Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with
peripheral nervous system oxidative stress in a murine model of type 2 diabetes.
Authors Hinder LM, Vivekanandan-Giri A, McLean LL, Pennathur S, Feldman EL
Submitted By Eva Feldman on 3/7/2013
Status Published
Journal The Journal of endocrinology
Year 2013
Date Published 1/1/2013
Volume : Pages 216 : 1 - 11
PubMed Reference 23086140
Abstract Diabetic neuropathy (DN) is the most common complication of diabetes and is
characterized by distal-to-proximal loss of peripheral nerve axons. The idea of
tissue-specific pathological alterations in energy metabolism in diabetic
complications-prone tissues is emerging. Altered nerve metabolism in type 1
diabetes models is observed; however, therapeutic strategies based on these
models offer limited efficacy to type 2 diabetic patients with DN. Therefore,
understanding how peripheral nerves metabolically adapt to the unique type 2
diabetic environment is critical to develop disease-modifying treatments. In the
current study, we utilized targeted liquid chromatography-tandem mass
spectrometry (LC/MS/MS) to characterize the glycolytic and tricarboxylic acid
(TCA) cycle metabolomes in sural nerve, sciatic nerve, and dorsal root ganglia
(DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Lepr(db); db/db) and controls
(db/+). We report depletion of glycolytic intermediates in diabetic sural nerve
and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate,
fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate,
2-phosphoglycerate, phosphoenolpyruvate, and lactate), with no significant
changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in
sural nerve, sciatic nerve, and DRG from diabetic mice. Utilizing
LC/electrospray ionization/MS/MS and HPLC methods, we also observed increased
protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids) in
db/db tissue, with a proximal-to-distal increase in oxidative stress, with
associated decreased aconitase enzyme activity. We propose a preliminary model,
whereby the greater change in metabolomic profile, increase in oxidative stress,
and decrease in TCA cycle enzyme activity may cause distal peripheral nerves to
rely on truncated TCA cycle metabolism in the type 2 diabetes environment.


Investigators with authorship
NameInstitution
Eva FeldmanUniversity of Michigan

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