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

Manuel Blandino-Rosano1, Rebecca Barbaresso2, Margarita Jimenez-Palomares2

  • 1Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.

Nature Communications
|July 13, 2017
PubMed

Insights

Loss of mTOR complex 1 (mTORC1) in pancreatic beta cells causes type 2 diabetes by impairing cell function and survival. Specific pathways regulate beta cell proliferation, autophagy, and insulin secretion.

Area of Science:

  • Cell Biology
  • Metabolic Diseases
  • Endocrinology

Background:

  • mTOR complex 1 (mTORC1) signaling is crucial for cellular functions.
  • Dysregulation of mTORC1 is linked to metabolic diseases like type 2 diabetes.
  • Pancreatic beta cells are key regulators of glucose homeostasis.

Purpose of the Study:

  • To investigate the role of mTORC1 in pancreatic beta cell function and survival.
  • To identify the specific downstream pathways regulated by mTORC1 in beta cells.
  • To explore the therapeutic potential of targeting mTORC1 in diabetes.

Main Methods:

  • Conditional and inducible knockout mice (βraKO and MIP-βraKOf/f) were used to delete raptor, a key component of mTORC1, specifically in beta cells.
  • Genetic reconstitution of mTORC1 downstream targets was performed.
  • Analysis of beta cell proliferation, apoptosis, autophagy, and insulin secretion was conducted.
  • Carboxypeptidase E (CPE) expression and insulin processing were examined.
  • Rapamycin treatment was applied to mice and human islets.

Main Results:

  • Loss of mTORC1 in beta cells led to diabetes and beta cell failure, characterized by defects in proliferation, autophagy, apoptosis, and insulin secretion.
  • The mTORC1/S6K pathway was identified as regulating beta cell apoptosis, size, and autophagy.
  • The mTORC1/4E-BP2-eIF4E pathway was found to regulate beta cell proliferation.
  • Restoration of both pathways partially rescued beta cell mass and hyperglycemia.
  • mTORC1 controls insulin processing via cap-dependent translation of carboxypeptidase E (CPE) in a 4EBP2/eIF4E-dependent manner.
  • Rapamycin treatment reduced CPE expression and insulin secretion in mice and human islets.

Conclusions:

  • mTORC1 plays a critical role in maintaining pancreatic beta cell mass, function, and survival.
  • Specific downstream pathways (mTORC1/S6K and mTORC1/4E-BP2-eIF4E) mediate distinct functions of mTORC1 in beta cells.
  • mTORC1 regulates insulin processing through the control of CPE translation.
  • Targeting mTORC1 pathways may offer a therapeutic strategy for type 2 diabetes.

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