Endogenous glucagon-like peptide 1 diminishes prandial glucose counterregulatory response to hypoglycemia after gastric bypass surgery

We have previously shown that prandial endogenous glucose production (EGP) during insulin-induced hypoglycemia is smaller in non-diabetic subjects with gastric bypass (GB), where prandial glucagon-like peptide 1 (GLP-1) concentrations are 5-10 times higher than those in non-operated controls. Here, we sought to determine the effect of endogenous GLP-1 on prandial counterregulatory response to hypoglycemia after GB. Glucose fluxes, and islet-cell and gut hormone responses before and after mixed-meal ingestion were compared during a hyperinsulinemic hypoglycemic ({bsim}3.2 mmol/l) clamp with and without a GLP-1 receptor (GLP-1R) antagonist exendin-(9-39) (Ex-9) in non-diabetic subjects with prior GB compared to matched subjects with SG and non-surgical controls. In this setting, GLP-1R blockade had no effect on insulin secretion or insulin action, whereas prandial glucagon was enhanced in all 3 groups. Ex-9 infusion raised prandial EGP response to hypoglycemia in every GB subject but had no consistent effects on EGP among subjects with SG or non-operated controls (P < 0.05 for interaction). These results indicate that impaired post-meal glucose counterregulatory response to hypoglycemia after GB is partly mediated by endogenous GLP-1, highlighting a novel mechanism of action of GLP-1R antagonists for the treatment of prandial hypoglycemia in this population.