The incretin notion and its relevance to diabetes.
Basic research on the cellular mechanisms that control the expression of the gene encoding glucagon has led to the discovery of proglucagon, which is processed alternatively by tissue-specific proteolysis to produce glucagon in the pancreatic alpha cells and a GLP-1 in the intestines. GLP-1 hormone is released into the circulation from intestinal L cells in response to meals and is the most potent incretin hormone known; GLP-1 and GIP appear to account for most, if not all, of the intestinal incretin effect in the augmentation of glucose-stimulated insulin secretion. Analyses of the mechanisms of action of GLP-1 and of glucose on isolated cultured rat beta cells using patch-clamp techniques to record ion channel activities has led to the glucose competence concept in which the combined glucose-signaling and GLP-1/cAMP-signaling pathways are required to affect depolarization of beta cells and to thereby stimulate insulin secretion. It is hypothesized that, among other possible target channels, the K-ATP channel is key first event in GLP-1/glucose-mediated activation of the beta cell secretory response. It is proposed that at least one factor contributing to the pathogenesis of NIDDM is a desensitization of the GLP-1 receptor on beta cells induced by the hypersecretion of GLP-1. Because of the discoveries that GLP-1 stimulates both secretion and production of insulin, and that the actions of GLP-1 are entirely glucose-dependent, GLP-1 may provide unique advantages over the sulfonylurea drugs in the treatment of NIDDM.
Habener
J F
JF
Howard Hughes Medical Institute, Boston, Massachusetts.
D000595:Amino Acid Sequence; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000502:physiology*; D005934:Glucagon / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000502:physiology*; D011498:Protein Precursors / Q000502:physiology*
D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose