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.gov NCT03200782; 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, pval_{likelihood 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, pval_LRT = 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.

餐后低血糖是胃绕道手术治疗肥胖症的致残并发症。迄今为止，尚无治疗方法，其潜在机制仍不清楚。在这里，我们假设葡萄糖诱导的 IL-1β 在这种情况下会导致胰岛素反应过度。因此，我们对 SGLT2 抑制剂恩格列净和 IL-1 受体拮抗剂阿那白滞素进行了一项安慰剂对照、随机、双盲、交叉研究（clinicaltrials.gov NCT03200782；n = 12）。两种药物均减少餐后胰岛素释放并预防低血糖（需要救援葡萄糖的症状事件：安慰剂 = 7/12，恩格列净 = 2/12，和阿那白滞素 = 2/12，pval_{似然比检验 (L RT )）}= 0.013; 最低点的血糖对于安慰剂= 2.4毫摩尔/ L，95％CI 2.18-2.62，恩格列净= 2.69毫摩尔/ L，95％CI 2.31-3.08，和阿那白滞= 2.99毫摩尔/ L，95％CI 2.43-3.55，PVAL _LRT  = 0.048）。此外，对离体单核细胞的分析揭示了一种高反应性炎症状态，其特征是对进餐的反应过度。我们的研究提出了葡萄糖诱导的 IL-1β 在胃绕道手术后餐后低血糖中的作用，并表明 SGLT2 抑制剂和 IL-1 拮抗剂可能会改善这种情况。