In Asians, the differences of alcohol tolerance are mainly determined by a polymorphism of aldehyde dehydrogenase 2 (ALDH2), which metabolizes acetaldehyde produced from ethanol into acetate (1). To examine whether the inactive ALDH2 influences the peripheral neuropathy in diabetes, 194 Japanese patients with type 2 diabetes (135 men and 58 women, aged 59.1 ± 11.7 years) were divided by ALDH2 phenotype and alcohol consumption and then the correlation of NCV (nerve conduction velocity in tibial motor nerve) with clinical parameters was compared. It was found that 99 and 95 patients had the active and inactive ALDH2 phenotype, respectively. In the first set of patients, 22 were nondrinkers (group 1) and 77 were drinkers (group 2). In the second set, 42 were nondrinkers (group 3) and 53 were drinkers (group 4). As determined by regression analysis, NCV was inversely correlated with diabetes duration and HbA1c in the nondrinkers (group 1: r = 0.433, P < 0.05 for HbA1c; group 3: r = 0.509, P < 0.01 for duration). In the drinkers, alcohol consumption was calculated as amounts of alcohol weight (in grams) per week. NCV was inversely correlated with the past maximum alcohol consumption per week in group 4 only (r = 0.502, P < 0.001), not in group 2. These results suggest that peripheral neuropathy in diabetes is related to alcohol consumption, especially in drinkers who are genetically alcohol intolerant.

Because the ALDH2 gene is transcribed in the nervous system, the ALDH2 deficiency may directly contribute to excess acetaldehyde accumulation after alcohol ingestion. Alternatively, nerve lipid peroxidation increases in experimental diabetic neuropathy (2). Among lipidperoxidative-derived toxic aldehydes, 4-hydroxynonenal (4-HNE) is one of the most reactive aldehydes under physiological conditions. 4-HNE inhibits Na/K ATPase and has multiple deleterious effects on nerve (3). Aldehydes, including 4-HNE and acetaldehyde, are cometabolized by ALDH isozymes (4). Therefore, in group 4, due to the increased needs of acetaldehyde oxidation after alcohol ingestion, the patients with inactive ALDH2 may have a high nerve tissue concentration of toxic aldehydes such as 4-HNE, thereby developing neuropathy and slowing NCV.

The authors thank Dr. R. Arakaki for reviewing the manuscript.

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J Clin Invest
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Free Radic Biol Med
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Alcohol Clin Exp Res

Address correspondence to Yoshihiko Suzuki, MD, Saiseikai Central Hospital, 1-4-17, Mita, Minato-ku, Tokyo 108, Japan. E-mail: