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Glucagon-Like Peptide-1 Augments Insulin-Mediated Glucose Uptake in the Obese State

Diabetes Section, Laboratory of Clinical Investigation (J.M.E.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224; Department of Medicine (G.S.M.), University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Laboratory of Molecular Endocrinology (J.F.H.), Howard Hughes Medical Institute, Boston, Massachusetts 02114; and Department of Medicine (J.F.H., D.E.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dariush Elahi, Ph.D., Massachusetts General Hospital, Geriatric Research Laboratory, Gray/Bigelow Sub-Basement 0015, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: . delahi{at}partners.org

Abstract

The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is being examined as a potential new agent for treatment in type 2 diabetic patients. Whereas the insulinotropic properties of this peptide are well established, another property of the hormone, an insulinomimetic effect per se, is controversial. In the normal glucose-tolerant lean state, it is difficult to demonstrate an insulinomimetic effect. The current study was conducted to examine whether GLP-1 has insulinomimetic effect in the obese state. Ten obese volunteers (body mass index, 34.6 ± 0.8 kg/m²), whose ages were 32.5 ± 3.0 yr, participated in two euglycemic clamp studies (n = 20 clamps) for 120 min. Five of the volunteers were females. The initial clamp was performed with a primed (0–10)-constant (10–60) infusion of GLP-1 at a final rate of 1.5 pmol · kg^-1 · min^-1. At 60 min, the GLP-1 infusion was terminated, and euglycemic was maintained from 60–120 min. After the GLP-1 study, each individual’s plasma insulin level was measured. A second study was performed that was identical to the first, with the infusion of regular insulin in place of GLP-1. Insulin infusion rates were regulated in each individual to simulate plasma insulin levels produced during the GLP-1 infusion. The rate of disappearance of glucose was calculated for each subject. Fasting plasma insulin levels were similar between studies. In response to the GLP-1 infusion, with maintenance of plasma glucose level clamped at fasting level, significant increases in plasma insulin occurred in all subjects (P < 0.001). The insulin levels during the insulin infusion study were similar to that induced by GLP-1. The rate of disappearance of glucose (insulin-mediated glucose uptake) progressively increased in response to both the GLP-1 and insulin infusion. However, the rate of disappearance of glucose during the GLP-1 study was significantly higher (P = 0.033) than during the insulin study. We conclude that in insulin-resistant states, GLP-1 has insulinomimetic properties per se.

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