Protection from diabetes-induced peripheral sensory neuropathy — A role for elevated glyoxalase I?

• Published in: Experimental neurology 2012-03, Vol.234 (1), p.62-69
• Main Authors: Jack, M.M., Ryals, J.M., Wright, D.E.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Biological and medical sciences; Blood Glucose; Body Weight; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Diabetes; Diabetic Neuropathies - chemically induced; Diabetic Neuropathies - complications; Diabetic Neuropathies - enzymology; Diabetic Neuropathies - genetics; Disease Models, Animal; Dorsal root ganglion; Epidermis; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Enzymologic - physiology; Glyoxalase I; Lactoylglutathione Lyase - genetics; Lactoylglutathione Lyase - metabolism; Male; Mechanical sensitivity; Medical sciences; Mice; Mice, Inbred BALB C; Mitochondrial Diseases - etiology; Multienzyme Complexes - metabolism; Nerve Fibers - pathology; Nervous system (semeiology, syndromes); Neural Conduction - physiology; Neurology; Neuropathy; Pain Measurement; Peripheral nerve; Psychomotor Performance; Skin innervation; Streptozocin - adverse effects
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2011.12.015

Diabetic neuropathy is a common complication of diabetes mellitus with over half of all patients developing neuropathy symptoms due to sensory nerve damage. Diabetes-induced hyperglycemia leads to the accelerated production of advanced glycation end products (AGEs) that alter proteins, thereby leading to neuronal dysfunction. The glyoxalase enzyme system, specifically glyoxalase I (GLO1), is responsible for detoxifying precursors of AGEs, such as methylglyoxal and other reactive dicarbonyls. The purpose of our studies was to determine if expression differences of GLO1 may play a role in the development of diabetic sensory neuropathy. BALB/cJ mice naturally express low levels of GLO1, while BALB/cByJ express approximately 10-fold higher levels on a similar genetic background due to increased copy numbers of GLO1. Five weeks following STZ injection, diabetic BALB/cJ mice developed a 68% increase in mechanical thresholds, characteristic of insensate neuropathy or loss of mechanical sensitivity. This behavior change correlated with a 38% reduction in intraepidermal nerve fiber density (IENFD). Diabetic BALB/cJ mice also had reduced expression of mitochondrial oxidative phosphorylation proteins in Complexes I and V by 83% and 47%, respectively. Conversely, diabetic BALB/cByJ mice did not develop signs of neuropathy, changes in IENFD, or alterations in mitochondrial protein expression. Reduced expression of GLO1 paired with diabetes-induced hyperglycemia may lead to neuronal mitochondrial damage and symptoms of diabetic neuropathy. Therefore, AGEs, the glyoxalase system, and mitochondrial dysfunction may play a role in the development and modulation of diabetic peripheral neuropathy. ►Glyoxalase I protects against damaging effects of advanced glycation end products. ►We examine two strains of mice that naturally express different levels of GLO1. ►Diabetic BALB/cJ mice with low levels develop several classic signs of neuropathy. ►Diabetic BALB/cByJ mice with high levels do not develop signs of neuropathy. ►These mice provide a new tool to explore the role of GLO1 and AGE-related damage.