THE ROLE OF GLYOXALASE I IN HYPERGLYCEMIA-INDUCED SENSORY NEURON DAMAGE AND DEVELOPMENT OF DIABETIC SENSORY NEUROPATHY SYMPTOMS

Abstract

Diabetic neuropathy is the most common and debilitating complication of diabetes mellitus with over half of all patients developing altered sensation as a result of damage to peripheral sensory neurons. Hyperglycemia results in altered nerve conduction velocities, loss of epidermal innervation, and the development of painful or painless signs and symptoms in the feet and hands. Current research has been unable to determine if a patient will develop insensate or painful neuropathy or be protected from peripheral nerve damage all together. One of the mechanisms that has been recognized to have a role in the pathogenesis of sensory neuron damage is the process of reactive dicarbonyls forming advanced glycation endproducts (AGEs) as a direct result of hyperglycemia. The glyoxalase system, composed of the enzymes glyoxalase I (GLO1) and glyoxalase II, is the main detoxification pathway involved in breaking down toxic reactive dicarbonyls before producing carbonyl stress and forming AGEs on proteins, lipids, or nucleic acids. The purpose of this study was to explore a role for GLO1 in the development, progression, and/or prevention of diabetic neuropathy in animal models of diabetic neuropathy. Initial studies characterized the pattern of expression of GLO1 in the peripheral nervous system and recognized restricted but variable expression in peptidergic C-fibers responsible for nociception. Diabetic mouse model of painful and insensate neuropathy showed reduced expression of GLO1 correlated with increased mechanical and thermal thresholds, while the strain with elevated GLO1 developed mechanical allodynia. These results suggest an imbalance of fiber types, as a direct result of hyperglycemia damage, may influence the development of signs and symptoms of neuropathy. A study of two inbred substrains that vary in GLO1 abundance showed reduced GLO1 correlated with development of mechanical insensitivity, reduced epidermal innervation, and reduced expression of mitochondrial oxidative phosphorylation proteins. Elevated GLO1 protected from these alterations. Finally, methylglyoxal treatment of cultured adult sensory neurons resulted in reduced expression of electron transport chain proteins in certain strains. Together, these studies suggest a protective role for GLO1 in preventing reactive dicarbonyl-mediated alterations of mitochondrial oxidative phosphorylation complexes and the development of insensate neuropathy.