Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice.
Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic beta-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 beta-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic beta cells (betaTSC2(-/-) 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 beta cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the betaTSC2(-/-) mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of beta cells. These results thus indicate that TSC2 regulates pancreatic beta-cell mass in a biphasic manner.
Shigeyama
Yutaka
Y
Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Kobayashi
Toshiyuki
T
Kido
Yoshiaki
Y
Hashimoto
Naoko
N
Asahara
Shun-Ichiro
S
Matsuda
Tomokazu
T
Takeda
Akihiko
A
Inoue
Tae
T
Shibutani
Yuki
Y
Koyanagi
Maki
M
Uchida
Tohru
T
Inoue
Maki
M
Hino
Okio
O
Kasuga
Masato
M
Noda
Tetsuo
T
D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D007328:Insulin; D010750:Phosphoproteins; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases