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 article

42 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 - Nov 3 2011

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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