Incretin Based Therapy for Type 2 Diabetes mellitus

Type 2 Diabetes Mellitus (T2DM) is associated with obesity, insulin resistance, beta-cell dysfunction and hyperglucagonaemia, leading to hyperglycaemia. With the currently available antidiabetic agents, long term glycaemic control remains poor and attaining a glycosylated Hb (HbA1c) of < 7% is often not achievable. Further the antidiabetic agents available induce weight gain (except metformin), hypoglycaemia and have a negligible effect on beta-cell dysfunction. New classes of drugs that affect incretin hormones show promise in the treatment of T2DM. Incretins i.e. Glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptides (GIP) are peptide hormones secreted from the gut in response to ingestion of food and enhance the glucose-stimulated insulin secretion from the pancreas. T2DM patients are resistant to the insulin secreting action of GIP but are responsive to GLP-1. Therefore, GLP-1 shows promise in the treatment of T2DM as it enhances glucose-stimulated insulin secretion and there are less chances of hypoglycaemia. In addition, it promotes insulin biosynthesis, suppresses glucagon secretion, improves fasting and post-prandial blood sugar, HbA1c, inhibits gastric emptying, reduces appetite and food intake. Further, GLP-1 has been found to prevent or reverse the destruction of β cells in preclinical studies and is also associated with beneficial effect on cardio-vascular risk factor including blood pressure (BP), weight, endothelial dysfunction and lipid profiles. The clinical use of GLP-1 is limited by its short t½ of 2 minutes, due to its degradation by the enzyme, dipeptidyl peptidase-4 (DPP-4). To combat this problem, drugs have been developed to increase the level of GLP-1 in the body i.e. GLP-1 receptor agonist (incretin mimetics) and DPP-4 inhibitors (incretin enhancers).