As GLO is the major detoxification system of

As GLO1 is the major detoxification system of reactive dicarbonyls, it is plausible that differences in production and activity of the enzyme influences AGE production and the development and/or modulation of diabetic neuropathy. Glo1 exists as a copy number variant (CNV) in many inbred strains mice where alterations in the genome that include either the gain or the loss of sections of DNA result in expression differences.106, 107 The region encompassing GLO1 has also been reported to be a CNV in humans. Studies have also recognized various single-nucleotide polymorphisms (SNPs) and null Sodium Danshensu of GLO1 in humans.109, 110, 111 A study of patients with autism recognized the GLO1 rs2736654 SNP results in Ala111Glu in the mature GLO1 protein and reduced activity of the enzyme. Another SNP that is located in the promoter region of GLO1 reduced promoter activity and was associated with the presence of nephropathy and retinopathy in type 2 diabetic patients. These studies suggest genetic differences of GLO1 could contribute to either the susceptibility to or protection from the development of diabetic neuropathy. Although the role GLO1 in diabetic neuropathy has received limited attention, many studies related to other secondary complications have developed a clear understanding of the protective role of GLO1 in these tissues. In vitro overexpression of GLO1 in endothelial cells under hyperglycemic conditions reduced reactive dicarbonyls and corrected defects in angiogenesis and relaxation. Overexpression in the lens and retinal capillary pericytes protected against hyperglycemia-induced protein modification and apoptosis, respectively. Similarly, markers of oxidative damage were reduced in kidneys from diabetic transgenic rats overexpressing GLO1. Our studies have used two inbred strains of mice that are substrains of BALB/c mice. As these mice were separated from the same parental strain, these 2 substrains likely have very similar genetic backgrounds. Indeed, the substrains are isogenic at all typed SNPs106, 119; however, BALB/cByJ mice have a nearly 10-fold higher abundance of GLO1 in the DRG as a result of a known CNV. Diabetic BALB/cJ mice with reduced GLO1 levels showed increased mechanical thresholds indicative of the development of insensate neuropathy, loss of epidermal fibers, and reduced amounts of components of mitochondrial oxidative phosphorylation proteins including Complex I and V. However, diabetic BALB/cByJ that have higher levels of GLO1 as a result of increased copy numbers were protected from these indices of diabetic neuropathy. Although a large proportion of patients develop altered peripheral sensation, others, nearly 30% to 40% of patients with diabetes, do not develop overt neuropathy signs and symptoms even after years of diabetes mellitus. A recent study highlights and complements our studies suggesting certain patients with diabetes mellitus may be protected from secondary complications as a result of differences in their individual genetic susceptibility. A study of Joslin Gold Medalists, patients who have survived type 1 diabetes mellitus for more than 50 years, determined that current glycemic control was unrelated to the development of diabetic complications. However, those patients with higher concentrations of AGEs, including methylglyoxal-derived N-(carboxyethyl)lysine, were 2.5 times more likely to suffer from neuropathy. Those authors and others have suggested that certain patients may have an abundance of protective mechanisms that allow them to remain complication free.
Therapeutic Strategies to Reduce Ages Therapeutic modalities can intervene at multiple levels to reduce either formation or the toxic effects of AGEs. Treatments that break down and/or prevent AGE cross-linking or interfere with the AGE–RAGE pathway may have benefit as clinical interventions. The initial approach, however, is to reduce the formation of AGEs. Aminoguanidine, the best characterized compound, is a nonspecific inhibitor of AGEs. Although early clinical trials showed promising therapeutic potential, the ACTION II trial was terminated early as a result of lack of efficacy and safety concerns. Despite these findings, other compounds and drugs have shown promise, both experimentally and clinically, in protecting against and/or reducing diabetic complications. Pyridoxamine showed benefit in clinical studies of diabetic nephropathy including reductions in urinary N(epsilon)-(carboxymethyl)lysine and N(epsilon)-(carboxyethyl)lysine. Metformin, a common treatment for type 2 diabetes, was able to reduce levels of serum reactive dicarbonyls and AGEs in type 2 diabetic patients.125, 126 Other compounds including aspirin, pioglitazone, benfotiamine, angiotensin converting enzyme inihbitors, angiostensin II-receptor blockers, and thiamine have also been shown to have anti-AGE effects. Soluble RAGE (sRAGE) has shown promising results as a decoy receptor for AGEs by preventing the development of sensory deficits in diabetic mice with chronic administration of sRAGE. A recent study using Akita mice, a spontaneous type 1 diabetic model, found fisetin, a naturally occurring flavone, increased Glo1 expression and activity and increased the synthesis of glutathione. Treatment reduced methylglyoxal modification of proteins and protected against kidney damage in these mice. Investigation into other compounds like fisetin that increase GLO1 levels or activity could have profound clinical impact on reducing the incidence of diabetic complications, including diabetic neuropathy.