Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing

Nat Commun. 2017 Jul 12;8:16014. doi: 10.1038/ncomms16014.

Abstract

Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that β-cell-specific loss of mTORC1 causes diabetes and β-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (βraKO) and inducible (MIP-βraKOf/f) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates β-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates β-cell proliferation. Restoration of both pathways partially recovers β-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in β-cells and identify downstream pathways driving β-cell mass, function and insulin processing.

Publication types

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

MeSH terms

  • Animals
  • Autophagy
  • Blood Glucose
  • Carboxypeptidase H / metabolism
  • Diabetes Mellitus, Experimental / etiology*
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factors / metabolism
  • Homeostasis
  • Humans
  • Insulin / metabolism*
  • Insulin-Secreting Cells / physiology*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Mice, Transgenic
  • Regulatory-Associated Protein of mTOR / genetics
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus

Substances

  • Blood Glucose
  • Eif4ebp2 protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Insulin
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • eIF4E protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases
  • Carboxypeptidase H
  • Sirolimus