School of Pharmacy, Fudan University, Shanghai 201203, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Biosci Rep. 2021 Jun 25;41(6). doi: 10.1042/BSR20210758.
Glucagon plays an important role in glucose homeostasis and amino acid metabolism. It regulates plasma amino acid levels which in turn modulate glucagon secretion from the pancreatic α-cell, thereby establishing a liver-α-cell axis described recently. We reported previously that the knock-in mice bearing homozygous V369M substitution (equivalent to a naturally occurring mutation V368M in the human glucagon receptor, GCGR) led to hypoglycemia with improved glucose tolerance. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia. Here, we investigated the effect of V369M/V368M mutation on glucagon-mediated amino acid metabolism. It was found that GcgrV369M+/+ mice displayed increased plasma amino acid levels in general, but significant accumulation of the ketogenic/glucogenic amino acids was observed in animals fed with a high-fat diet (HFD), resulting in deleterious metabolic consequence characteristic of α-cell proliferation and hyperglucagonemia.
胰高血糖素在葡萄糖稳态和氨基酸代谢中发挥重要作用。它调节血浆氨基酸水平，进而调节胰腺α细胞的胰高血糖素分泌，从而建立了最近描述的肝脏-α细胞轴。我们之前报道过，携带 V369M 同源突变（相当于人类胰高血糖素受体 GCGR 中的天然发生突变 V368M）的纯合子敲入小鼠导致低血糖和改善葡萄糖耐量。它们还表现出高胰高血糖素血症、胰腺增大和α细胞增生。在这里，我们研究了 V369M/V368M 突变对胰高血糖素介导的氨基酸代谢的影响。结果发现，GcgrV369M+/+ 小鼠的血浆氨基酸水平普遍升高，但在高脂肪饮食 (HFD) 喂养的动物中观察到酮体/生糖氨基酸的显著积累，导致以 α 细胞增殖和高胰高血糖素血症为特征的有害代谢后果。
