The Role of Incretins on Insulin Function and Glucose Homeostasis

Abstract

The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.

Keywords: exendin 9-39; glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotropic polypeptide (GIP); hormone antagonists; hormone coagonists.

Figure 1.

Localization of glucose-dependent insulinotropic polypeptide (GIP)- and glucagon-like peptide-1 (GLP-1)-secreting cells in the gastrointestinal tract (left) and secretion profiles of GIP, GLP-1, and insulin in response to ingestion of low (25 g), medium (50-75 g) or high (100-125 g) amounts of glucose (right). Curves adapted from Nauck et al (27) and Bagger et al (28).

Figure 2.

Central events in the history of the 2 incretin receptor antagonists, exendin(9-39)NH₂ and GIP(3-30)NH₂.

Figure 3.

Exendin(9-39)NH₂ actions on pancreatic δ (delta), α (alpha), and β (beta) cells, which can result in increased insulin secretion. Glucagon-like peptide-1 (GLP-1) receptors are red, glucagon receptors are blue, and somatostatin receptors black. The yellow peptide is exendin(9-39)NH₂, GLP-1 is red, glucagon is blue, and somatostatin black. Blockage of the GLP-1R on δ cells by exendin(9-39)NH₂ prevents somatostatin inhibition of α cells. Increasing glucagon secretion may stimulate insulin secretion via the glucagon receptor in the β cells. Exendin(9-39)NH₂ may also inhibit GLP-1 action on beta cells or act as inverse agonist.

Figure 4.

Contribution of gut-derived factors to postprandial insulin secretion, expressed in per cent of the total C-peptide secretion (area under curve, 0-240 minutes) following ingestion of 75-g glucose orally with or without incretin receptor antagonist infusions in healthy individuals. Calculations performed by Gasbjerg et al (64). GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1.