Honka Henri, Gastaldelli Amalia, Pezzica Samantha, Peterson Richard, DeFronzo Ralph, Salehi Marzieh
medRxiv. 2023 Dec 22:2023.09.20.23295840. doi: 10.1101/2023.09.20.23295840.
We have previously shown that prandial endogenous glucose production (EGP) during insulin-induced hypoglycemia is smaller in non-diabetic subjects with gastric bypass (GB), where prandial glucagon-like peptide 1 (GLP-1) concentrations are 5-10 times higher than those in non-operated controls. Here, we sought to determine the effect of endogenous GLP-1 on prandial counterregulatory response to hypoglycemia after GB. Glucose fluxes, and islet-cell and gut hormone responses before and after mixed-meal ingestion were compared during a hyperinsulinemic hypoglycemic (~3.2 mmol/l) clamp with and without a GLP-1 receptor (GLP-1R) antagonist exendin-(9-39) (Ex-9) in non-diabetic subjects with prior GB compared to matched subjects with SG and non-surgical controls. In this setting, GLP-1R blockade had no effect on insulin secretion or insulin action, whereas prandial glucagon was enhanced in all 3 groups. Ex-9 infusion raised prandial EGP response to hypoglycemia in every GB subject but had no consistent effects on EGP among subjects with SG or non-operated controls (P < 0.05 for interaction). These results indicate that impaired post-meal glucose counterregulatory response to hypoglycemia after GB is partly mediated by endogenous GLP-1, highlighting a novel mechanism of action of GLP-1R antagonists for the treatment of prandial hypoglycemia in this population.
我们之前已经表明，在胰岛素诱导的低血糖期间，接受胃旁路手术（GB）的非糖尿病受试者的餐时内源性葡萄糖生成（EGP）较少，其中餐时胰高血糖素样肽1（GLP-1）浓度比未手术的对照组高5至10倍。在此，我们试图确定内源性GLP-1对GB术后低血糖的餐时反调节反应的影响。在有和没有GLP-1受体（GLP-1R）拮抗剂艾塞那肽（9-39）（Ex-9）的高胰岛素低血糖（约3.2 mmol/l）钳夹期间，比较了混合餐摄入前后，既往接受GB手术的非糖尿病受试者与匹配的接受袖状胃切除术（SG）的受试者和非手术对照组的葡萄糖通量、胰岛细胞和肠道激素反应。在这种情况下，GLP-1R阻断对胰岛素分泌或胰岛素作用没有影响，而所有3组的餐时胰高血糖素均增强。Ex-9输注增加了每个GB受试者对低血糖的餐时EGP反应，但对SG受试者或未手术对照组的EGP没有一致影响（交互作用P<0.05）。这些结果表明，GB术后对低血糖的餐后葡萄糖反调节反应受损部分由内源性GLP-1介导，突出了GLP-1R拮抗剂在该人群中治疗餐时低血糖的一种新作用机制。
