Islet biology, the CDKN2A/B locus and type 2 diabetes risk.
Islet biology, the CDKN2A/B locus and type 2 diabetes risk.
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DOI：
10.1007/s00125-016-3967-7
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发表时间：
2016-08
期刊：
影响因子：
8.2
通讯作者：
Alonso LC
中科院分区：
文献类型：
--
作者：
Kong Y;Sharma RB;Nwosu BU;Alonso LC
2型糖尿病，由肥胖流行病推动，是一个不断升级的全球性个人困难和公共成本的原因。糖尿病发病率随着年龄的增长而增加，许多研究将经典的衰老和衰老蛋白p16 INK 4A通过胰岛生物学与糖尿病病理生理学联系起来。全基因组关联研究（GWAS）已明确将CDKN 2 A/B基因座与人类糖尿病风险联系起来，CDKN 2 A/B基因座编码p16细胞周期蛋白依赖性激酶抑制剂（p16 INK 4 A）和其他三种基因产物，p14交替阅读框（p14 ARF），p15 INK 4 B和INK 4基因座中的反义非编码RNA（ANRIL）。然而，CDKN 2A/B基因座影响糖尿病风险的机制仍不确定。在这里，我们权衡了CDKN 2A/B多态性通过胰岛生物学影响代谢健康的证据与其他组织中的影响。我们开始总结了CDKN 2A/B基因座影响糖尿病风险的证据，并简要回顾了CDKN 2A/B基因产物的基础生物学。这项工作的主要重点是深入研究CDKN 2 A/B基因产物和相关蛋白在β细胞质量、增殖和胰岛素分泌功能的调节中所起的微妙作用，以及在其他代谢组织中的作用。最后，我们综合了基础生物学和临床观察，并结合了人体生理学数据。我们的结论是CDKN 2A/B位点可能通过胰岛和非胰岛机制影响糖尿病风险。
Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16INK4A to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16INK4A) and three other gene products, p14 alternate reading frame (p14ARF), p15INK4B and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.