Critical roles for the TSC-mTOR pathway in β-cell function

Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1013-22. doi: 10.1152/ajpendo.00262.2009. Epub 2009 Aug 18.

Abstract

TSC1 is a tumor suppressor that associates with TSC2 to inactivate Rheb, thereby inhibiting signaling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 stimulates cell growth by promoting anabolic cellular processes, such as translation, in response to growth factors and nutrient signals. To test roles for TSC1 and mTORC1 in β-cell function, we utilized Rip2/Cre to generate mice lacking Tsc1 in pancreatic β-cells (Rip-Tsc1cKO mice). Although obesity developed due to hypothalamic Tsc1 excision in older Rip-Tsc1cKO animals, young animals displayed a prominent gain-of-function β-cell phenotype prior to the onset of obesity. The young Rip-Tsc1cKO animals displayed improved glycemic control due to mTOR-mediated enhancement of β-cell size, mass, and insulin production but not determinants of β-cell number (proliferation and apoptosis), consistent with an important anabolic role for mTOR in β-cell function. Furthermore, mTOR mediated these effects in the face of impaired Akt signaling in β-cells. Thus, mTOR promulgates a dominant signal to promote β-cell/islet size and insulin production, and this pathway is crucial for β-cell function and glycemic control.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / physiology
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Appetite / genetics
  • Appetite / physiology
  • Blood Glucose / metabolism
  • Blotting, Western
  • Cell Size
  • Immunohistochemistry
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Mice, Knockout
  • Nerve Net / physiology
  • Obesity / genetics
  • Obesity / physiopathology
  • Signal Transduction / physiology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / physiology*
  • Transcription Factors / genetics
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*

Substances

  • Anti-Bacterial Agents
  • Blood Glucose
  • Crtc1 protein, mouse
  • Insulin
  • Transcription Factors
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Sirolimus