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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cAMP, carbachol, and insulin secretion. (a) IBMX and insulin secretion. ...
cAMP, carbachol, and insulin secretion. (a) IBMX and insulin secretion. Islets were perifused successively with 2.8 mM glucose for 10 minutes, 16.7 mM glucose for 10 minutes, 2.8 mM glucose for 20 minutes, first in the absence and then in the presence of IBMX 100 μM. Shown are the AUCs of insulin responses normalized to WT values set at 1. Absolute values of AUCs for WT are 0.32% of insulin content (without IBMX) and 0.99 % of insulin content (with IBMX). (b) Forskolin and insulin secretion. Islets were perifused in the presence of 100 μM IBMX as follows: 2.8 mM glucose for 10 minutes, 16.7 mM glucose for 10 minutes, 2.8 mM glucose for 20 minutes, 16.7 mM glucose + forskolin (10 μM) for 10 minutes, and 2.8 mM glucose for 25 minutes. Results are AUCs of insulin responses (n = 4). Inset: double-KO values normalized to WT values, set at 1. (c) Static incubations of isolated islets. Insulin secretion from 10 islets incubated for 15 minutes at 16.7 mM glucose in the presence or absence of IBMX 100 μM and forskolin (FSK) 10 μM (n = 3 separate experiments). Inset, double-KO values normalized to WT values, set at 1. (d) cAMP accumulation in 20 islets incubated in presence of IBMX 250 μM with or without forskolin 10 μM (n = 4–9, pooled from two separate experiments). Data are expressed as means ± SE of femtomoles cAMP accumulated per islet during 20 minutes. **P < 0.01, §P < 0.005, §§P < 0.001 vs. WT controls. (e) Carbachol and insulin secretion. Islets were perifused with 16.7 mM glucose in the presence or absence of carbachol (Cch, 1 μM). The data are AUCs of secreted insulin. Data are mean ± SEM (n = 3).