Ghosh Chandrachur, Das Neeladrisingha, Saha Sarama, Kundu Tathagata, Sircar Debabrata, Roy Partha
Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247 667 India.
Department of Biochemistry, All India Institute of Medical Sciences Rishikesh, Rishikesh, Uttarakhand India.
J Diabetes Metab Disord. 2022 Jan 13;21(1):991-1001. doi: 10.1007/s40200-021-00953-6. eCollection 2022 Jun.
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.
糖尿病作为一种多基因疾病，有一组风险基因参与胰岛素抵抗、肥胖和胰岛素合成受损的发病过程。最近的全基因组关联研究（GWAS）显示了细胞周期蛋白依赖性激酶5调节亚基相关蛋白1样蛋白1（Cdkal1）与糖尿病及其并发症病理生理学之间的密切关系，尽管确切的分子关系仍不清楚。在这篇简短的综述中，我们总结了Cdkal1在糖尿病发病过程中的各种生物学作用。Cdkal1转录本的变异导致错误折叠的胰岛素积累，从而在胰腺β细胞中产生氧化应激和内质网应激，导致细胞破坏。最近的研究表明，Cdkal1具有内在的硫甲基转移酶活性，这对于胰岛素原正确的翻译后加工以产生成熟胰岛素至关重要。此外，Cdkal1也被认为是细胞周期蛋白依赖性激酶5的内源性抑制剂，它通过胰腺十二指肠同源盒1（PDX1）从细胞核易位到细胞质来防止细胞周期蛋白依赖性激酶5诱导的胰岛素合成中断。最近的临床研究已确定Cdkal1的风险单核苷酸多态性（SNP）是糖尿病并发症发病的根本原因之一。据我们所知，这是第一篇详细阐述了目前已研究的大多数潜在的Cdkal1依赖性分子机制的全面综述。在这篇综述中，我们对Cdkal1在2型糖尿病及其相关并发症背景下的各种作用进行了汇编和简要总结。这篇综述将有助于将Cdkal1作为未来治疗2型糖尿病的一个潜在选择。
