Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1β

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18–2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31–3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43–3.55, pvalLRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition. [Display omitted] •Post gastric bypass surgery, glucose-induced IL-1β triggers insulin and hypoglycemia•SGLT2-inhibition prevents glucose-induced IL-1β effects•SGLT2 or IL-1β inhibition prevents postprandial hypoglycemia after gastric bypass•Monocytes after gastric bypass surgery are in a hyper-reactive inflammatory state Postprandial hypoglycemia is a disabling complication of bariatric surgery. Hepprich et al. show that both the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra reduced postprandial insulin release and prevented hypoglycemia. The study therefore proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after bariatric surgery, along with two treatments.