DPP-IV inhibitions represent a new class of oral antihyperglycemic agents based on incretin hormone action. DPP-IV inhibition by the alkaloids rich fraction of Withania somnifera (WS) might have a pleiotropic effect due to DPP-IV receptor present on various tissues mostly renal. As such, we hypothesized that treatment of diabetes with DPP-IV inhibitors may influence homeostatic model assessment along with improvement renal failure from isolated alkaloids rich WS extracts with different approached ex-vivo, in-vivo; and tissue histology. Effects of DPP-IV inhibitors from WS in high sucrose diet with dexamethasone-induced T2DM was explored in-vivo in rat. Apart from serum glucose; DPP-IV inhibition activity, renal toxicology, HbA1c, HOMA-IR, HOMA-β, insulin and renal lipid per-oxidation , superoxide dismutase , catalase and glutathione were measured with lipid profiles to correlate hematological effects of WS with renal tissue histology The diabetes induction by corticosteroid and high sucrose diet confirmed by HOMA-IR = 2.3 %, HOMA β % = 36.1 % and HOMA sensitivity = 44.1 %. Consequently. An increased concentration of serum glucose, triglyceride, cholesterol and tissue LPO (renal) with concomitant initial increase in tissue antioxidant to scavenging free radicals but prolong time antioxidants reduced. However, after administration of alkaloids WS extract DPP-IV inhibition increase in WS (83.39%), as compared to Sitagliptin (93.16%) with significant reduction in levels of glucose, TC, TG, and improves antioxidant properties. Renal tissue histology and hematological showed some significant change as compared to diabetes DPP-IV inhibitors isolated from WS extract caused significant (? ≤ 0.001) alterations in HOMA indices, insulin and glucose levels along with protective effects on kidney in addition to their antioxidant properties.  Consequently, WS caused significant alterations in renal tissue and pancreas by improving histoarchitectures through DPP-IV inhibition. DPP-IV inhibition lower blood glucose by increasing endogenous levels of glucagon-like peptide-1, an incretin with fewer side effects