Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy

Oliver J. Freeman, Richard D. Unwin, Andrew W. Dowsey, Paul Begley, Sumia Ali, Katherine A. Hollywood, Nitin Rustogi, Rasmus S. Petersen, Warwick B. Dunn, Garth J S Cooper*, Natalie J. Gardiner

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

75 Citations (Scopus)


High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However, our understanding of the molecular mechanisms that cause the marked distal pathology is incomplete. We performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN. We integrated proteomics and metabolomics from the sciatic nerve (SN), the lumbar 4/5 dorsal root ganglia (DRG), and the trigeminal ganglia (TG) of streptozotocin-diabetic and healthy control rats. Even though all tissues showed a dramatic increase in glucose and polyol pathway intermediates in diabetes, a striking upregulation of mitochondrial oxidative phosphorylation and perturbation of lipid metabolism was found in the distal SN that was not present in the corresponding cell bodies of the DRG or the cranial TG. This finding suggests that the most severe molecular consequences of diabetes in the nervous system present in the SN, the region most affected by neuropathy. Such spatial metabolic dysfunction suggests a failure of energy homeostasis and/or oxidative stress, specifically in the distal axon/Schwann cell-rich SN. These data provide a detailed molecular description of the distinct compartmental effects of diabetes on the PNS that could underlie the distal-proximal distribution of pathology.

Original languageEnglish
Pages (from-to)228-238
Number of pages11
Issue number1
Early online date22 Dec 2015
Publication statusPublished - Jan 2016

Structured keywords

  • Jean Golding


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