The Incretin System and Type 2 Diabetes

While antidiabetes therapies target glycemic control, most do not address the underlying problems of excess bodyweight and deteriorating pancreatic beta-cell function. Some therapies also provoke hypoglycemia and/or weight gain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the gut in response to nutrient intake and has a major role in the post-prandial insulin response in healthy individuals. The incretin response is, however, impaired in individuals with type 2 diabetes. There are two therapeutic approaches that target the incretin system: GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1 receptor agonists provide pharmacological levels of GLP-1 activity, while DPP-4 inhibitors restore physiological levels. The pharmacological levels of GLP-1 induced by GLP-1 receptor agonists provide effective glycemic control and weight reduction. The DPP-4 inhibitors also improve glycemic control but are weight-neutral. Pre-clinical studies in animal models andin vitrosystems suggest that incretin-based therapies have the potential to preserve beta-cell mass and improve their function. Initial clinical data show improvements in beta-cell function in patients treated with incretin-based therapies, supporting the pre-clinical observations. A further benefit of incretin-based therapies is that they provide glucose-dependent glucose control, which means that they have a low inherent risk of inducing hypoglycemia. These agents therefore look extremely promising in the management of type 2 diabetes, being efficacious and having positive benefits on weight, low risk of hypoglycemia, and the potential to improve pancreatic islet cell function in the long term.