Sitagliptin treatment prevented pancreatic lesions evolution in a rat modelo f type 2 diabetes-proposal of antooxidant, antiapoptotic, anti-inflammatory and proproliferative mechanism

Background: This study aimed to elucidate mechanisms underlying the protective effects of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, against pancreatic lesions, in an animal model of T2DM. Methods: Male obese diabetic ZDF (fa/fa) rats, 20-weeks-old, were treated with vehicle or sitagliptin (10mg/kg BW/day) for 6 weeks, and compared with lean control littermates (n=8/each). Biochemical parameters and lipid peroxidation were evaluated in serum/blood/tissues. Pancreatic lesions were assessed semiquantitatively by routine histopathological and PAS staining methods. Expression in mRNA of apoptotic (Bax, Bcl2, caspase 9), inflammatory (TNFα, IL-1β, IL6), proliferative (PCNA) and angiogenic (VEGF) mediators was assessed by RT-qPCR. Immunohistochemical methods were used to confirm Bax/Bcl2 protein expression. Results are means  s.e.m. ANOVA and Post-hoc tests were used (P<0.05 was considered statistically significant). Results: Sitagliptin treatment of diabetic ZDF (fa/fa) rats, ameliorated biochemical serum/blood parameters, pancreatic lipid peroxidation and diabetic lesions. Immunohistochemistry confirmed antiapoptotic effect observed by reduced expression of Bax/Bcl2 ratio by RT-qPCR. Caspase 9, IL-1β mRNA expression was decreased and proliferative and angiogenic factors overexpressed. Conclusions: Sitagliptin, in this animal model of T2DM, may derive its protective pancreatic effect by antioxidant, antiapoptotic, anti-inflammatory and proproliferative/proangiogenic mechanisms.

FCT/COMPETE-Strategic Project (Ref: PEst-C/SAU/UI3282/2011), PROTEC- Superior Polytechnic Institute of Viseu (ISPV)