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

• Wei Fan-Yan

  Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan

• Tomizawa Kazuhito

  Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan

Bibliographic Information

Other Title

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

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-N⁶-threonylcarbamoyladenosine (ms²t⁶A) at position 37 of tRNA^Lys(UUU). The ms²t⁶A 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 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.

Journal

• Endocrine Journal

  Endocrine Journal 58 (10), 819-825, 2011

  The Japan Endocrine Society

Keywords

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

Details

• CRID: 1390282681276735232
• NII Article ID: 10029862922
• NII Book ID: AA10901436
• DOI: 10.1507/endocrj.ej11-0099
• ISSN: 13484540
• ISSN: 09188959
• Web Site: http://www.jstage.jst.go.jp/article/endocrj/58/10/58_EJ11-0099/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2012300904
• Text Lang: en
• Data Source:
  • JaLC
  • Crossref
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed