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Review
. 2022 Jan 13;21(1):991-1001.
doi: 10.1007/s40200-021-00953-6. eCollection 2022 Jun.

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

Chandrachur Ghosh  1 , Neeladrisingha Das  1 , Sarama Saha  2 , Tathagata Kundu  1 , Debabrata Sircar  3 , Partha Roy  1
Affiliations
Review

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

Chandrachur Ghosh et al. J Diabetes Metab Disord. .

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.

Keywords: Cdkal1; Diabetes mellitus; Inflammation; Microvascular complications; SNPs; β cell regeneration.

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Conflict of interest statement

Conflict of interestAuthors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
t-RNALys modification by Cdkal1. The two Fe-S clusters present in Cdkal1 cause the addition of a 2-methylthio group (CH3-S) at the 2C position of A37 residue of the t-RNALys(UUU), which is necessary for the Lys amino acid recognition by the t-RNA
Fig. 2
Fig. 2
Inhibitory role of cdk5 in insulin synthesis. Cdkal1 prevents the nucleus to cytosolic translocation of Pdx1 to ensure un-interrupted insulin synthesis by preventing the formation of active Cdk5-p25 complex, that results from a hyperglycemic state through a calpain-mediated mechanism
Fig. 3
Fig. 3
SNP compilation and nomenclature. Newly discovered SNPs are submitted from different sources and are assigned respective numbers (ss#). Then the data from different sources are compiled by dbSNP and given the rs number (rs#) for a specific SNP, which are then used to study different aspects in research
Fig. 4
Fig. 4
Role of the variant and the SNPs of Cdkal1 in insulin synthesis. The Cdkal1 gene produces Cdkal1 mRNA and a Cdkal1 variant (by alternative splicing) which are a common target for the miR-494, having similar seed sequence in their 3’UTR region. In normal condition, the miR-494 binds to the Cdkal1 variant which protects Cdkal1 mRNA from being a target for miR-494 that in turn continues the mature insulin synthesis. But in diabetic condition, the intron 5 of the Cdkal1 gene produces a set of SNPs which are responsible for the inhibition of the production of Cdkal1 variant. As a result, the masking action of miR-494 is abrogated subsequently degrading Cdkal1 mRNA and interrupting the biosynthesis of insulin
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References

    1. Who. c2020. World Health Organization. [Online]. [5 July 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/diabetes
    1. Gerich JE. Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? Diabetes. 2002;51(suppl 1):S117–S121. doi: 10.2337/diabetes.51.2007.S117. - DOI - PubMed
    1. Wei FY, Tomizawa K. tRNA modifications and islet function. Diabetes Obes Metab. 2018;20:20–27. doi: 10.1111/dom.13405. - DOI - PubMed
    1. Ohara-Imaizumi M, Yoshida M, Aoyagi K, Saito T, Okamura T, Takenaka H, et al. Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. PLoS One. 2010;5(12):e15553. doi: 10.1371/journal.pone.0015553. - DOI - PMC - PubMed
    1. Watanabe S, Wei FY, Tomizawa K. Functional characterization of Cdkal1, a risk factor of type 2 diabetes, and the translational opportunities. Drug Discov Today Dis Models. 2013;10(2):e65–e69. doi: 10.1016/j.ddmod.2012.12.001. - DOI