Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
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DOI：
10.1038/nm1187
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发表时间：
2005-01
期刊：
影响因子：
82.9
通讯作者：
T. Uchida;Takehiro Nakamura;Naoko Hashimoto;Tomokazu Matsuda;K. Kotani;H. Sakaue;Y. Kido;Y. Hayashi;K. Nakayama;M. White;M. Kasuga
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作者：
T. Uchida;Takehiro Nakamura;Naoko Hashimoto;Tomokazu Matsuda;K. Kotani;H. Sakaue;Y. Kido;Y. Hayashi;K. Nakayama;M. White;M. Kasuga
p27 Kip 1蛋白通过抑制细胞周期蛋白依赖性激酶（CDKs）的活性来调节哺乳动物的细胞周期进程。在这里，我们发现p27 Kip 1在缺乏胰岛素受体底物2（Irs 2-/-）或瘦素受体长型（Lepr-/-ordb/db）的小鼠胰腺β细胞核中进行性积累。在这些2型糖尿病动物模型中，缺失编码p27 Kip 1（Cdkn 1b）的基因可通过增加胰岛质量和维持代偿性高胰岛素血症来改善高血糖，这种作用主要归因于刺激胰腺β细胞增殖。因此，p27 Kip 1在Irs 2-/-和Lepr-/-小鼠2型糖尿病发展过程中导致β细胞衰竭，并代表了治疗这种疾病的潜在新靶点。
The protein p27Kip1regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27Kip1progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2−/−) or the long form of the leptin receptor (Lepr−/−ordb/db). Deletion of the gene encoding p27Kip1(Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27Kip1contributes to beta-cell failure during the development of type 2 diabetes inIrs2−/−andLepr−/−mice and represents a potential new target for the treatment of this condition.