Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes

Brain. 2012 Jun;135(Pt 6):1751-66. doi: 10.1093/brain/aws097. Epub 2012 May 4.


Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Triphosphate / pharmacology
  • Analysis of Variance
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / complications
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Ganglia, Spinal / pathology*
  • Gene Expression Regulation / drug effects
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hyperalgesia / physiopathology
  • Male
  • Membrane Potentials / genetics
  • Mice
  • Mitochondrial Diseases / drug therapy
  • Mitochondrial Diseases / etiology
  • Mitochondrial Diseases / pathology*
  • Mitochondrial Membranes / drug effects
  • Mutation / genetics
  • Nerve Fibers, Myelinated / pathology
  • Neurites / pathology
  • Oxygen Consumption / drug effects
  • Patch-Clamp Techniques
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / etiology
  • Peripheral Nervous System Diseases / pathology*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Physical Stimulation / adverse effects
  • RNA-Binding Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Reaction Time / genetics
  • Resveratrol
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / enzymology*
  • Sensory Receptor Cells / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Stilbenes / therapeutic use
  • Transcription Factors / metabolism
  • Transduction, Genetic


  • Anti-Inflammatory Agents, Non-Steroidal
  • Blood Glucose
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • RNA-Binding Proteins
  • Stilbenes
  • Transcription Factors
  • Green Fluorescent Proteins
  • Adenosine Triphosphate
  • AMP-Activated Protein Kinases
  • Resveratrol