Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes

Fan Yan Wei, Kazuhito Tomizawa

    Research output: Contribution to journalReview articlepeer-review

    50 Citations (Scopus)

    Abstract

    A number of whole-genome association studies show the cdk5 regulatory associated protein 1-like 1 (cdkal1) gene to be one of the most reproducible risk genes in type 2 diabetes (T2D). Variations in the gene are associated with impaired insulin secretion but not insulin resistance or obesity. Although the physiological functions of Cdkal1 had been unclear, recent studies show that it is a tRNA modification enzyme, a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N 6-threonylcarbamoyladenosine (ms 2t 6A) at position 37 of tRNA Lys(UUU). The ms 2t 6A modification in tRNA Lys(UUU) is important for preventing the misreading of its cognate codons, especially when the rate of translation is relatively high. In both general and pancreatic β-cell-specific cdkal1-deficient mice, impaired mitochondrial ATP generation and first-phase insulin secretion are observed. Moreover, the β-cell-specific knockout mice show pancreatic islet hypertrophy and impaired blood glucose control. The mice are also hypersensitive to high-fat diet-induced endoplasmic reticulum (ER) stress. In this review, we provide an overview of the physiological functions of Cdkal1 and the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

    Original languageEnglish
    Pages (from-to)819-825
    Number of pages7
    JournalEndocrine journal
    Volume58
    Issue number10
    DOIs
    Publication statusPublished - 2011

    Keywords

    • Cdk5
    • Endoplasmic reticulum (ER)
    • Insulin synthesis
    • SNPs
    • Translation

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Endocrinology

    Fingerprint

    Dive into the research topics of 'Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes'. Together they form a unique fingerprint.

    Cite this