Department of Surgery, BC Children's Hospital Research Institute and University of British Columbia, Vancouver, British Columbia, Canada.
Department of Pathology and Laboratory Medicine, BC Children's Hospital Research Institute and University of British Columbia, Vancouver, British Columbia, Canada.
Diabetes Obes Metab. 2018 Sep;20 Suppl 2:64-76. doi: 10.1111/dom.13401.
Biosynthesis of peptide hormones by pancreatic islet endocrine cells is a tightly orchestrated process that is critical for metabolic homeostasis. Like neuroendocrine peptides, insulin and other islet hormones are first synthesized as larger precursor molecules that are processed to their mature secreted products through a series of proteolytic cleavages, mediated by the prohormone convertases Pc1/3 and Pc2, and carboxypeptidase E. Additional posttranslational modifications including C-terminal amidation of the β-cell peptide islet amyloid polypeptide (IAPP) by peptidyl-glycine α-amidating monooxygenase (Pam) may also occur. Genome-wide association studies (GWAS) have showed genetic linkage of these processing enzymes to obesity, β-cell dysfunction, and type 2 diabetes (T2D), pointing to their important roles in metabolism and blood glucose regulation. In both type 1 diabetes (T1D) and T2D, and in the face of metabolic or inflammatory stresses, islet prohormone processing may become impaired; indeed elevated proinsulin:insulin (PI:I) ratios are a hallmark of the β-cell dysfunction in T2D. Recent studies suggest that genetic or acquired defects in proIAPP processing may lead to the production and secretion of incompletely processed forms of proIAPP that could contribute to T2D pathogenesis, and additionally that impaired processing of both PI and proIAPP may be characteristic of β-cell dysfunction in T1D. In islet α-cells, the prohormone proglucagon is normally processed to bioactive glucagon by Pc2 but may express Pc1/3 under certain conditions leading to production of GLP-1(7-36 ). A better understanding of how β-cell processing of PI and proIAPP, as well as α-cell processing of proglucagon, are impacted by genetic susceptibility and in the face of diabetogenic stresses, may lead to new therapeutic approaches for improving islet function in diabetes.
胰岛内分泌细胞的肽类激素生物合成是一个精确协调的过程，对代谢稳态至关重要。与神经内分泌肽一样，胰岛素和其他胰岛激素最初是作为较大的前体分子合成的，这些前体分子通过一系列蛋白水解切割被加工成成熟的分泌产物，这些切割由前激素转化酶 Pc1/3 和 Pc2 以及羧肽酶 E 介导。其他翻译后修饰，包括肽基甘氨酸 α-酰胺化单加氧酶 (Pam) 对β细胞肽胰岛淀粉样多肽 (IAPP) 的 C 端酰胺化，也可能发生。全基因组关联研究 (GWAS) 表明这些加工酶与肥胖、β细胞功能障碍和 2 型糖尿病 (T2D) 的遗传连锁，这表明它们在代谢和血糖调节中的重要作用。在 1 型糖尿病 (T1D) 和 2 型糖尿病中，以及在代谢或炎症应激下，胰岛前激素加工可能受损；事实上，升高的胰岛素原：胰岛素 (PI:I) 比值是 2 型糖尿病中β细胞功能障碍的标志。最近的研究表明，前 IAPP 加工的遗传或获得性缺陷可能导致不完全加工形式的前 IAPP 的产生和分泌，这可能有助于 2 型糖尿病的发病机制，此外，PI 和前 IAPP 加工受损可能是 1 型糖尿病中β细胞功能障碍的特征。在胰岛 α 细胞中，前激素 proglucagon 通常被 Pc2 加工为生物活性胰高血糖素，但在某些条件下可能表达 Pc1/3，导致 GLP-1(7-36 ) 的产生。更好地了解 PI 和前 IAPP 的β细胞加工以及 proglucagon 的 α 细胞加工如何受到遗传易感性的影响以及面对糖尿病原性应激，可能会为改善糖尿病中的胰岛功能提供新的治疗方法。
