Hayashi Yoshitaka, Seino Yusuke
Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya, Japan.
Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Japan.
J Diabetes Investig. 2018 Jan 3;9(3):464-72. doi: 10.1111/jdi.12797.
Both glucagon and glucagon-like peptide-1 (GLP-1) are produced from proglucagon through proteolytic cleavage. Blocking glucagon action increases the circulating levels of glucagon and GLP-1, reduces the blood glucose level, and induces the proliferation of islet α-cells. Glucagon blockade also suppresses hepatic amino acid catabolism and increases the serum amino acid level. In animal models defective in both glucagon and GLP-1, the blood glucose level is not reduced, indicating that GLP-1 is required for glucagon blockade to reduce the blood glucose level. In contrast, hyperplasia of α-cells and hyperaminoacidemia are observed in such animal models, indicating that GLP-1 is not required for the regulation of α-cell proliferation or amino acid metabolism. These findings suggest that the regulation of amino acid metabolism is a more important specific physiological role of glucagon than the regulation of glucose metabolism. Although the effects of glucagon deficiency on glucose metabolism are compensated by the suppression of insulin secretion, the effects on amino acid metabolism are not. Recently, data showing a feedback regulatory mechanism between the liver and islet α-cells, which is mediated by glucagon and amino acids, are accumulating. However, a number of questions on the mechanism of this regulation remain to be addressed. The profile of glucagon as a regulator of amino acid metabolism must be carefully considered for glucagon blockade to be applied therapeutically in the treatment of patients with diabetes.
胰高血糖素和胰高血糖素样肽-1（GLP-1）均由胰高血糖素原经蛋白水解切割产生。阻断胰高血糖素的作用会增加循环中胰高血糖素和GLP-1的水平，降低血糖水平，并诱导胰岛α细胞增殖。胰高血糖素阻断还会抑制肝脏氨基酸分解代谢并提高血清氨基酸水平。在胰高血糖素和GLP-1均有缺陷的动物模型中，血糖水平并未降低，这表明胰高血糖素阻断降低血糖水平需要GLP-1。相反，在这类动物模型中观察到α细胞增生和高氨基酸血症，这表明调节α细胞增殖或氨基酸代谢不需要GLP-1。这些发现表明，与调节葡萄糖代谢相比，调节氨基酸代谢是胰高血糖素更重要的特定生理作用。尽管胰高血糖素缺乏对葡萄糖代谢的影响可通过抑制胰岛素分泌得到补偿，但其对氨基酸代谢的影响却不能。最近，由胰高血糖素和氨基酸介导的肝脏与胰岛α细胞之间的反馈调节机制的数据不断积累。然而，关于这种调节机制仍有许多问题有待解决。在将胰高血糖素阻断疗法应用于糖尿病患者治疗时，必须仔细考虑胰高血糖素作为氨基酸代谢调节剂的作用特点。
