Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes
Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes
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DOI：
10.2174/157339913804143225
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发表时间：
2013-01-01
影响因子：
3.3
通讯作者：
Liu, Dongmin
中科院分区：
文献类型：
--
作者：
Fu, Zhuo;Gilbert, Elizabeth R.;Liu, Dongmin
胰腺β细胞功能障碍在1型和2型糖尿病的发病机制中发挥着重要作用。胰岛素由β细胞产生，是新陈代谢的关键调节剂。胰岛素被合成为前胰岛素原并加工成胰岛素原。然后胰岛素原转化为胰岛素和 C 肽，并储存在秘书颗粒中，等待按需释放。胰岛素合成在转录和翻译水平上受到调节。 5' 侧翼区域内的顺式作用序列和反式激活因子包括配对盒基因 6 (PAX6)、胰腺和十二指肠同源盒-1 (PDX-1)、MafA 和 B-2/神经源性分化 1 (NeuroD1) 调节胰岛素转录，而前胰岛素原 mRNA 及其非翻译区的稳定性控制蛋白质翻译。胰岛素分泌涉及β细胞中的一系列事件，导致分泌颗粒与质膜融合。胰岛素主要是响应葡萄糖而分泌的，而其他营养素（例如游离脂肪酸和氨基酸）可以增强葡萄糖诱导的胰岛素分泌。此外，多种激素，如褪黑激素、雌激素、瘦素、生长激素、胰高血糖素样肽-1等也调节胰岛素分泌。因此，β细胞是体内的代谢中心，连接营养代谢和内分泌系统。虽然细胞内 [Ca2+] 的增加是主要的胰岛素分泌信号，但 cAMP 信号依赖机制在胰岛素分泌的调节中也至关重要。本文回顾了有关 β 细胞如何合成和分泌胰岛素的最新知识。此外，本综述提供的证据表明，遗传和环境因素可导致高血糖、血脂异常、炎症和自身免疫，导致β细胞功能障碍，从而引发糖尿病的发病机制。
Pancreatic beta-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in beta-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5' flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in beta-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the beta-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how beta-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in beta-cell dysfunction, thereby triggering the pathogenesis of diabetes.