Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice
Benjamin J. Lamont, Yazhou Li, Edwin Kwan, Theodore J. Brown, Herbert Gaisano, Daniel J. Drucker
Benjamin J. Lamont, Yazhou Li, Edwin Kwan, Theodore J. Brown, Herbert Gaisano, Daniel J. Drucker
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Research Article Endocrinology

Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice

Abstract

Glucagon-like peptide-1 (GLP-1) circulates at low levels and acts as an incretin hormone, potentiating glucose-dependent insulin secretion from islet β cells. GLP-1 also modulates gastric emptying and engages neural circuits in the portal region and CNS that contribute to GLP-1 receptor–dependent (GLP-1R–dependent) regulation of glucose homeostasis. To elucidate the importance of pancreatic GLP-1R signaling for glucose homeostasis, we generated transgenic mice that expressed the human GLP-1R in islets and pancreatic ductal cells (Pdx1-hGLP1R:Glp1r–/– mice). Transgene expression restored GLP-1R–dependent stimulation of cAMP and Akt phosphorylation in isolated islets, conferred GLP-1R–dependent stimulation of β cell proliferation, and was sufficient for restoration of GLP-1–stimulated insulin secretion in perifused islets. Systemic GLP-1R activation with the GLP-1R agonist exendin-4 had no effect on food intake, hindbrain c-fos expression, or gastric emptying but improved glucose tolerance and stimulated insulin secretion in Pdx1-hGLP1R:Glp1r–/– mice. i.c.v. GLP-1R blockade with the antagonist exendin(9–39) impaired glucose tolerance in WT mice but had no effect in Pdx1-hGLP1R:Glp1r–/– mice. Nevertheless, transgenic expression of the pancreatic GLP-1R was sufficient to normalize both oral and i.p. glucose tolerance in Glp1r–/– mice. These findings illustrate that low levels of endogenous GLP-1 secreted from gut endocrine cells are capable of augmenting glucoregulatory activity via pancreatic GLP-1Rs independent of communication with neural pathways.

Authors

Benjamin J. Lamont, Yazhou Li, Edwin Kwan, Theodore J. Brown, Herbert Gaisano, Daniel J. Drucker

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Figure 3

The effect of GLP-1 on glucose-stimulated insulin secretion is restored in Pdx1-hGLP1R:Glp1r–/– islets.

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The effect of GLP-1 on glucose-stimulated insulin secretion is restored ...
Insulin secretion was assessed in isolated islets that were perifused with a Krebs-Ringer buffer that initially contained low glucose (2.8 mM), followed by high glucose (16.7 mM), and then by high glucose plus GLP-1 (10 nM). (A) The insulin secretory response to high glucose is presented as a fold change from the low-glucose condition, and (C) the response to the addition of GLP-1 is presented as a fold change from the high-glucose condition. Differences in the insulin secretory response stimulated by (B) high glucose and (D) high glucose plus GLP-1 were quantified by analysis of the incremental AUC for the change in insulin secretion over the 20-minute time period. n = 3–6. *P < 0.05 versus WT.