Exogenous Glucagon Acutely Reduces Insulin Clearance in Healthy Humans

Abstract Context Glucagon is secreted from pancreatic alpha-cells in response to hypoglycemia and protein intake and acts as a counterregulatory hormone to insulin by stimulating hepatic glucose production, thereby maintaining euglycemia. However, some studies suggest that glucagon regulates insulin availability by stimulating insulin secretion and reducing insulin clearance. Objective To investigate the glucose-independent effect of glucagon on insulin secretion and insulin clearance in healthy individuals. Methods A total of 15 healthy participants were included in this single arm, crossover clinical study with two study days. The participants received a four-hour intravenous infusion of glucagon (10 ng × kg(bodyweight)-1×min-1) on the first study day and a four-hour intravenous infusion of glucose (to match the glucose excursions from the glucagon infusion) on the second study day. The primary endpoint was insulin secretion (c-peptide). Results Overall glucose exposure did not differ significantly between study days (P = 0.0717); however, peak plasma glucose was significantly higher on the glucose clamp day (8.1 (7.5-8.7) vs 7.7 (7.0-8.3) mmol/L, P = 0.0027), reflecting incomplete glucose matching. Steady state concentrations of glucagon were 124 (110-137) pmol/L on the glucagon study day and 3 (2-4) pmol/L on the glucose clamp study day. There was no statistically significant difference in insulin secretion between study days (P = 0.1179), whereas insulin clearance (post hoc analysis) was significantly reduced during glucagon infusion at both hyper- and euglycemia (P = 0.0003). Conclusions Exogenous glucagon rapidly reduces insulin clearance without a statistically significant effect on insulin secretion, suggesting that glucagon affects hepatic insulin removal in healthy individuals.