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Involvement of Cdkal1 in the etiology of type 2 diabetes mellitus and microvascular diabetic complications: a review

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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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  1. Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247 667, India

    Chandrachur Ghosh, Neeladrisingha Das, Tathagata Kundu & Partha Roy

  2. Department of Biochemistry, All India Institute of Medical Sciences Rishikesh, Rishikesh, Uttarakhand, India

    Sarama Saha

  3. Plant Molecular Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247 667, India

    Debabrata Sircar

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  1. Chandrachur Ghosh
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All the authors have contributed in the following manner: CG, ND and TK made the substantial contribution in conceptualizing, designing and writing the article; SS, DS and PR drafted the article and revised it for critically important intellectual contents; and finally, PR approved the final version to be published.

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Ghosh, C., Das, N., Saha, S. et al. Involvement of Cdkal1 in the etiology of type 2 diabetes mellitus and microvascular diabetic complications: a review. J Diabetes Metab Disord 21, 991–1001 (2022). https://doi.org/10.1007/s40200-021-00953-6

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