Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis
Safina Ali, … , Maureen J. Charron, Daniel J. Drucker
Safina Ali, … , Maureen J. Charron, Daniel J. Drucker
Published April 11, 2011
Citation Information: J Clin Invest. 2011;121(5):1917-1929. https://doi.org/10.1172/JCI43615.
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Research Article Metabolism

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Abstract

Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr–/– mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr–/– mice by generating Gcgr–/–Glp1r–/– mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr–/–Glp1r–/– mice. Elimination of the Glp1r normalized gastric emptying and impaired intraperitoneal glucose tolerance in Gcgr–/– mice. Unexpectedly, deletion of Glp1r in Gcgr–/– mice did not alter the improved oral glucose tolerance and increased insulin secretion characteristic of that genotype. Although Gcgr–/–Glp1r–/– islets exhibited increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), mice lacking both Glp1r and the GIP receptor (Gipr) maintained preservation of the enteroinsular axis following reduction of Gcgr signaling. Moreover, Gcgr–/–Glp1r–/– islets expressed increased levels of the cholecystokinin A receptor (Cckar) and G protein–coupled receptor 119 (Gpr119) mRNA transcripts, and Gcgr–/–Glp1r–/– mice exhibited increased sensitivity to exogenous CCK and the GPR119 agonist AR231453. Our data reveal extensive functional plasticity in the enteroinsular axis via induction of compensatory mechanisms that control nutrient-dependent regulation of insulin secretion.

Authors

Safina Ali, Benjamin J. Lamont, Maureen J. Charron, Daniel J. Drucker

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Figure 5

Function of GPCRs in isolated islets.

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Function of GPCRs in isolated islets. Islet insulin secretion was assess...
Islet insulin secretion was assessed by preincubation of islets in KRB for 60 minutes at 2.8 mM glucose at 37°C before distribution in batches of 10 islets per condition into wells containing 16.7 mM glucose with or without (A) exendin-4 (Ex-4, 10 nM), [d-Ala2]GIP (GIP, 10 nM), (B) PACAP (10 nM), tolbutamide (Tol, 100 μM), or l-arginine (L-arg, 10 mM) for 1 hour at 37°C. Levels of insulin in the secretion medium were normalized to levels of islet insulin content and are expressed as a fold change in insulin secretion relative to WT high-glucose treatment. Insulin content values averaged approximately 30–40 ng/islet for Glp1r–/– and WT mice and 15–25 ng/islet for Gcgr–/– and Gcgr–/–Glp1r–/– mice (n = 3 mice per group). Data shown are representative of 2–3 independent experiments, each with 3 replicates per condition. (C) Total cellular and media cAMP in islets from WT, Glp1r–/–, Gcgr–/–, and Gcgr–/–Glp1r–/– mice was quantified following treatment of the islets with 0, 1, 3, or 10 nM [d-Ala2]GIP. Levels of cAMP in the secretion medium were normalized to levels of islet insulin content and are expressed as a fold change in islet cAMP levels relative to WT high-glucose treatment (n = 3 mice per group). Values are expressed as mean ± SEM. §P < 0.05, Glp1r–/– versus Gcgr–/–Glp1r–/– mice; #P < 0.05, Gcgr–/– versus Gcgr–/–Glp1r–/– mice; ‡P < 0.05, Gcgr–/–Glp1r–/– versus WT mice; †P < 0.05, Glp1r–/– versus WT mice; *P < 0.05, Gcgr–/– versus WT mice.