title: Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy.
abstract: 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.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, U.K. Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K.
authors.forename: Oliver J
authors.identifier: http://orcid.org/0000-0003-4009-282X
authors.initials: OJ
authors.lastname: Freeman
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K. Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Unwin
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K. Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Dowsey
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K. Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Begley
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Sumia
authors.initials: S
authors.lastname: Ali
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K. Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hollywood
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K. Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Nitin
authors.initials: N
authors.lastname: Rustogi
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Rasmus S
authors.initials: RS
authors.lastname: Petersen
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K. Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Warwick B
authors.initials: WB
authors.lastname: Dunn
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K. Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, U.K. School of Biological Sciences, The University of Auckland, Auckland, New Zealand Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, U.K. natalie.gardiner@manchester.ac.uk garth.cooper@manchester.ac.uk.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, U.K. natalie.gardiner@manchester.ac.uk garth.cooper@manchester.ac.uk.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Gardiner
mesh_terms: D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005632:Fructose / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007294:Inositol / Q000378:metabolism; D050356:Lipid Metabolism; D008159:Lumbar Vertebrae; D055432:Metabolomics; D008928:Mitochondria / Q000378:metabolism*; D009431:Neural Conduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D011108:Polymers / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000378:metabolism*
chemical_list: D011108:Polymers; C116917:acylcarnitine; C024617:polyol; C009217:scyllitol; D005632:Fructose; D007294:Inositol; D013012:Sorbitol; D005947:Glucose; D002331:Carnitine