Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.
Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Clin Invest. 2021 Jan 19;131(2). doi: 10.1172/JCI142240.
Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β cell identity), or β cell dedifferentiation, or β cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for β cell failure in type 1 diabetes.
基础胰岛素和葡萄糖刺激的胰岛素释放主要通过胰岛β细胞胰岛素分泌颗粒的胞吐作用发生，两者均有助于维持血糖正常。胰岛素分泌β细胞的丧失伴随着异常的葡萄糖耐量，可能涉及胰岛素储备的简单耗竭（通过免疫染色，表现为β细胞特征的丧失），或β细胞去分化，或β细胞死亡。虽然各种感应和信号缺陷会导致胰岛素分泌减少，但人们对生物合成产生和维持总胰岛素颗粒储存池不足导致的糖尿病风险关注较少。这篇综述概述了胰岛素的生物合成，从前胰岛素原 mRNA（翻译和易位到内质网）、胰岛素原折叠和从内质网输出，以及通过高尔基体复合物运输到分泌颗粒，转化为胰岛素和最终的激素储存开始。所有这些步骤都是生成和维持总胰岛素颗粒库所必需的，这些步骤中的任何缺陷都可能弱或强地破坏血糖控制。上述考虑显然与 2 型糖尿病和某些形式的单基因糖尿病的发病机制有关；可以想象，这些概念中的一些可能也与 1 型糖尿病的β细胞衰竭有关。
