Zhong Lingwen, Georgia Senta, Tschen Shuen-Ing, Nakayama Keiko, Nakayama Keiichi, Bhushan Anil
Larry Hillblom Islet Research Center and Molecular Biology Institute, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
J Clin Invest. 2007 Oct;117(10):2869-76. doi: 10.1172/JCI32198.
Diabetes results from an inadequate mass of functional beta cells, due to either beta cell loss caused by immune assault or the lack of compensation to overcome insulin resistance. Elucidating the mechanisms that regulate beta cell mass has important ramifications for fostering beta cell regeneration and the treatment of diabetes. We report here that Skp2, a substrate recognition component of Skp1-Cul1-F-box (SCF) ubiquitin ligase, played an essential and specific role in regulating the cellular abundance of p27 and was a critical determinant of beta cell proliferation. In Skp2(-/-) mice, accumulation of p27 resulted in enlarged polyploid beta cells as a result of endoreduplication replacing proliferation. Despite beta cell hypertrophy, Skp2(-/-) mice exhibited diminished beta cell mass, hypoinsulinemia, and glucose intolerance. Increased insulin resistance resulting from diet-induced obesity caused Skp2(-/-) mice to become overtly diabetic, because beta cell growth in the absence of cell division was insufficient to compensate for increased metabolic demand. These results indicate that the Skp2-mediated degradation pathway regulating the cellular degradation of p27 is essential for establishing beta cell mass and to respond to increased metabolic demand associated with insulin resistance.
糖尿病是由于功能性β细胞数量不足所致，这要么是由免疫攻击导致β细胞丢失，要么是缺乏克服胰岛素抵抗的代偿机制。阐明调节β细胞数量的机制对于促进β细胞再生和治疗糖尿病具有重要意义。我们在此报告，Skp2是Skp1-Cul1-F盒（SCF）泛素连接酶的底物识别成分，在调节p27的细胞丰度方面发挥了重要且特定的作用，并且是β细胞增殖的关键决定因素。在Skp2基因敲除小鼠中，p27的积累导致多倍体β细胞增大，这是由于核内复制取代了增殖。尽管β细胞肥大，但Skp2基因敲除小鼠的β细胞数量减少、胰岛素血症降低且糖耐量异常。饮食诱导的肥胖导致的胰岛素抵抗增加使Skp2基因敲除小鼠明显患糖尿病，因为在没有细胞分裂的情况下β细胞生长不足以补偿增加的代谢需求。这些结果表明，Skp2介导的调节p27细胞降解的途径对于建立β细胞数量以及应对与胰岛素抵抗相关的代谢需求增加至关重要。
