Functional Polymorphisms of UCP2 and UCP3 Are Associated With a Reduced Prevalence of Diabetic Neuropathy in Patients With Type 1 Diabetes

Abstract

OBJECTIVE -We studied the association between polymorphisms in the UCP genes and diabetes complications in patients with type 1 diabetes.RESEARCH DESIGN AND METHODS -We analyzed 227 patients with type 1 diabetes using PCR and subsequent cleavage by restriction endonucleases for the promoter variants A-3826G in the UCP1 gene, G-866A in the UCP2 gene, and C-55T in the UCP3 gene.RESULTS -No effect of the A-3826G polymorphism in the UCP1 gene on diabetes complications was found. Patients who were heterozygous or homozygous for the G-866A polymorphism in the UCP2 gene or the C-55T polymorphism in the UCP3 gene had a significantly reduced prevalence of diabetic neuropathy (UCP2: odds ratio 0.44 [95% CI 0.24 -0.79], P ϭ 0.007; UCP3: 0.48 [0.25-0.92], P ϭ 0.031), whereas there was no association with other diabetes complications. This effect was stronger when G-866A and C-55T occurred in a cosegregatory manner (UCP2 and UCP3: 0.28 [0.12-0.65], P ϭ 0.002). Furthermore, a multiple logistic regression model showed an age-and diabetes duration-independent effect of the cosegregated polymorphisms on the prevalence of diabetic neuropathy (P ϭ 0.013).CONCLUSIONS -Our data indicate that both the G-866A polymorphism in the UCP2 gene and the C-55T polymorphism in the UCP3 gene are associated with a reduced risk of diabetic neuropathy in type 1 diabetes. Thus, the results presented here support the hypothesis that higher expression of uncoupling protein might prevent mitochondria-mediated neuronal injury and, ultimately, diabetic neuropathy. Diabetes Care 29:89 -94, 2006D iabetic neuropathy is the most common neuropathy in the western world. Hyperglycemia triggers a number of mechanisms thought to underlie diabetic neuropathy (1). Next to others, increased production of reactive oxygen species (ROS) (2,3) and formation of advanced glycation end products (AGEs) (4,5) are of pathophysiological importance. In patients with diabetes, mitochondrial ROS generation, especially at high blood glucose levels, is one of the main sources of oxidative stress (6,7). Increased levels of ROS are known to promote nonenzymatic glycation and AGE formation. AGEs and, in particular, carboxymethyllysine accumulate in peripheral nerves of patients with diabetes (4,8,9). Subsequent enhanced AGE-RAGE (receptor of AGEs) interaction leads to sustained nuclear factor-B activation (10,11) with consecutively increased interleukin-6 and tumor necrosis factor-␣ expression, resulting in neuronal dysfunction and, ultimately, diabetic neuropathy (11-13).To neutralize ROS and prevent harm, several antioxidant defense mechanisms exist. One of these is represented by the uncoupling proteins (UCPs). Cellular energy and mitochondrial membrane function in response to glucose are regulated in part by a group of UCPs. Members of this family of inner mitochondrial membrane proteins function as anion carriers. The originally identified uncoupling protein, now classified as UCP1, is expressed exclusively in brown adipocytes and can disperse the mitochondrial proton gradient, ...

Hyperglycemia, Hypoglycemia and Dementia: Role of Mitochondria and Uncoupling Proteins

“…In contrast, the addition of IGF-1, which positively regulates UCP3 expression [170,171], protected against glucose-induced neurite degeneration and UCP3 down-regulation leading to the normalization of ROS and m levels [171]. Interestingly, it was also shown that variants in UCP2 and UCP3 are associated with a reduced risk for diabetic neuropathy in T1DM patients, suggesting that an increased expression of UCPs related to specific gene polymorphisms can limit hyperglycemia-related neuronal death [172]. In a recent study of wholegenome expression changes, a significant downregulation of UCP2 gene expression was observed in the hippocampus of a T2DM animal model [173], implying that diabetic brains are more prone to neurodegenerative events.…”

Genetic Variance inUncoupling Protein 2in Relation to Obesity, Type 2 Diabetes, and Related Metabolic Traits: Focus on the Functional −866G>A Promoter Variant (rs659366)

“…It is important to note that genome-wide association studies (GWAS) have not identified SNPs in the UCP2-UCP3 locus as being associated with obesity or type 2 diabetes [109, 110]. However, if the mechanism of action of the −866G>A SNP, as some studies indicate, occurs predominantly in already obese and type 2 diabetic subjects to increase late-diabetic complications, such as cardiovascular disease via changes in oxidative stress levels [77, 103–105], then this polymorphism is unlikely to be identified through a GWAS strategy looking primarily at obesity or type 2 diabetes. Furthermore, early disease onset and a more frequent requirement for insulin may be related to a reduced capacity of insulin secretion.…”

“…In another study of 280 children and adolescents CRP was unaltered, but fibrinogen, complement C3 and C4 were lower in AA-carriers [106]. Finally, Rudofsky et al (2006, 2007) showed increased prevalence of the G-allele in type 1 diabetic patients, whereas there was no association with microvascular complications [105, 108]. …”

Mechanisms of distal axonal degeneration in peripheral neuropathies

“…UCPs are also critical for the attenuation of damage from ROS secondary to hyperglycemia. A variety of studies have shown all three UCP family members to protect cells from hyperglycemia induced ROS generation when the proteins are overexpressed [209, 257]. Interestingly, in the setting of hyperglycemia, UCP-3 expression is actually reduced [257].…”