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Molecular and Cellular Biology, May 2008, p. 2971-2979, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.01695-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Yutaka Shigeyama,¹ Toshiyuki Kobayashi,^2, Yoshiaki Kido,^1* Naoko Hashimoto,¹ Shun-ichiro Asahara,¹ Tomokazu Matsuda,¹ Akihiko Takeda,¹ Tae Inoue,¹ Yuki Shibutani,¹ Maki Koyanagi,¹ Tohru Uchida,¹ Maki Inoue,³ Okio Hino,^2, Masato Kasuga,¹ and Tetsuo Noda³

Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan,¹ Department of Experimental Pathology,² Department of Cell Biology, Cancer Institute, Japanese Foundation of Cancer Research, Tokyo 135-8550, Japan³

Received 14 September 2007/ Returned for modification 17 October 2007/ Accepted 15 February 2008

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.

Published ahead of print on 3 March 2008.

Present address: Department of Molecular Pathogenesis, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.