The Effects of Incretin Mimetics on Islet Cell Function in Type 2 Diabetes
The term incretins is used to denote intestinal hormones released in response to nutrient ingestion that are able to potentiate glucosestimulated insulin secretion.1,2 The communication between the intestine and the endocrine pancreas is demonstrated by the observation that the increase of plasma insulin levels following oral glucose administration is much greater than that seen after intravenous glucose.1–4 This phenomenon has been termed the ‘incretin effect,’ and accounts for 50–70% of the total insulin secreted after oral glucose.1–4 The first incretin hormone to be identified was gastric inhibitory polypeptide (GIP), named because of its ability to reduce gastric acid secretion in dogs. However, this effect is seen at pharmacological doses, whereas the incretin action is observed at physiological levels. The hormone was therefore re-named glucose-dependent insulinotropic polypeptide, but retains the acronym GIP.
A second incretin hormone was discovered showing 50% homology with glucagon, and named glucagon-like peptide-1 (GLP-1). Both GLP-1 (mainly from L cells in the distal intestine) and GIP (primarily produced by K cells in the duodenum) are released within minutes following food ingestion and contribute to the rapid disposal of nutrients through several pathways, with the action on the pancreatic β cell probably representing the most important mechanism.1–4 Their circulating levels decrease rapidly (the half-life of GLP-1 is approximately two minutes and that of GIP is approximately six minutes) due to enzymatic inactivation by dipeptidyl peptidase-4 (DPP-4). Both GIP and GLP-1 contain alanine at position two, which render them excellent substrates for DPP-4.1–4
The pleiotropic actions of incretins on the regulation of blood glucose have led to the concept that GLP-1 and/or GIP could be used in the treatment of type 2 diabetes. In type 2 diabetes GIP action is reduced, whereas its secretion does not seem to be altered. GLP-1 shows a lower insulinotropic effect. Individuals with type 2 diabetes show a small but significant reduction in meal-stimulated levels of GLP-1 and the action of this incretin remains relatively preserved, so most efforts have focused on GLP-1.2–5 Two main classes of drug have been developed: GLP-1 receptor agonists resistant to the action of DPP-4 (GLP-1 mimetics) and inhibitors of DDP-4 (GLP-1 enhancers) (see Figure 1).2–5 This article will discuss the effects of GLP-1 and its mimetics on the function of pancreatic islets, particularly in the case of type 2 diabetes.
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