The role of β cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs.
Glucagon-like peptide-1 (GLP-1), an insulinotropic gut peptide released after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β cells, we developed mice with β cell-specific knockdown of Glp1r. β cell Glp1r knockdown mice had impaired GT after intraperitoneal (i.p.) glucose and did not secrete insulin in response to i.p. or intravenous GLP-1. However, they had normal GT after oral glucose, a response that was impaired by a GLP1R antagonist. β cell Glp1r knockdown mice had blunted responses to a GLP1R agonist but intact glucose lowering with a dipeptidylpeptidase 4 (DPP-4) inhibitor. Thus, in mice, β cell Glp1rs are required to respond to hyperglycemia and exogenous GLP-1, but other factors compensate for reduced GLP-1 action during meals. These results support a role for extraislet GLP1R in oral glucose tolerance and paracrine regulation of β cells by islet GLP-1.
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Eric P
EP
Smith
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Zhibo
Z
An
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Constance
C
Wagner
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Alfor G
AG
Lewis
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Eric B
EB
Cohen
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Bailing
B
Li
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Parinaz
P
Mahbod
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Darleen
D
Sandoval
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Diego
D
Perez-Tilve
Department of Medicine, The Kovler Diabetes Center, University of Chicago, Chicago, IL 60637, USA.
Natalia
N
Tamarina
Department of Medicine, The Kovler Diabetes Center, University of Chicago, Chicago, IL 60637, USA.
Louis H
LH
Philipson
Institute for Diabetes, Obesity and Metabolism and the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Doris A
DA
Stoffers
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Randy J
RJ
Seeley
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45237, USA. Electronic address: dalessd@ucmail.uc.edu.
David A
DA
D'Alessio
D000818:Animals; D001786:Blood Glucose; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D018149:Glucose Intolerance; D006943:Hyperglycemia / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology
D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D018027:Receptors, Glucagon; D013629:Tamoxifen; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D005947:Glucose