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

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

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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 which cause the marked distal pathology is incomplete. Here 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, there was a striking upregulation of mitochondrial oxidative phosphorylation and perturbation of lipid metabolism in the distal SN that was not present in the corresponding cell bodies of the DRG or the cranial TG. This 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 which 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

Research Beacons, Institutes and Platforms

  • Manchester Institute of Biotechnology


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