Incretin mimetics and DPP-4 inhibitors: new approach to treatment of type 2 diabetes mellitus.

Type 2 diabetes constitutes the main bulk (85-90%) of diabetic population. It is a chronic metabolic disorder with progressive ?beta-cell dysfunction, impaired insulin actions and various other abnormalities. Insulin response of beta-cell is more after oral glucose or following meal than intravenous infusion of glucose. Gut related peptides, the incretin hormones released after meal following activation of the enteroinsular axis plays an important role in glucose homeostasis by pancreatic and extrapancreatic glucoregulatory effects and helps in preservation of beta-cell function. In type 2 diabetes, there is progressive decline of these incretins level, glucagons like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) with loss of beta-cell mass, beta-cell function and glycemic deterioration. These peptides are rapidly degraded by endogenous proteases, dipeptidyl peptides-4 (DPP-4) giving a very short half life of 2-3 minutes. Currently available anti-diabetic drugs do not address these arms of glucoregulatory dysfunction of type 2 diabetes. Modern therapeutic strategy should be targeted at preservation of beta-cell mass and function by exploiting the incretin hormones and enteroinsular axis. DPP-4 resistant incretin analogues/mimetics (e.g. exenatide, liraglutide) that have been developed by modifications/ substitutions in the polypeptide chain may be an effective alternative of the existing therapy of type-2 DM. DPP-4 inhibitors (e.g. sitagliptin, vindagliptin) prevent the degradation of endogenous GLP-1 and GIP, thereby potentiate their actions and help in glycemic control. Distinctive features of incretin mimetics are: their action is glucose dependent, do not produce hypoglycemia, help in preservation of beta-cell mass and function, help in weight reduction. DPP-4 inhibitors are weight neutral. Ongoing studies will reveal newer avenues and long term outcome of these molecules.