Skp2-Mediated Regulation of P27 Turnover Is Essential for Growth and Expansion of Beta Cell Mass

Bhushan, Anil; Zhong, Lingwen; Georgia, Senta
June 2007
Diabetes;Jun2007 Supplement 1, Vol. 56, pA418
Academic Journal
Diabetes results from an inadequate mass of functional beta cells. Such inadequacy could result from loss of beta cells due to an immune assault or the lack of compensation to overcome insulin resistance. Thus, mechanisms that regulate the number of beta cells will be key to understanding both the pathogenesis of diabetes and for developing therapies. We report here that Skp2, a substrate recognition component of SCF ubiquitin ligase, plays an essential role in regulating the cellular abundance of p27 and a critical determinant of beta cell proliferation. In mice that lacked Skp2, accumulation of p27 resulted in enlarged polyploid beta cells due to endoreduplication replacing proliferation. Despite beta cell hypertrophy, Skp2-/- mice exhibited diminished beta cell mass, hypoinsulinaemic and glucose intolerance compared to their Skp2+/- littermates. Increased insulin resistance due to diet-induced obesity resulted in Skp2-/- mice becoming overtly diabetic indicating that p27 turnover was required for the compensatory growth of beta cell mass. Furthermore, accumulation of p27 in the beta cells of db/db mice (that lack leptin receptor) coincided with the absence of Skp2 protein indicating that Skp2ââ¬â€œmediated p27 degradation may be dysregulated in animal models of type 2 diabetes. These results indicate that Skp2-mediated degradation pathway that regulate the cellular turnover of p27 is essential not only for beta cell growth but also the expansion of beta cell mass in response to increased metabolic demand associated with insulin resistance.


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