[HTML][HTML] Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes

LM Hinder, A Vivekanandan-Giri… - The Journal of …, 2013 - ncbi.nlm.nih.gov
LM Hinder, A Vivekanandan-Giri, LL McLean, S Pennathur, EL Feldman
The Journal of endocrinology, 2013ncbi.nlm.nih.gov
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 …
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 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, 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/ESI/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids, HODEs) 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 nerve to rely on truncated TCA cycle metabolism in the type 2 diabetes environment.
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