Protection from diabetes-induced peripheral sensory neuropathy--a role for elevated glyoxalase I?
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.
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
M M
MM
Jack
J M
JM
Ryals
D E
DE
Wright
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D003929:Diabetic Neuropathies / Q000139:chemically induced / Q000150:complications / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology*; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D028361:Mitochondrial Diseases / Q000209:etiology; D009097:Multienzyme Complexes / Q000378:metabolism; D009412:Nerve Fibers / Q000473:pathology; D009431:Neural Conduction / Q000502:physiology; D010147:Pain Measurement; D011597:Psychomotor Performance; D013311:Streptozocin / Q000009:adverse effects
D001786:Blood Glucose; D009097:Multienzyme Complexes; D013311:Streptozocin; D007791:Lactoylglutathione Lyase