Department of Clinical Science and Education, Södersjukhuset, Research Center, Karolinska Institutet, Stockholm, Sweden.
Department of Emergency Care and Internal Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
Adv Exp Med Biol. 2020;1131:943-963. doi: 10.1007/978-3-030-12457-1_37.
Insulin secretion in humans is usually induced by mixed meals, which upon ingestion, increase the plasma concentration of glucose, fatty acids, amino acids, and incretins like glucagon-like peptide 1. Beta-cells can stay in the off-mode, ready-mode or on-mode; the mode-switching being determined by the open state probability of the ATP-sensitive potassium channels, and the activity of enzymes like glucokinase, and glutamate dehydrogenase. Mitochondrial metabolism is critical for insulin secretion. A sound understanding of the intermediary metabolism, electrophysiology, and cell signaling is essential for comprehension of the entire spectrum of the stimulus-secretion coupling. Depolarization brought about by inhibition of the ATP sensitive potassium channel, together with the inward depolarizing currents through the transient receptor potential (TRP) channels, leads to electrical activities, opening of the voltage-gated calcium channels, and exocytosis of insulin. Calcium- and cAMP-signaling elicited by depolarization, and activation of G-protein-coupled receptors, including the free fatty acid receptors, are intricately connected in the form of networks at different levels. Activation of the glucagon-like peptide 1 receptor augments insulin secretion by amplifying calcium signals by calcium induced calcium release (CICR). In the treatment of type 2 diabetes, use of the sulfonylureas that act on the ATP sensitive potassium channel, damages the beta cells, which eventually fail; these drugs do not improve the cardiovascular outcomes. In contrast, drugs acting through the glucagon-like peptide-1 receptor protect the beta-cells, and improve cardiovascular outcomes. The use of the glucagon-like peptide 1 receptor agonists is increasing and that of sulfonylurea is decreasing. A better understanding of the stimulus-secretion coupling may lead to the discovery of other molecular targets for development of drugs for the prevention and treatment of type 2 diabetes.
人类的胰岛素分泌通常是由混合餐诱导的，混合餐摄入后会增加血糖、脂肪酸、氨基酸和胰高血糖素样肽 1 等激素的血浆浓度。β细胞可以处于关闭模式、准备模式或开启模式；模式转换由 ATP 敏感性钾通道的开放状态概率和酶（如葡萄糖激酶和谷氨酸脱氢酶）的活性决定。线粒体代谢对胰岛素分泌至关重要。深入了解中间代谢、电生理学和细胞信号传导对于理解刺激-分泌偶联的整个范围至关重要。ATP 敏感性钾通道的抑制引起的去极化，以及通过瞬时受体电位 (TRP) 通道的内向去极化电流，导致电活动、电压门控钙通道的开放和胰岛素的胞吐作用。去极化引起的钙和 cAMP 信号传导，以及 G 蛋白偶联受体（包括游离脂肪酸受体）的激活，以不同水平的网络形式错综复杂地连接在一起。胰高血糖素样肽 1 受体的激活通过钙诱导钙释放 (CICR) 放大钙信号来增强胰岛素分泌。在 2 型糖尿病的治疗中，作用于 ATP 敏感性钾通道的磺酰脲类药物会损害β细胞，最终导致β细胞衰竭；这些药物不能改善心血管结局。相比之下，通过胰高血糖素样肽 1 受体作用的药物可保护β细胞，并改善心血管结局。胰高血糖素样肽 1 受体激动剂的使用正在增加，而磺酰脲类药物的使用正在减少。对刺激-分泌偶联的更好理解可能会导致发现其他分子靶点，从而开发用于预防和治疗 2 型糖尿病的药物。
