Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice

J Clin Invest. 2011 Sep;121(9):3598-608. doi: 10.1172/JCI58056. Epub 2011 Aug 15.


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 tRNA(Lys)(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 tRNA(Lys)(UUU), which could potentially explain the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / biosynthesis
  • Animals
  • Cell Line
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Genes, Reporter
  • Glucagon / genetics
  • Glucagon / metabolism
  • Glucose / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nucleic Acid Conformation
  • Proinsulin / genetics
  • Proinsulin / metabolism
  • Protein Biosynthesis
  • RNA, Transfer, Amino Acyl / chemistry
  • RNA, Transfer, Amino Acyl / genetics
  • RNA, Transfer, Amino Acyl / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Threonine / analogs & derivatives
  • Threonine / biosynthesis
  • tRNA Methyltransferases


  • 2-methylthio-N6-threonylcarbamoyladenosine
  • Nerve Tissue Proteins
  • RNA, Transfer, Amino Acyl
  • Recombinant Fusion Proteins
  • Threonine
  • Glucagon
  • Proinsulin
  • tRNA Methyltransferases
  • Cyclin-Dependent Kinase 5
  • CDKAL1 protein, mouse
  • Glucose
  • Adenosine