Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice

Fan Yan Wei, Takeo Suzuki, Sayaka Watanabe, Satoshi Kimura, Taku Kaitsuka, Atsushi Fujimura, Hideki Matsui, Mohamed Atta, Hiroyuki Michiue, Marc Fontecave, Kazuya Yamagata, Tsutomu Suzuki, Kazuhito Tomizawa

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Abstract

The worldwide prevalence of type 2 diabetes (T2D), which is caused by a combination of environmental and genetic factors, is increasing. With regard to genetic factors, variations in the gene encoding Cdk5 regulatory associated protein 1-like 1 (Cdkal1) have been associated with an impaired insulin response and increased risk of T2D across different ethnic populations, but the molecular function of this protein has not been characterized. Here, we show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6- threonylcarbamoyladenosine (ms2t 6A) in tRNALys(UUU) and that it is required for the accurate translation of AAA and AAG codons. Mice with pancreatic β cell-specific KO of Cdkal1 (referred to herein as β cell KO mice) showed pancreatic islet hypertrophy, a decrease in insulin secretion, and impaired blood glucose control. In Cdkal1-deficient β cells, misreading of Lys codon in proinsulin occurred, resulting in a reduction of glucosestimulated proinsulin synthesis. Moreover, expression of ER stress-related genes was upregulated in these cells, and abnormally structured ER was observed. Further, the β cell KO mice were hypersensitive to high fat diet-induced ER stress. These findings suggest that glucose-stimulated translation of proinsulin may require fully modified tRNALys(UUU), which could potentially explain the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

Original languageEnglish
Pages (from-to)3598-3608
Number of pages11
JournalJournal of Clinical Investigation
Volume121
Issue number9
DOIs
Publication statusPublished - 2011 Sep 1
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Wei, F. Y., Suzuki, T., Watanabe, S., Kimura, S., Kaitsuka, T., Fujimura, A., Matsui, H., Atta, M., Michiue, H., Fontecave, M., Yamagata, K., Suzuki, T., & Tomizawa, K. (2011). Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice. Journal of Clinical Investigation, 121(9), 3598-3608. https://doi.org/10.1172/JCI58056