PMID- 26470786
OWN - NLM
STAT- MEDLINE
DCOM- 20160428
LR  - 20211006
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 65
IP  - 1
DP  - 2016 Jan
TI  - Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic 
      Neuropathy.
PG  - 228-38
LID - 10.2337/db15-0835 [doi]
AB  - 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.
CI  - (c) 2016 by the American Diabetes Association. Readers may use this article as long 
      as the work is properly cited, the use is educational and not for profit, and the 
      work is not altered.
FAU - Freeman, Oliver J
AU  - Freeman OJ
AUID- ORCID: 0000-0003-4009-282X
AD  - 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.
FAU - Unwin, Richard D
AU  - Unwin RD
AD  - 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.
FAU - Dowsey, Andrew W
AU  - Dowsey AW
AD  - 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.
FAU - Begley, Paul
AU  - Begley P
AD  - 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.
FAU - Ali, Sumia
AU  - Ali S
AD  - Faculty of Life Sciences, The University of Manchester, Manchester, U.K.
FAU - Hollywood, Katherine A
AU  - Hollywood KA
AD  - 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.
FAU - Rustogi, Nitin
AU  - Rustogi N
AD  - 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.
FAU - Petersen, Rasmus S
AU  - Petersen RS
AD  - Faculty of Life Sciences, The University of Manchester, Manchester, U.K.
FAU - Dunn, Warwick B
AU  - Dunn WB
AD  - 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.
FAU - Cooper, Garth J S
AU  - Cooper GJ
AD  - 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.
FAU - Gardiner, Natalie J
AU  - Gardiner NJ
AD  - Faculty of Life Sciences, The University of Manchester, Manchester, U.K. 
      natalie.gardiner@manchester.ac.uk garth.cooper@manchester.ac.uk.
LA  - eng
GR  - 097820/Z/11/B/WT_/Wellcome Trust/United Kingdom
GR  - MR/L011093/2/MRC_/Medical Research Council/United Kingdom
GR  - MR/L01064X/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/L011093/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/L011093/3/MRC_/Medical Research Council/United Kingdom
GR  - G1001609/MR/J500410/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151015
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Polymers)
RN  - 0 (acylcarnitine)
RN  - 0 (polyol)
RN  - 1VS4X81277 (scyllitol)
RN  - 30237-26-4 (Fructose)
RN  - 4L6452S749 (Inositol)
RN  - 506T60A25R (Sorbitol)
RN  - IY9XDZ35W2 (Glucose)
RN  - S7UI8SM58A (Carnitine)
SB  - IM
MH  - Animals
MH  - Carnitine/analogs & derivatives/metabolism
MH  - Diabetes Mellitus, Experimental/complications/*metabolism
MH  - Diabetic Neuropathies/etiology/*metabolism
MH  - Disease Models, Animal
MH  - Energy Metabolism
MH  - Fructose/metabolism
MH  - Ganglia, Spinal/*metabolism
MH  - Glucose/*metabolism
MH  - Homeostasis
MH  - Inositol/metabolism
MH  - Lipid Metabolism
MH  - Lumbar Vertebrae
MH  - Metabolomics
MH  - Mitochondria/*metabolism
MH  - Neural Conduction
MH  - Oxidative Phosphorylation
MH  - Oxidative Stress
MH  - Polymers/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sciatic Nerve/*metabolism
MH  - Sorbitol/metabolism
MH  - Trigeminal Ganglion/*metabolism
EDAT- 2015/10/17 06:00
MHDA- 2016/04/29 06:00
CRDT- 2015/10/17 06:00
PHST- 2015/06/17 00:00 [received]
PHST- 2015/10/07 00:00 [accepted]
PHST- 2015/10/17 06:00 [entrez]
PHST- 2015/10/17 06:00 [pubmed]
PHST- 2016/04/29 06:00 [medline]
AID - db15-0835 [pii]
AID - 10.2337/db15-0835 [doi]
PST - ppublish
SO  - Diabetes. 2016 Jan;65(1):228-38. doi: 10.2337/db15-0835. Epub 2015 Oct 15.