Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes Lucy M Hinder, Anuradha Vivekanandan-Giri 1 , Lisa L McLean, Subramaniam Pennathur 1 and Eva L Feldman Department of Neurology, University of Michigan, AATBSRB, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200, USA 1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA Correspondence should be addressed to E L Feldman Email efeldman@med.umich.edu 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 charac- terize 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-mC/CLepr db ; db/db) and controls (db/C). 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. Key Words " diabetes " neuropathy " metabolomics " sural nerve " sciatic nerve " dorsal root ganglia Journal of Endocrinology (2013) 216, 1–11 Journal of Endocrinology Research L M HINDER and others Metabolic profiles in diabetic mouse nerve 216 :1 1–11 http://www.joe.endocrinology-journals.org Ñ 2013 Society for Endocrinology DOI: 10.1530/JOE-12-0356 Printed in Great Britain Published by Bioscientifica Ltd.