Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle

  1. Tore Bengtsson1,*
  1. 1Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
  2. 2Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA
  3. 3Department of Pharmacology and
  4. 4Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, 399 Royal Parade, Parkville, Victoria 3052, Australia
  1. *Corresponding author: Tore Bengtsson, Email: tore.bengtsson{at}su.se
  1. # contributed equally

Abstract

Type 2 diabetes is an increasing worldwide epidemic that poses major health problems. We have identified a novel physiological system that increases glucose uptake in skeletal muscle but not in white adipocytes. Activation of this system improves glucose tolerance in Goto-Kakizaki rats or mice fed a high fat diet, which are established models for type 2 diabetes. The pathway involves activation of β2-adrenoceptors that increase cAMP levels and activate PKA that phosphorylates mammalian target of rapamycin complex 2 (mTORC2) at S2481. The active mTORC2 causes translocation of GLUT4 to the plasma membrane and glucose uptake without the involvement of Akt or AS160. Stimulation of glucose uptake into skeletal muscle following activation of the sympathetic nervous system is likely to be of high physiological relevance since mTOR complex 2 activation was observed at the cellular, tissue and whole animal level in rodent and human systems. This signaling pathway provides new opportunities for the treatment of type 2 diabetes.

  • Received December 9, 2013.
  • Accepted June 29, 2014.

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This Article

  1. Diabetes
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