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Signaling Mechanisms Underlying the Release of Glucagon-Like Peptide 1

From the Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, U.K

Address correspondence and reprint requests to Dr. Fiona Gribble, Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Rd., Cambridge CB2 2XY, U.K. E-mail: fmg23{at}cam.ac.uk

Abbreviations: CGRP, calcitonin gene–related protein; DPPIV, dipeptidyl peptidase IV; GABA, -amino butyric acid; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; IP₃, inositol-1,4,5-triphosphate; K_ATP channel, ATP-sensitive K⁺ channel; SGLT, sodium glucose cotransporter

Glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells in response to a range of nutrients, hormones, and neurotransmitters. Its potency as an insulin secretagogue has led to pharmaceutical interest in developing strategies to enhance GLP-1 receptor activation in type 2 diabetes. A complementary approach, to stimulate endogenous release of GLP-1, would be facilitated by a better understanding of L-cell physiology. Using GLP-1–secreting cell lines such as GLUTag and STC-1, mechanisms underlying GLP-1 release have been identified at a single-cell level. A number of stimuli, including glucose and certain amino acids, result in membrane depolarization and Ca²⁺ entry through voltage-gated Ca²⁺ channels. Glucose triggers membrane depolarization both by closing ATP-sensitive potassium channels and because of its uptake by Na⁺-coupled glucose transporters. Whereas glutamine also triggers depolarization by Na⁺-coupled uptake, glycine opens Cl^– channels on the surface membrane. A number of agents, including fatty acids and hormones, enhance GLP-1 secretion by acting at stages downstream of depolarization. Some of these target G protein–coupled receptors, triggering elevation of cAMP or release of Ca²⁺ from intracellular stores. Understanding these different pathways and how they could be targeted to maximize GLP-1 secretion may be a step toward developing therapeutic GLP-1 secretagogues.

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