Glucagon-like peptide-1 accelerates the onset of insulin action on glucose disappearance in mice

Abstract

Glucagon-like peptide-1 (GLP-1) plays a significant role in glucose homeostasis through its incretin effect on insulin secretion. However, GLP-1 also exhibits extrapancreatic actions, and in particular its possible influences on insulin sensitivity are controversial. To study the dynamic action of GLP-1 on insulin sensitivity, we applied advanced statistical modeling methods to study glucose disappearance in mice that underwent intravenous glucose tolerance test with administration of GLP-1 at various dose levels. In particular, the minimal model of glucose disappearance was exploited within a population estimation framework for accurate detection of relationships between glucose disappearance parameters and GLP-1. Minimal model parameters were estimated from glucose and insulin data collected in 209 anesthetized normal mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). Insulin secretion markedly increased, as expected, with increasing GLP-1 dose. However, minimal model-derived indexes, i.e., insulin sensitivity and glucose effectiveness, did not significantly change with GLP-1 dose. Instead, fractional turnover rate of insulin action [P2 = 0.0207 +/- 24.3% (min) at zero GLP-1 dose] increased steadily with administered GLP-1 dose, with significant differences at 10.4 nmol/kg (P2 = 0.040 +/- 15.5%, P = 0.0046) and 31.2 nmol/kg (P2 = 0.050 +/- 29.2%, P = 0.01). These results show that GLP-1 influences the dynamics of insulin action by accelerating insulin action following glucose challenge. This is a novel mechanism contributing to the glucose-lowering action of GLP-1.