Glucagon-like peptide-1 (GLP-1) inhibits glucagon secretion from a cells and stimulates insulin secretion from ß cells in a blood-glucose dependent manner. Whereas the effects of GLP-1 on ß cells are mediated by GLP-1 receptor (GLP-1R) has been described in detail. The action of GLP-1 on a-cells, however, is not clear. To determine whether the inhibition is due to a direct effect that occurs through GLP-1R of a-cells, or indirect effect on a-cells through insulin stimulation from ß-cells, we generated a-cell specific GLP-1R knockout (aGLP-1R KO) mice after GLP-1R expression was verified by glucagon-producing a-cells at protein and mRNA level in both mouse and human pancreas. Compared to control mice, the aGLP-1R KO female mice had impaired glucose tolerance following intraperitoneal glucose administration, and had more impaired glucose tolerance after 1m high fat diet-fed, but their insulin secretion and insulin sensitivity were maintained. Interestingly, non-fasting glucagon level of aGLP-1R KO mice was significantly higher than that of the control mice, whereas insulin and GLP-1 levels were similar between the two groups of mice. More importantly, we found glucagon secretion was stimulated by glucose 15 minutes following glucose administration in the aGLP-1R KO mice, but not in the control mice. Furthermore, we isolated islets from aGLP-1R KO mice and directly examined the effects of aGLP-1R deletion on glucagon secretion. Glucose-stimulated insulin secretion assay showed the aGLP-1R KO islets had no significant differences from the control islets. However, arginine significantly stimulated glucagon secretion in the two group islets and the stimulation was significantly enhanced in aGLP-1R KO islets. Taken together, these data showed that aGLP-1R deletion disturbed glucose-dependent glucagon secretion, whereas insulin secretion was not affected, demonstrating aGLP-1R plays a direct role in regulating glucagon secretion.

Disclosure

Y. Zhang: None. K.R. Parajuli: None. G.E. Smith: None. R. Gupta: None. W. Xu: None. L.U. Nguyen: None. A.F. Zakaria: None. F. Mauvais-Jarvis: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis. K.W. Sloop: Employee; Self; Eli Lilly and Company. H. Wu: None.

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