ALDH2/ADH2 Polymorphism Associated with Vasculopathy and Neuropathy in Type 2 Diabetes

Authors

  • Yoshihiko Suzuki,

    Corresponding author
    1. From Saiseikai Central Hospital (YS, YA, KM), Tokyo, Japan; Fujigaoka Hospital (YS, MT), Showa University, Kanagawa, Japan; Department of Neuropsychiatry (TM), Keio University, Tokyo, Japan; National Institute of Alcoholism (SH), Kurihama National Hospital, Kanagawa, Japan; and Department of Biochemistry and Cell Biology (YS, SO), Institute of Gerontology, Nippon Medical School, Kanagawa, Japan; Hoken Dohjin Medical Foundation Clinic (YS), Tokyo, Japan.
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  • Matsuo Taniyama,

    1. From Saiseikai Central Hospital (YS, YA, KM), Tokyo, Japan; Fujigaoka Hospital (YS, MT), Showa University, Kanagawa, Japan; Department of Neuropsychiatry (TM), Keio University, Tokyo, Japan; National Institute of Alcoholism (SH), Kurihama National Hospital, Kanagawa, Japan; and Department of Biochemistry and Cell Biology (YS, SO), Institute of Gerontology, Nippon Medical School, Kanagawa, Japan; Hoken Dohjin Medical Foundation Clinic (YS), Tokyo, Japan.
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  • Taro Muramatsu,

    1. From Saiseikai Central Hospital (YS, YA, KM), Tokyo, Japan; Fujigaoka Hospital (YS, MT), Showa University, Kanagawa, Japan; Department of Neuropsychiatry (TM), Keio University, Tokyo, Japan; National Institute of Alcoholism (SH), Kurihama National Hospital, Kanagawa, Japan; and Department of Biochemistry and Cell Biology (YS, SO), Institute of Gerontology, Nippon Medical School, Kanagawa, Japan; Hoken Dohjin Medical Foundation Clinic (YS), Tokyo, Japan.
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  • Susumu Higuchi,

    1. From Saiseikai Central Hospital (YS, YA, KM), Tokyo, Japan; Fujigaoka Hospital (YS, MT), Showa University, Kanagawa, Japan; Department of Neuropsychiatry (TM), Keio University, Tokyo, Japan; National Institute of Alcoholism (SH), Kurihama National Hospital, Kanagawa, Japan; and Department of Biochemistry and Cell Biology (YS, SO), Institute of Gerontology, Nippon Medical School, Kanagawa, Japan; Hoken Dohjin Medical Foundation Clinic (YS), Tokyo, Japan.
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  • Shigeo Ohta,

    1. From Saiseikai Central Hospital (YS, YA, KM), Tokyo, Japan; Fujigaoka Hospital (YS, MT), Showa University, Kanagawa, Japan; Department of Neuropsychiatry (TM), Keio University, Tokyo, Japan; National Institute of Alcoholism (SH), Kurihama National Hospital, Kanagawa, Japan; and Department of Biochemistry and Cell Biology (YS, SO), Institute of Gerontology, Nippon Medical School, Kanagawa, Japan; Hoken Dohjin Medical Foundation Clinic (YS), Tokyo, Japan.
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  • Yoshihito Atsumi,

    1. From Saiseikai Central Hospital (YS, YA, KM), Tokyo, Japan; Fujigaoka Hospital (YS, MT), Showa University, Kanagawa, Japan; Department of Neuropsychiatry (TM), Keio University, Tokyo, Japan; National Institute of Alcoholism (SH), Kurihama National Hospital, Kanagawa, Japan; and Department of Biochemistry and Cell Biology (YS, SO), Institute of Gerontology, Nippon Medical School, Kanagawa, Japan; Hoken Dohjin Medical Foundation Clinic (YS), Tokyo, Japan.
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  • Kempei Matsuoka

    1. From Saiseikai Central Hospital (YS, YA, KM), Tokyo, Japan; Fujigaoka Hospital (YS, MT), Showa University, Kanagawa, Japan; Department of Neuropsychiatry (TM), Keio University, Tokyo, Japan; National Institute of Alcoholism (SH), Kurihama National Hospital, Kanagawa, Japan; and Department of Biochemistry and Cell Biology (YS, SO), Institute of Gerontology, Nippon Medical School, Kanagawa, Japan; Hoken Dohjin Medical Foundation Clinic (YS), Tokyo, Japan.
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Reprint requests: Y. Suzuki, MD, Saiseikai Central Hospital, 1-4-17, Mita, Minato-ku, Tokyo, 108 Japan; Fax: +81-3-5351-3283; E-mail: drsuzuki@cts.ne.jp.

Abstract

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N1-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 “activity” and ADH2 “superactivity.” The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.

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