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

Abstract

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 Complex 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 1 and glyoxalase 2 activities in blood and neuronal tissue samples from experimental animal models of obesity and type 2 diabetes mellitus

“…In the present study, before the appearance of functional impairments in the neuronal tissue of 24-week-old Goto-Kakizaki rats, reduced Glo1 activity was found in the brain, spinal cord and sciatic nerve. Other recent studies have characterised GLO1 expression in the peripheral nervous system in different murine strains and have shown that reduced GLO1 expression in a streptozotocin-induced hyperglycaemia model may lead to symptoms of diabetic neuropathy [43,44]. However, in our study, GLO1 expression at the gene level was not significantly altered (data not shown), even though the activity was significantly reduced.…”

Streptozotocin Stimulates the Ion Channel TRPA1 Directly

“…Oxidative stress and an increased production of reactive carbonyl compounds such as methylglyoxal are prominent factors leading to the development of diabetic neuropathy and other diabetic complications (45)(46)(47). Methylglyoxal, oxidants, and electrophilic agents formed during oxidative stress all stimulate TRPA1 (14, 16 -18), and earlier studies have demonstrated that inhibition of TRPA1 reduces or prevents both the loss of intraepidermal nerve fibers and the behavioral manifestations of STZ-induced diabetic neuropathy in the rat (14,15).…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…Glyoxalase activity may also be a potential biomarker for susceptibility to DPN. BALB/cByJ mouse express a 10-fold greater level of glyoxalase 1 than BALB/cJ mice and were resistant to developing an insensate neuropathy and loss of intraepidermal nerve fibers compared with the diabetic BALB/cJ mice (Jack et al, 2012).…”

“…Although the underlying origin of the antigen was not identified, these data suggest that elevated Hsp70 antibody levels may serve as a positive biomarker for patients less prone to developing diabetic complications (Gruden et al, 2009). It may be worthwhile to determine whether a relationship exists between Hsp70 antibody levels and the level of glyoxalase 1 expression (Jack et al, 2012) as a predictive biomarker pair for the development of DPN in humans (Rabbani and Thornalley, 2011).…”