Disordered branched chain amino acid catabolism in pancreatic islets is associated with postprandial hypersecretion of glucagon in diabetic mice
Disordered branched chain amino acid catabolism in pancreatic islets is associated with postprandial hypersecretion of glucagon in diabetic mice
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DOI：
10.1016/j.jnutbio.2021.108811
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发表时间：
2021-07-22
影响因子：
5.6
通讯作者：
Kitamura, Tadahiro
中科院分区：
文献类型：
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作者：
Wada, Eri;Kobayashi, Masaki;Kitamura, Tadahiro
胰升糖素调节失调与2型糖尿病的病理生理机制有关。我们以前报道过，在2型糖尿病患者中，餐后高血糖较空腹高血糖更为明显。然而，哪些营养素在糖尿病状态下刺激胰升糖素的分泌，以及营养素摄入后的潜在机制尚不清楚。为了回答这些问题，我们测量了口服各种营养素后糖尿病小鼠的血浆胰高血糖素水平。用从糖尿病小鼠分离的胰岛和棕榈树处理的胰岛来评估营养对胰升糖素分泌的影响。此外，我们分析了支链氨基酸(BCAA)分解代谢相关酶及其代谢产物在糖尿病胰岛中的表达水平。我们发现，蛋白质，而不是碳水化合物或脂肪，会增加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，可提高血浆胰高血糖素水平。支链氨基酸还可直接增加α细胞内钙离子浓度。当支链氨基酸转运被L-氨基酸转运体系统的抑制剂抑制时，即使在支链氨基酸存在的情况下，胰升糖素的分泌也会减少。我们还发现糖尿病胰岛和棕榈酸处理的胰岛与对照胰岛相比，BCAA分解代谢相关酶的表达水平及其代谢物含量发生了变化，表明糖尿病胰岛的BCAA分解代谢紊乱。此外，BCKDK抑制剂BT2抑制BCAA诱导的糖尿病胰岛和棕榈酸酯处理的胰岛高分泌胰高血糖素。综上所述，糖尿病状态下餐后高分泌高血糖素可归因于胰岛细胞支链氨基酸分解代谢紊乱。(C)2021年提交人(S)。由爱思唯尔公司出版。
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 palmitatetreated 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 alpha 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. (C) 2021 The Author(s). Published by Elsevier Inc.