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 N-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.