Development of type 2 diabetes caused by a deficiency of a tRNA lys modification

Fan Yan Wei, Kazuhito Tomizawa

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Genetic variations in the cdk5 regulator associated protein 1-like 1 (cdkal1) gene have been identified in whole genome association studies as a risk factor for the development of type 2 diabetes (T2D). A recent study showed that Cdkal1 was a mammalian methythiotransferase, which specifically synthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t 6A) at position 37 of tRNAlys(UUU). The ms 2t6A modification in tRNAlys(UUU) was important for the accurate decoding of its cognate codon. In pancreatic β-cell-specific Cdkal1 knockout (Cdkal1 KO) mice, a deficiency of ms 2t6A caused the mistranslation of a Lys codon in proinsulin, resulting in improper processing. The mice showed a decrease in insulin secretion and glucose intolerance. In addition, the mistranslation contributed to the expression of the endoplasmic reticulum (ER) stress response in Cdkal1-deficient β-cells. Furthermore, Cdkal1 KO mice were hypersensitive to high-fat diet-induced glucose intolerance, as well as the ER stress response. These findings might potentially explain the molecular pathogenesis of T2D in patients carrying Cdkal1 variations.

Original languageEnglish
JournalIslets
Volume4
Issue number1
DOIs
Publication statusPublished - Jan 1 2012
Externally publishedYes

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Keywords

  • Cdkal1
  • ER stress
  • Islet
  • Translation
  • tRNA

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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