Dysregulation of glucagon is associated with the pathophysiology of type 2 diabetes. We previously reported that postprandial hyperglucagonemia is more obvious than fasting hyperglucagonemia in type 2 diabetes patients. However, which nutrient stimulates glucagon secretion in the diabetic state and the underlying mechanism after nutrient intake are unclear. To answer these questions, we measured plasma glucagon levels in diabetic mice after oral administration of various nutrients. The effects of nutrients on glucagon secretion were assessed using islets isolated from diabetic mice and palmitate-treated islets. In addition, we analyzed the expression levels of branched chain amino acid (BCAA) catabolism-related enzymes and their metabolites in diabetic islets. We found that protein, but not carbohydrate or lipid, increased plasma glucagon levels in diabetic mice. Among amino acids, BCAAs, but not the other essential or nonessential amino acids, increased plasma glucagon levels. BCAAs also directly increased the intracellular calcium concentration in α cells. When BCAAs transport was suppressed by an inhibitor of system L-amino acid transporters, glucagon secretion was reduced even in the presence of BCAAs. We also found that the expression levels of BCAA catabolism-related enzymes and their metabolite contents were altered in diabetic islets and palmitate-treated islets compared to control islets, indicating disordered BCAA catabolism in diabetic islets. Furthermore, BCKDK inhibitor BT2 suppressed BCAA-induced hypersecretion of glucagon in diabetic islets and palmitate-treated islets. Taken together, postprandial hypersecretion of glucagon in the diabetic state is attributable to disordered BCAA catabolism in pancreatic islet cells.

胰高血糖素失调与 2 型糖尿病的病理生理学有关。我们之前报道2型糖尿病患者餐后高血糖比空腹高血糖更明显。然而，哪种营养素在糖尿病状态下刺激胰高血糖素分泌以及摄入营养素后的潜在机制尚不清楚。为了回答这些问题，我们测量了糖尿病小鼠口服各种营养素后的血浆胰高血糖素水平。使用从糖尿病小鼠中分离的胰岛和棕榈酸酯处理的胰岛评估营养物质对胰高血糖素分泌的影响。此外，我们分析了糖尿病胰岛中支链氨基酸（BCAA）分解代谢相关酶及其代谢物的表达水平。我们发现蛋白质，而不是碳水化合物或脂质，增加了糖尿病小鼠的血浆胰高血糖素水平。在氨基酸中，支链氨基酸（而不是其他必需或非必需氨基酸）会增加血浆胰高血糖素水平。支链氨基酸还直接增加α细胞内的钙离子浓度。当 L-氨基酸转运蛋白系统抑制剂抑制支链氨基酸转运时，即使存在支链氨基酸，胰高血糖素分泌也会减少。我们还发现，与对照胰岛相比，糖尿病胰岛和棕榈酸处理的胰岛中支链氨基酸分解代谢相关酶的表达水平及其代谢物含量发生了变化，表明糖尿病胰岛中的支链氨基酸分解代谢紊乱。此外，BCKDK 抑制剂 BT2 可以抑制糖尿病胰岛和棕榈酸酯处理的胰岛中 BCAA 诱导的胰高血糖素分泌过多。总而言之，糖尿病状态下餐后胰高血糖素分泌过多可归因于胰岛细胞中支链氨基酸分解代谢紊乱。