Differential effect of endogenous glucagon‐like peptide‐1 on prandial glucose counterregulatory response to hypoglycaemia in humans with and without bariatric surgery

Aim To determine the effect of endogenous glucagon‐like peptide 1 (GLP‐1) on prandial counterregulatory response to hypoglycaemia after gastric bypass (GB). Materials and Methods Glucose fluxes, and islet‐cell and gut hormone responses before and after mixed‐meal ingestion, were compared during a hyperinsulinaemic‐hypoglycaemic ( ~ 3.2 mmol/L) clamp with and without a GLP‐1 receptor (GLP‐1R) antagonist exendin‐(9–39) infusion in non‐diabetic patients who had previously undergone GB compared to matched participants who had previously undergone sleeve gastrectomy (SG) and non‐surgical controls. Results Exendin‐(9–39) infusion raised prandial endogenous glucose production (EGP) response to insulin‐induced hypoglycaemia in the GB group but had no consistent effect on EGP response among the SG group or non‐surgical controls ( p < 0.05 for interaction). The rates of systemic appearance of ingested glucose or prandial glucose utilization did not differ among the three groups or between studies with and without exendin‐(9–39) infusion. Blockade of GLP‐1R had no effect on insulin secretion or insulin action but enhanced prandial glucagon in all three groups. Conclusions These results indicate that impaired post‐meal glucose counterregulatory response to hypoglycaemia after GB is partly mediated by endogenous GLP‐1, highlighting a novel pathogenic mechanism of GLP‐1 in developing hypoglycaemia in this population.