title: Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications.
abstract: The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1), which are secreted by cells of the gastrointestinal tract in response to meal ingestion, exercise important glucoregulatory effects, including the glucose-dependent potentiation of insulin secretion by pancreatic β-cells. Research on the defective incretin action in type 2 diabetes mellitus suggests that the observed loss of insulinotropic activity may be due primarily to a decreased responsiveness of β-cells to GIP. GLP-1 does retain efficacy, albeit not at physiologic levels. Accordingly, augmentation of GLP-1 is a logical therapeutic strategy to ameliorate this deficiency, although the short metabolic half-life of the native hormone renders direct infusion impractical. GLP-1 receptor agonists that resist degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) and have protracted-action kinetics have been developed, and DPP-4 inhibitors that slow the enzymatic cleavage of native GLP-1 provide alternative approaches to enhancing incretin-mediated glucose control. However, GLP-1 receptor agonists and DPP-4 inhibitors are premised on highly divergent mechanisms of action. DPP-4 is ubiquitously expressed in many tissues and is involved in a wide range of physiologic processes in addition to its physiologic influence on incretin hormone biological activity. GLP-1 receptor agonists provide a pharmacologic level of GLP-1 receptor stimulation, whereas DPP-4 inhibitors appear to increase levels of circulating GLP-1 to within the physiologic range. This article examines the physiology of the incretin system, mechanistic differences between GLP-1 receptor agonists and DPP-4 inhibitors used as glucose-lowering agents in the treatment of type 2 diabetes, and the implications of these differences for treatment. The results of recent head-to-head trials are reviewed, comparing the effects of incretin-based therapies on a range of clinical parameters, including glycemia, β-cell function, weight, and cardiovascular function.
authors.affiliation: Bad Lauterberg Diabetes Center, Bad Lauterberg im Harz, Germany. nauck@diabeteszentrum.de
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nauck
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D054795:Incretins / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D054795:Incretins