title: Development of type 2 diabetes caused by a deficiency of a tRNA(lys) modification.
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-N (6)-threonylcarbamoyladenosine (ms (2)t (6)A) at position 37 of tRNA(lys)(UUU). The ms (2)t (6)A modification in tRNA(lys)(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 (2)t (6)A 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.
authors.affiliation: Department of Molecular Physiology; Faculty of Life Sciences; Kumamoto University; Kumamoto, Japan.
authors.forename: Fan-Yan
authors.initials: FY
authors.lastname: Wei
authors.affiliation: Department of Molecular Physiology; Faculty of Life Sciences; Kumamoto University; Kumamoto, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tomizawa
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000235:genetics; D000818:Animals; D003062:Codon; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D012357:RNA, Transfer, Lys / Q000235:genetics* / Q000378:metabolism*; D013912:Threonine / Q000031:analogs & derivatives* / Q000235:genetics; D012359:tRNA Methyltransferases
chemical_list: C515568:2-methylthio-N6-threonylcarbamoyladenosine; D003062:Codon; D009419:Nerve Tissue Proteins; D012357:RNA, Transfer, Lys; D013912:Threonine; D012359:tRNA Methyltransferases; C559068:CDKAL1 protein, mouse; D000241:Adenosine