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Am J Physiol Endocrinol Metab 285: E701-E707, 2003. First published May 28, 2003; doi:10.1152/ajpendo.00024.2003
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Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Ronald L. Prigeon,1,2 Shaista Quddusi,1 Breay Paty,1 and David A. D'Alessio1,3

1Division of Metabolism, Endocrinology, and Nutrition, University of Washington, 2Veterans Affairs Medical Center/Geriatric Research, Education, and Clinical Center, Baltimore, Maryland 21201; and 3Division of Endocrinology, University of Cincinnati, Cincinnati, Ohio 45267-0547

Submitted 16 January 2003 ; accepted in final form 27 May 2003

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (Ra) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [3H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 ± 14 vs. 113 ± 11 pM; 0.153 ± 0.029 vs. 0.156 ± 0.026 nM; and 64.7 ± 11.5 vs. 65.8 ± 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steady-state levels of 4.8 ± 0.2 to a nadir of 4.1 ± 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in Ra, from 22.6 ± 2.8 to 19.1 ± 2.8 µmol · kg–1 · min–1 (P < 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.

incretin; glucose production; pancreatic clamp; gastrointestinal hormone; glucose tolerance


Address for reprint requests and other correspondence: D. D'Alessio, Univ. of Cincinnati, Division of Endocrinology, Box 670547, Cincinnati, OH 45267-0547 (E-mail: david.'alessio{at}uc.edu).




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