Poy Matthew N, Hausser Jean, Trajkovski Mirko, Braun Matthias, Collins Stephan, Rorsman Patrik, Zavolan Mihaela, Stoffel Markus
Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, ETH Zurich, CH-8093 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5813-8. doi: 10.1073/pnas.0810550106. Epub 2009 Mar 16.
Altered growth and development of the endocrine pancreas is a frequent cause of the hyperglycemia associated with diabetes. Here we show that microRNA-375 (miR-375), which is highly expressed in pancreatic islets, is required for normal glucose homeostasis. Mice lacking miR-375 (375KO) are hyperglycemic, exhibit increased total pancreatic alpha-cell numbers, fasting and fed plasma glucagon levels, and increased gluconeogenesis and hepatic glucose output. Furthermore, pancreatic beta-cell mass is decreased in 375KO mice as a result of impaired proliferation. In contrast, pancreatic islets of obese mice (ob/ob), a model of increased beta-cell mass, exhibit increased expression of miR-375. Genetic deletion of miR-375 from these animals (375/ob) profoundly diminished the proliferative capacity of the endocrine pancreas and resulted in a severely diabetic state. Bioinformatic analysis of transcript data from 375KO islets revealed that miR-375 regulates a cluster of genes controlling cellular growth and proliferation. These data provide evidence that miR-375 is essential for normal glucose homeostasis, alpha- and beta-cell turnover, and adaptive beta-cell expansion in response to increasing insulin demand in insulin resistance.
内分泌胰腺生长发育的改变是糖尿病相关高血糖的常见原因。我们在此表明，在胰岛中高度表达的微小RNA-375（miR-375）是正常葡萄糖稳态所必需的。缺乏miR-375的小鼠（375KO）出现高血糖，胰腺α细胞总数增加，空腹和进食后血浆胰高血糖素水平升高，糖异生和肝脏葡萄糖输出增加。此外，由于增殖受损，375KO小鼠的胰腺β细胞量减少。相反，肥胖小鼠（ob/ob）的胰岛作为β细胞量增加的模型，miR-375的表达增加。从这些动物（375/ob）中基因删除miR-375会显著降低内分泌胰腺的增殖能力，并导致严重的糖尿病状态。对375KO胰岛转录数据的生物信息学分析表明，miR-375调节一组控制细胞生长和增殖的基因。这些数据证明，miR-375对于正常葡萄糖稳态、α细胞和β细胞更新以及在胰岛素抵抗中对胰岛素需求增加做出反应时β细胞的适应性扩张至关重要。
