日本研究人員在新一期美國(guó)《臨床研究期刊》（The Journal of Clinical Investigation）網(wǎng)絡(luò)版上發(fā)表論文指出，很多并不肥胖的日本人也會(huì)患Ⅱ型糖尿病，這是他們體內(nèi)的特定基因出現(xiàn)變異，導(dǎo)致有降血糖功效的胰島素分泌減少引起的。
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.
