Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans

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 β-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.