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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
-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
-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;
-cell
sensitivity
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