The incretin hormones: from scientific discovery to practical therapeutics.

ABSTRACT

The incretins are gut hormones secreted in response to nutrient/carbohydrate ingestion and act on the pancreatic beta cell to amplify glucose-stimulated insulin secretion. Incretin hormone-based treatments for patients with type 2 diabetes represent a major advance in diabetes therapeutics. The ability of the incretin agents (glucagon-like peptide 1 [GLP-1] agonists and dipeptidyl peptidase IV [DPP-4] inhibitors) to improve glycaemia with a low associated risk of hypoglycaemia, together with beneficial/neutral effects on body weight, offers a significant advantage for both patients and treating clinicians. In this edition of 'Then and Now,' it is useful to look back 25 years and reflect upon the developments in this field since Nauck and colleagues published two seminal papers. In 1986 they first documented a reduced incretin effect in patients with type 2 diabetes (Diabetologia 2946-52), and then in 1993 they demonstrated that, in patients with poorly controlled type 2 diabetes, a single exogenous infusion of an incretin (GLP-1) increased insulin levels in a glucose-dependent manner and normalised fasting hyperglycaemia (Diabetologia 36741-744). In the ensuing 26 years, progress in the field of incretin hormones has resulted in a greater understanding of the relative roles of GLP-1 and glucose-dependent insulinotropic polypeptide secretion and activity in the pathogenesis of type 2 diabetes and the important recognition that native GLP-1 is quickly degraded by the ubiquitous protease DPP-4. This has led to the development of GLP-1 agonists that are resistant to degradation by DPP-4 and of selective inhibitors of DPP-4 activity as therapeutic agents. GLP-1 agonists (exenatide and liraglutide) and DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin and linagliptin) currently represent effective treatment options for patients with type 2 diabetes. Several additional agents are in the pipeline, including longer acting DPP-4-resistant GLP-1 agonists. More exciting, however, is the increasing recognition that the incretin agents have numerous extra-glycaemic effects that could translate into potential cardiovascular and other benefits.