Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy

Abstract

Diabetic neuropathy is the most common and debilitating complication of diabetes mellitus with more than 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 development of painful or painless signs and symptoms in the feet and hands. Current research has been unable to determine whether a patient will develop insensate or painful neuropathy or be protected from peripheral nerve damage all together. One mechanism 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. This review discusses AGEs, GLO1, their role in diabetic neuropathy, and potential therapeutic targets of the AGE pathway.

Figure 1

A schematic illustrating the pathways that lead to the production of reactive dicarbonyls and AGEs and the mechanisms by which AGEs cause to sensory neuron dysfunction.

Figure 2

The glyoxalase system is composed of two enzymes, glyoxalase I (GLO1) and glyoxalase II. Reactive dicarbonyls, like methylglyoxal, are effectively detoxified via this metabolic pathway. The glyoxalase enzyme pathway catalyzes the conversion of reactive α-oxoaldehydes into the corresponding α-hydroxyacids. In this schematic, methylglyoxal reacts with glutathione and is converted to S-d-Lactoylglutathione by GLO1. This intermediate is then broken down into d-lactate by glyoxalase II and reduced glutathione is recycled.

Figure 3

The DRG from C57BL/6 mice were stained with an antibody against Glo1. Glo1 is highly abundant in small, unmyelinated peptidergic neurons. This subpopulation of neurons is particularly important in transmitting noxious pain information. Genetic differences in the expression of GLO1 in human diabetic patients may protect this neuronal population from the damaging effects of AGEs. Scale bar = 50 μm.