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Differential Effects of Acute and Extended Infusions of Glucagon-Like Peptide-1 on First- and Second-Phase Insulin Secretion in Diabetic and Nondiabetic Humans

¹ Department of Medicine, University of Washington, Seattle, Washington
² Department of Medicine, University of Cincinnati, Cincinnati, Ohio
³ University of Maryland School of Medicine and Geriatric Research Education and Clinical Center (GRECC), Baltimore VA Medical Center, Baltimore, Maryland

OBJECTIVE—The purpose of this study was to determine whether an extended infusion of the incretin hormone glucagon-like peptide 1 (GLP-1) has a greater effect to promote insulin secretion in type 2 diabetic subjects than acute administration of the peptide.

RESEARCH DESIGN AND METHODS—Nine diabetic subjects and nine nondiabetic volunteers of similar age and weight were studied in identical protocols. First-phase insulin release (FPIR; the incremental insulin response in the first 10 min after the intravenous glucose bolus) and second-phase insulin release (SPIR; the incremental insulin response from 10–60 min after intravenous glucose) were measured during three separate intravenous glucose tolerance tests (IVGTTs): 1) without GLP-1 (control); 2) with acute administration of GLP-1 as a square wave starting just before glucose administration; and 3) with an extended infusion of GLP-1 for 3 h before and during the IVGTT.

RESULTS—In the subjects with diabetes, FPIR was severely impaired—a defect that was only modestly improved by acute administration of GLP-1 (197 ± 97 vs. 539 ± 218 pmol/l · min, P < 0.05), while SPIR was substantially increased (1,952 ± 512 vs. 8,072 ± 1,664 pmol/l · min, P < 0.05). In contrast, the 3-h preinfusion of GLP-1 normalized fasting hyperglycemia (7.9 ± 0.5 vs. 5.2 ± 0.6, P < 0.05), increased FPIR by 5- to 6-fold (197 ± 97 vs. 1,141 ± 409 pmol/l · min, P < 0.05), and augmented SPIR significantly (1,952 ± 512 vs. 4,026 ± 851 pmol/l · min, P < 0.05), but to a lesser degree than the acute administration of GLP-1. In addition, only the 3-h GLP-1 preinfusion significantly improved intravenous glucose tolerance (K_g control 0.61 ± 0.04, acute infusion 0.71 ± 0.04, P = NS; 3-h infusion 0.92 ± 0.08%/min, P < 0.05). These findings were also noted in the nondiabetic subjects in whom acute administration of GLP-1 significantly increased SPIR relative to the control IVGTT (9,439 ± 2,885 vs. 31,553 ± 11660 pmol/l · min, P < 0.001) with less effect on FPIR (3,221 ± 918 vs. 4,917 ± 1,614 pmol/l · min, P = 0.075), while the 3-h preinfusion of GLP-1 significantly increased both FPIR (3,221 ± 918 vs. 7,948 ± 2,647 pmol/l · min, P < 0.01) and SPIR (9,439 ± 2,885 vs. 21,997 ± 9,849 pmol/l · min, P < 0.03).

CONCLUSIONS—Extended administration of GLP-1 not only augments glucose-stimulated insulin secretion, but also shifts the dynamics of the insulin response to earlier release in both diabetic and nondiabetic humans. The restitution of some FPIR in subjects with type 2 diabetes is associated with significantly improved glucose tolerance. These findings demonstrate the benefits of a 3-h infusion of GLP-1 on ß-cell function beyond those of an acute insulin secretagogue, and support the development of strategies using continuous or prolonged GLP-1 receptor agonism for treating diabetic patients.

Abbreviations: CRC, clinical research centers • FPIR, first-phase insulin release • GLP-1, glucagon-like peptide 1 • GLP-1-A, GLP-1 acute infusion • GLP-1-PI, GLP-1 3-h preinfusion • GLP-1-IR, GLP-1 immunoreactivity • IVGTT, intravenous glucose tolerance test • SPIR, second-phase insulin release

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