Contribution of endogenous glucagon-like peptide 1 to prandial counterregulatory responses to hypoglycemia after bariatric surgery.

AIMS/HYPOTHESIS: Exogenous glucagon-like peptide 1 (GLP-1) infusion lowers endogenous glucose production ( EGP ) in euglycemic or hyperglycemic settings. Previously, we have shown that prandial EGP during insulin-induced hypoglycemia is smaller in non-diabetic subjects with gastric bypass (GB) and sleeve gastrectomy (SG), where prandial GLP-1 concentrations are increased by 5-10 fold compared to non-operated controls. The goal of this study was to determine the effect of endogenous GLP-1 on prandial counterregulatory response to hypoglycemia.

METHODS: Glucose fluxes and islet-cell and gut hormone responses before and after mixed-meal ingestion were compared among 8 subjects with prior GB, 7 with prior SG, and 5 matched non-surgical controls during a hyperinsulinemic (120 mU/min/m 2 ) hypoglycemic ( ∼ 3.2 mmol/l) clamp with and without a specific GLP-1 receptor (GLP-1R) antagonist exendin-(9-39) (Ex-9).

RESULTS: Before meal ingestion, plasma glucagon and glucose fluxes were similar among 3 groups. GLP-1R blockade had no effect on insulin secretion or insulin action before or after meal ingestion whereas prandial glucagon was enhanced in all 3 groups ( P < 0.05). Ex-9 infusion raised prandial EGP response to hypoglycemia in surgical groups ( P < 0.05) but decreased this parameter in controls ( P = 0.08 for interaction). The rates of systemic appearance of ingested glucose or prandial glucose utilization did not differ among 3 groups and between studies with and without Ex-9 infusion.

CONCLUSIONS/INTERPRETATION: Under hypoglycemic condition, the glucagonostatic effect, but not insulinotropic action of GLP-1, is preserved in the prandial condition in humans. Endogenous GLP-1 contributes to the impaired post-meal glucose counterregulatory response to hypoglycemia in non-diabetic subjects after bariatric surgery.

RESEARCH IN CONTEXT: What is already known about this subject? The physiologic response to hypoglycemia includes the inhibition of insulin secretion, followed by stimulation of counterregulatory hormones, mainly glucagon, raising endogenous glucose production ( EGP ). Glucagon-like peptide 1 (GLP-1) has been shown to diminish EGP by direct or indirect effect on liver glucose metabolism. Rerouted gut after gastric bypass or sleeve gastrectomy, where prandial GLP-1 secretion is enhanced, leads to a blunted EGP response to insulin-induced hypoglycemia in the fed state. What is the key question? To determine the contribution of endogenous GLP-1 to post-meal counterregulatory response to hypoglycemia in individuals with and without prior bariatric surgery. What are the new findings? Under hypoglycemic conditions, the glucagonostatic effect, but not insulinotropic action of GLP-1 is preserved, indicating differential glucose-dependency of this peptide on pancreatic alpha- versus beta-cells. Endogenous GLP-1 contributes to diminished prandial EGP response to hypoglycemia in non-diabetic subjects after bariatric surgery. How might this impact on clinical practice in the foreseeable future?The results of this study support the use of GLP-1 receptor antagonists as therapeutic targets in post-bariatric hypoglycemia and related conditions.