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
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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Research Article Metabolism

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

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 (ms2t6A) 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 glucose-stimulated 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.

Authors

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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Figure 6

β cell KO mice exhibit increased ER stress and glucose intolerance after consuming an HFD.

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β cell KO mice exhibit increased ER stress and glucose intolerance after...
(A) Changes in body weight of β cell KO and Flox mice on an HFD and a LFD starting from 20 weeks old. (B and C) Results of the glucose tolerance test after 3 weeks (B) and 8 weeks (C) of consuming an HFD or a LFD. Mice were fasted for 7 hours from 8 am and injected with glucose (1 g/kg body weight). *P < 0.05; ***P < 0.001, KO-HFD versus Flox-HFD mice. n = 4–6. (D and E) Nonfasting blood glucose (D) and 7-hour fasting blood glucose (E) levels after 3 weeks on an HFD or an LFD. *P < 0.05; n = 6. (F) The insulin tolerance test was performed in mice fed an HFD or an LFD for 7 weeks. (G) β cell KO mice and Flox mice were fed an HFD for 8 weeks. Plasma insulin level during IPGTT (1 g/kg body weight) was examined in β cell KO mice and Flox mice fasted for 14 hours. **P < 0.01; n = 6. (H) Relative expression of ER stress–related genes in β cell KO mice and Flox mice fed an HFD for 8 weeks. **P < 0.01; n = 4–5. Significant differences between groups were examined by repeated measure of ANOVA (A–C, F, and G), 2-way ANOVA (D and E), or Student’s t test (H). All data are presented as mean ± SEM.