[HTML][HTML] Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic β cells

L Zhong, S Georgia, S Tschen… - The Journal of …, 2007 - Am Soc Clin Investig
L Zhong, S Georgia, S Tschen, K Nakayama, K Nakayama, A Bhushan
The Journal of clinical investigation, 2007Am Soc Clin Investig
Diabetes results from an inadequate mass of functional β cells, due to either β cell loss
caused by immune assault or the lack of compensation to overcome insulin resistance.
Elucidating the mechanisms that regulate β cell mass has important ramifications for
fostering β 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 …
Diabetes results from an inadequate mass of functional β cells, due to either β cell loss caused by immune assault or the lack of compensation to overcome insulin resistance. Elucidating the mechanisms that regulate β cell mass has important ramifications for fostering β 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 β cell proliferation. In Skp2–/–mice, accumulation of p27 resulted in enlarged polyploid β cells as a result of endoreduplication replacing proliferation. Despite β cell hypertrophy, Skp2–/–mice exhibited diminished β cell mass, hypoinsulinemia, and glucose intolerance. Increased insulin resistance resulting from diet-induced obesity caused Skp2–/–mice to become overtly diabetic, because β 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 β cell mass and to respond to increased metabolic demand associated with insulin resistance.
The Journal of Clinical Investigation