Department of Molecular and Cellular Endocrinology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Int J Mol Sci. 2021 Feb 12;22(4):1833. doi: 10.3390/ijms22041833.
Type 2 diabetes (T2D) is one of the prominent causes of morbidity and mortality in the United States and beyond, reaching global pandemic proportions. One hallmark of T2D is dysfunctional glucose-stimulated insulin secretion from the pancreatic β-cell. Insulin is secreted via the recruitment of insulin secretory granules to the plasma membrane, where the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and SNARE regulators work together to dock the secretory granules and release insulin into the circulation. SNARE proteins and their regulators include the Syntaxins, SNAPs, Sec1/Munc18, VAMPs, and double C2-domain proteins. Recent studies using genomics, proteomics, and biochemical approaches have linked deficiencies of exocytosis proteins with the onset and progression of T2D. Promising results are also emerging wherein restoration or enhancement of certain exocytosis proteins to β-cells improves whole-body glucose homeostasis, enhances β-cell function, and surprisingly, protection of β-cell mass. Intriguingly, overexpression and knockout studies have revealed novel functions of certain exocytosis proteins, like Syntaxin 4, suggesting that exocytosis proteins can impact a variety of pathways, including inflammatory signaling and aging. In this review, we present the conventional and unconventional functions of β-cell exocytosis proteins in normal physiology and T2D and describe how these insights might improve clinical care for T2D.
2 型糖尿病（T2D）是美国乃至全球发病率和死亡率的主要原因之一，已达到全球大流行的程度。T2D 的一个标志是胰腺β细胞葡萄糖刺激的胰岛素分泌功能障碍。胰岛素通过将胰岛素分泌颗粒募集到质膜来分泌，在质膜中可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体（SNAREs）和 SNARE 调节剂协同作用，将分泌颗粒停靠并将胰岛素释放到循环中。SNARE 蛋白及其调节剂包括Syntaxin、SNAP、Sec1/Munc18、VAMP 和双 C2 结构域蛋白。最近使用基因组学、蛋白质组学和生化方法的研究将胞吐作用蛋白的缺陷与 T2D 的发生和进展联系起来。令人鼓舞的结果也正在出现，即将某些胞吐作用蛋白恢复或增强到β细胞中可以改善全身葡萄糖稳态、增强β细胞功能，并且令人惊讶的是，保护β细胞数量。有趣的是，过表达和敲除研究揭示了某些胞吐作用蛋白（如 Syntaxin 4）的新功能，表明胞吐作用蛋白可以影响多种途径，包括炎症信号和衰老。在这篇综述中，我们介绍了β细胞胞吐作用蛋白在正常生理和 T2D 中的传统和非传统功能，并描述了这些见解如何改善 T2D 的临床护理。
