PDF(Pubmed)
Abstract：
Diabetes Mellitus, being a polygenic disorder, have a set of risk genes involved in the onset of the insulin resistance, obesity and impaired insulin synthesis. Recent genome wide association studies (GWAS) shows the intimacy of CDK5 regulatory subunit Associated protein 1-Like 1 (Cdkal1) with the pathophysiology of the diabetes mellitus and its complications, although the exact molecular relation is still unknown. In this short review, we have summarized all the diverse biological roles of Cdkal1 in relation to the onset of diabetes mellitus. Variations in the Cdkal1 transcript are responsible for the accumulation of misfolded insulin and thus generating oxidative and ER stress in the pancreatic β-cells, leading to their destruction. Recent studies have shown that Cdkal1 has an intrinsic thiomethyl transferase activity, which is essential for proper posttranslational processing of pre-proinsulin to produce mature insulin. Moreover, Cdkal1 has also been claimed as an endogenous inhibitor of cdk5, which prevents the cdk5-induced interruption in insulin synthesis through PDX1 translocation from nucleus to cytosol. Recent clinical studies have identified the risk single nucleotide polymorphisms (SNPs) of Cdkal1 as one of the root causes for the onset of diabetic complications. To the best of our knowledge, it is the first comprehensive review which elaborates most of the potential Cdkal1-dependent molecular mechanisms studied yet. In this review, we present a compiled and concise summary about all the diverse roles of Cdkal1 in the context of type 2 diabetes mellitus and its associated complications. This review will be helpful to target Cdkal1 as a potential option for the management of type 2 diabetes mellitus in future.
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摘要：
糖尿病,是一种多基因疾病，有一组参与胰岛素抵抗发作的风险基因，肥胖和胰岛素合成受损。最近的全基因组关联研究（GWAS）表明CDK5调节亚基相关蛋白1-like1（Cdkal1）与糖尿病及其并发症的病理生理学密切相关，尽管确切的分子关系仍然未知。在这篇简短的评论中，我们总结了Cdkal1与糖尿病发病有关的各种生物学作用。Cdkal1转录物的变化负责错误折叠胰岛素的积累，从而在胰腺β细胞中产生氧化和ER应激，导致他们的毁灭。最近的研究表明，Cdkal1具有固有的硫甲基转移酶活性，这对于前胰岛素原的适当翻译后加工产生成熟的胰岛素至关重要。此外，Cdkal1也被认为是cdk5的内源性抑制剂，它可以防止cdk5诱导的胰岛素合成中断，通过PDX1从细胞核易位到细胞质。最近的临床研究已经确定Cdkal1的风险单核苷酸多态性（SNP）是糖尿病并发症发作的根本原因之一。据我们所知,这是第一个全面的综述，详细阐述了大多数潜在的Cdkal1依赖性分子机制。在这次审查中,我们对Cdkal1在2型糖尿病及其相关并发症中的各种作用进行了简要的总结。这篇综述将有助于将Cdkal1作为未来2型糖尿病管理的潜在选择。
