Uncoupling Protein 2 Promoter Polymorphism −866G/A Affects Peripheral Nerve Dysfunction in Japanese Type 2 Diabetic Patients

Abstract

OBJECTIVE -To determine genetic predispositions for diabetic polyneuropathy, we investigated the relationship between the Ϫ866G/A polymorphism of uncoupling protein (UCP) 2 and neurological manifestations in 197 type 2 diabetic patients.RESEARCH DESIGN AND METHODS -We first examined whether UCP2 mRNA had been expressed in the dorsal root ganglion (DRG) in four Long-Evans Tokushima Otsuka rats using RT-PCR and electrophoresis. Genotyping of UCP2 promoter polymorphism Ϫ866G/A was then performed in 197 unrelated Japanese type 2 diabetic patients, who were subjected to nerve conduction, quantitative vibratory perception, head-up tilt, and heart rate variability tests, by PCR restriction fragment-length polymorphism. The relationships between UCP2 genotype and various nerve functions were analyzed by uni-and multivariable analysis.RESULTS -Expression of UCP2 mRNA was confirmed in rat DRG. Multiple regression analysis clarified the hypothesis that the G/A ϩ A/A genotype was significantly related to decreased motor nerve conduction velocity and impaired blood pressure maintenance on the head-up tilt test. Multiple logistic regression analysis revealed that the G/A ϩ A/A genotypes are a significant risk factor for sensory nerve conduction slowing and orthostatic hypotension.CONCLUSIONS -UCP2 promoter gene polymorphism Ϫ866 G/A was significantly associated with nerve conduction slowing and vasomotor sympathetic functions. These findings suggest that the higher UCP2 activity related to the A allele has an energy-depleting effect on peripheral nerve function in type 2 diabetic patients. Diabetes Care 29:888 -894, 2006D iabetic peripheral polyneuropathy (DPN) is a multifactorial disorder arising from hyperglycemia and/or insulin deficiency. Advanced DPN causes serious complications, such as diabetic foot ulcers, gangrene, and Charcot joint, all of which reduce the quality of life of diabetic patients with DPN (1). Severe cardiovascular autonomic neuropathy also increases the risk of mortality (2). Therefore, elucidation of genetic predispositions for DPN is important for preventing DPN and inhibiting its progression. There are, however, few reports on the genetic predispositions for DPN (3-5).Oxidative damage due to hyperglycemia is reported to be one of the major factors contributing to the development of DPN (6). The main source of reactive oxygen species (ROS) in diabetes is thought to be the mitochondria (7). Uncoupling proteins (UCPs) can provide a controlled leak of protons across the inner membrane of the mitochondria and thus uncouple oxidative phosphorylation from respiration, with a concomitant decrease in inner mitochondrial membrane potential (8) and free radical generation (9,10). The mitochondrial UCP families, particularly UCP2, which is expressed in various human tissues, are thought to contribute to control of body temperature and energy metabolism as well as to regulation of mitochondrial production of ROS. Therefore, the UCP2 gene is considered to be involved in DPN.In experimental studies, the protective...

Association of UCP2 and UCP3 gene polymorphisms with serum high-density lipoprotein cholesterol among Korean women

“…In East Asian populations, however, metabolic risk is moderate at a BMI of 25 and becomes severe at a BMI of 30 [44]. In this study, we determined that the frequency (0.48) of the risky A allele of À866G N A in the Korean population is similar to that of the Japanese population (0.46-0.47) [43,45], both of which are significantly higher than the frequencies (0.36-0.38) determined in white population studies [14,36,46]. The higher frequency of the risky allele in the East Asian population may contribute, at least in part, to the higher susceptibility to metabolic disorders compared with white populations.…”

Truncal Pruritus of Unknown Origin May Be a Symptom of Diabetic Polyneuropathy

“…All examinations were conducted in a temperature-controlled room at 25°C. Methods for each examination are described only briefly in the following because they were described in our previous report (3). …”

Mechanisms of distal axonal degeneration in peripheral neuropathies

“…The uncoupling protein (UCP) family includes three proteins, UCP-1, UCP-2, and UCP-3, which are all hydrogen ion channels or transporters. UCP-1 was identified to be involved in thermogenesis from brown fat [181], while UCP-2 and UCP-3 were found [85]to be important for homeostasis [99] and thermogenesis [31] in a variety of tissues including white adipose tissue and brain for UCP-2[99] and DRG, brown adipose tissue, and skeletal muscle for UCP-3[257, 284]. UCP-2 and UCP-3were also quickly identified as inhibitors of ROS generation in the mitochondria [179, 253] since null mice displayed evidence of increased ROS production and damage (as reviewed in [30]).…”