Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors
Frédéric Preitner, … , Rémy Burcelin, Bernard Thorens
Frédéric Preitner, … , Rémy Burcelin, Bernard Thorens
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):635-645. https://doi.org/10.1172/JCI20518.
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Article Metabolism

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

Abstract

The role of the gluco-incretin hormones GIP and GLP-1 in the control of β cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R–/– but not in Gipr–/– mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on β cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a β cell autonomous secretion defect when both receptors are inactivated.

Authors

Frédéric Preitner, Mark Ibberson, Isobel Franklin, Christophe Binnert, Mario Pende, Asllan Gjinovci, Tanya Hansotia, Daniel J. Drucker, Claes Wollheim, Rémy Burcelin, Bernard Thorens

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Figure 1

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Generation of Gipr–/– mice. (a) Diagram showing the mouse GIP-receptor g...
Generation of Gipr–/– mice. (a) Diagram showing the mouse GIP-receptor gene, the GIP-receptor targeting vector, and the recombined allele. The genomic fragments diagnostic of homologous recombination using the external StuI-NheI probe are shown at the bottom of the figure. Positions of exons are marked as light gray boxes. In the mutant allele the AflII site denoted with * is replaced by a HindIII site on the 3′ end of the pgkNeo gene (marked with **). In the targeting vector, the arrows indicate the transcriptional orientation of the selection genes. (b) Southern blot analysis of the recombined alleles in mouse genomic DNA using the StuI-NheI probe. (c) Confirmation of receptor gene inactivation. Perifused isolated pancreatic islets from WT, Glp-1R–/–, Gipr–/–, or double-KO mice were challenged with successive 10-minute stimulation periods to 11.1 mM glucose, 2.8 mM glucose, 11.1 mM glucose + GLP-1 (10 nM), 2.8 mM glucose, 11.1 mM glucose + GIP (10 nM), and 2.8 mM glucose. Total insulin responses, quantified as AUC, are normalized for each genotype to the insulin response at 11.1 mM glucose alone, set at 100%. n = 4. Cont, control.