Biphasic Response of Pancreatic β-Cell Mass to Ablation of Tuberous Sclerosis Complex 2 in Mice

Abstract

Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic β-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on β-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic β cells (βTSC2^−/− mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual β cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the βTSC2^−/− mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of β cells. These results thus indicate that TSC2 regulates pancreatic β-cell mass in a biphasic manner.

ACKNOWLEDGMENTS

We thank K. H. Yoon (Catholic University of Korea, Seoul, Korea) for helpful discussion and S. Hirahara, M. Nagano, M. Oya, and A. Tanida for technical assistance.

This work was supported by a grant for the 21st Century COE Program “Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as Model” from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) to M.K.; a grant for the Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER) from MEXT to M.K.; and a Grant-in-Aid for Creative Scientific Research from MEXT to M.K.