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Am J Physiol Endocrinol Metab 281: E242-E247, 2001;
0193-1849/01 $5.00
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Vol. 281, Issue 2, E242-E247, August 2001

GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve

Andreas Brandt1, Martin Katschinski1, Rudolf Arnold1, Kenneth S. Polonsky2, Burkhard Göke3, and Maria M. Byrne1

1 The Clinical Research Unit for Gastrointestinal Endocrinology, Department of Internal Medicine, Philipps University, 35033 Marburg, Germany; 2 Department of Internal Medicine, Washington University, St. Louis, Missouri 63110; and 3 Department of Gastroenterology, Inselspital, University of Bern, CH-3010 Bern, Switzerland

The present study was undertaken to establish in normal volunteers the alterations in beta -cell responsiveness to glucose associated with a constant infusion of glucagon-like peptide-1 (GLP-1) or a pretreatment infusion for 60 min. A high-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels by use of a two-compartmental model that utilized mean kinetic parameters. During the saline study, from 5 to 15 mM glucose, the relationship between glucose and ISR was linear. Constant GLP-1 infusion (0.4 pmol · kg-1 · min-1) shifted the dose-response curve to the left, with an increase in the slope of this curve from 5 to 9 mM glucose from 71.0 ± 12.4 pmol · min-1 · mM-1 during the saline study to 241.7 ± 36.6 pmol · min-1 · mM-1 during the constant GLP-1 infusion (P < 0.0001). GLP-1 consistently stimulated a >200% increase in ISR at each 1 mM glucose interval, maintaining plasma glucose at <10 mM (P < 0.0007). Pretreatment with GLP-1 for 60 min resulted in no significant priming of the beta -cell response to glucose (P = 0.2). Insulin clearance rates were similar in all three studies at corresponding insulin levels. These studies demonstrate that physiological levels of GLP-1 stimulate glucose-induced insulin secretion in a linear manner, with a consistent increase in ISR at each 1 mM glucose interval, and that they have no independent effect on insulin clearance and no priming effect on subsequent insulin secretory response to glucose.

insulin secretion; connecting peptide; priming; beta -cell sensitivity


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