title: Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1.
abstract: OBJECTIVE
  We previously found that chronic tuberous sclerosis protein 2 (TSC2) deletion induces activation of mammalian target of rapamycin Complex 1 (mTORC1) and leads to hypertrophy of pancreatic beta cells from pancreatic beta cell-specific TSC2 knockout (βTSC2(-/-)) mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells.
  
  
  METHODS
  Isolated islets from βTSC2(-/-) mice and TSC2 knockdown insulin 1 (INS-1) insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes.
  
  
  RESULTS
  Activation of mTORC1 increased mitochondrial DNA expression, mitochondrial density and ATP production in pancreatic beta cells of βTSC2(-/-) mice. In TSC2 knockdown INS-1 cells, mitochondrial DNA expression, mitochondrial density and ATP production were increased compared with those in control INS-1 cells, consistent with the phenotype of βTSC2(-/-) mice. TSC2 knockdown INS-1 cells also exhibited augmented insulin secretory response to glucose. Rapamycin inhibited mitochondrial DNA expression and ATP production as well as insulin secretion in response to glucose. Thus, βTSC2(-/-) mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1.
  
  
  CONCLUSIONS
  Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells.
authors: Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Maki
authors: M
authors: Koyanagi
authors: Shun-ichiro
authors: S
authors: Asahara
authors: Tomokazu
authors: T
authors: Matsuda
authors: Naoko
authors: N
authors: Hashimoto
authors: Yutaka
authors: Y
authors: Shigeyama
authors: Yuki
authors: Y
authors: Shibutani
authors: Ayumi
authors: A
authors: Kanno
authors: Megumi
authors: M
authors: Fuchita
authors: Tomoko
authors: T
authors: Mikami
authors: Tetsutya
authors: T
authors: Hosooka
authors: Hiroshi
authors: H
authors: Inoue
authors: Michihiro
authors: M
authors: Matsumoto
authors: Masato
authors: M
authors: Koike
authors: Yasuo
authors: Y
authors: Uchiyama
authors: Tetsuo
authors: T
authors: Noda
authors: Susumu
authors: S
authors: Seino
authors: Masato
authors: M
authors: Kasuga
authors: Yoshiaki
authors: Y
authors: Kido
mesh_terms: D000818:Animals; D002460:Cell Line; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D046912:Multiprotein Complexes; D009928:Organ Specificity / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D007328:Insulin; D046912:Multiprotein Complexes; D011506:Proteins; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus