost equal between both Ctrl and IR groups, as well as IR and IR+S groups. Increased homeostasis model assessment for insulin resistance, HOMA-, triglycerides, and very low-density lipoprotein in the IR group were comparatively decreased by saxagliptin administration. The area percentage of caspase-3 and apoptotic peptidase activating factor-1 immunopositive cells in the IR+S group decreased compared with the IR group. Similarly, the percentages of caspase-8 and -9 immunopositive cells in the IR group were higher than the IR+S group. It was observed that the percentage of poly (ADP-ribose) polymerase-1 immunopositive cells was increased in the IR+S group compared with the IR group. Thus, saxagliptin may prevent IR-induced apoptotic cell death and regulate impaired homeostasis model assessment for insulin resistance and serum lipid levels.