Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans

OBJECTIVE

Gastric bypass (GB) surgery is associated with postprandial hyperinsulinemia, and this effect is accentuated in postsurgical patients who develop recurrent hypoglycemia. Plasma levels of the incretin glucagon-like peptide 1 (GLP-1) are dramatically increased after GB, suggesting that its action contributes to alteration in postprandial glucose regulation. The aim of this study was to establish the role of GLP-1 on insulin secretion in patients with GB.

RESEARCH DESIGN AND METHODS

Twelve asymptomatic individuals with previous GB (Asym-GB), 10 matched healthy nonoperated control subjects, and 12 patients with recurrent hypoglycemia after GB (Hypo-GB) had pre- and postprandial hormone levels and insulin secretion rates (ISR) measured during a hyperglycemic clamp with either GLP-1 receptor blockade with exendin-(9–39) or saline.

RESULTS

Blocking the action of GLP-1 suppressed postprandial ISR to a larger extent in Asym-GB individuals versus control subjects (33 ± 4 vs.16 ± 5%; P = 0.04). In Hypo-GB patients, GLP-1 accounted for 43 ± 4% of postprandial ISR, which was not significantly higher than that in Asym-GB subjects (P = 0.20). Glucagon was suppressed similarly by hyperglycemia in all groups but rose significantly after the meal in surgical individuals but remained suppressed in nonsurgical subjects. GLP-1 receptor blockade increased postprandial glucagon in both surgical groups.

CONCLUSIONS

Increased GLP-1–stimulated insulin secretion contributes significantly to hyperinsulinism in GB subjects. However, the exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycemia.Surgery to induce weight loss has become increasingly common (1) as obesity has become pandemic (2). Roux-en-Y gastric bypass (GB), which is associated with substantial and durable weight loss (3), has been reported to cause near complete remission of diabetes within days—before any significant weight loss (4,5). The mechanisms for these metabolic benefits independent of weight loss are still unknown, but it is clear that the insulin response to meal ingestion is exaggerated after surgery (6). Postprandial insulin secretion is augmented by the actions of hormones released from the gastrointestinal (GI) tract, primarily glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (7), and GB subjects have elevated plasma concentrations of GLP-1 (6,8–13). These findings are the basis for a popular but as yet unproven hypothesis that increased GLP-1 secretion is responsible for the improvement in glucose regulation following GB.Moreover, in recent years there have been increasing reports of severe hyperinsulinemic hypoglycemia occurring in patients several years after GB (14,15). Affected individuals have exaggerated insulin and GLP-1 responses to meal consumption compared with asymptomatic individuals with GB (16). These observations raise the question as to whether an amplified GLP-1 effect, either from higher plasma levels or increased sensitivity to the peptide, accounts for the syndrome of post-GB hypoglycemia.In the current study, exendin-(9–39) (Ex-9), a specific GLP-1 receptor (GLP-1r) antagonist (17), was used to test the hypothesis that GB-associated hyperinsulinemia is mediated by increased GLP-1 action and to determine whether enhanced GLP-1 action accounts for greater β-cell stimulation in subjects with postsurgical hypoglycemia.