A model of GLP-1 action on insulin secretion in nondiabetic subjects

Abstract

Glucagon-like peptide-1 (GLP-1)-based therapies for diabetes have aroused interest because of their effects on insulin secretion and glycemic control. However, a mechanistic model enabling quantitation of pancreatic response to GLP-1 has never been developed. To develop such a model we studied 88 healthy individuals (age 26.3 +/- 0.6 yr, BMI 24.9 +/- 0.4 kg/m(2)) by use of a hyperglycemic clamp. A variable infusion maintained glucose concentrations at 150 mg/dl for 240 min. At 120 min, an intravenous infusion of GLP-1 was started (0.75 pmol kg(-1) min(-1) from 120-180 min, 1.5 pmol kg(-1) min(-1) from 181-240 min). Consequently, plasma C-peptide concentration rose from 1,852.0 +/- 62.8 pmol/l at 120 min to 4,272.2 +/- 176.4 pmol/l at 180 min and to 6,995.8 +/- 323.5 pmol/l at 240 min. Four models of GLP-1 action on insulin secretion were considered. All models share the common assumption that insulin secretion is made up of two components, one proportional to glucose rate of change through dynamic responsivity, Phi(d), and one proportional to glucose through static responsivity, Phi(s), but differing by modality of GLP-1 control. The model that best fit C-peptide data assumes that above-basal insulin secretion depends linearly on GLP-1 concentration and its rate of change. An index (Pi) measuring the percentage increase of secretion due to GLP-1 is derived. Before GLP-1 infusion, Phi(d) = 245.7 +/- 15.6 10(-9) and Phi(s) = 25.2 +/- 1.4 10(-9) min(-1). Under GLP-1 stimulus, Pi = 12.6 +/- 0.71% per pmol/l, meaning that an increase of 5 pmol/l in peripheral GLP-1 concentrations induces an approximately 60% increase in over-basal insulin secretion.