Alcohol and Alcoholism Advance Access originally published online on August 21, 2006
Alcohol and Alcoholism 2006 41(6):672-677; doi:10.1093/alcalc/agl067
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INFLUENCE OF DRINKING ALCOHOL ON ATHEROSCLEROTIC RISK IN ALCOHOL FLUSHERS AND NON-FLUSHERS OF ORIENTAL PATIENTS WITH TYPE 2 DIABETES MELLITUS
1 Department of Hygiene and Preventive Medicine, Yamagata University School of Medicine, Yamagata and 2 Department of Internal Medicine, Nishinomiya Kaisei Hospital, Hyogo, Japan
* Author to whom correspondence should be addressed at: Department of Hygiene and Preventive Medicine, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan. Tel: +81 23 628 5252; Fax: +81 23 628 5255; E-mail: wakabaya{at}med.id.yamagata-u.ac.jp
(Received 7 May 2006; in revised form 27 June 2006; accepted 5 July 2006)
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ABSTRACT |
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Aims: Facial flushing caused by alcohol drinking is a typical symptom of high sensitivity to alcohol in orientals. We investigated whether drinking alcohol influences atherosclerotic risk factors in alcohol flushers and non-flushers in patients with diabetes mellitus. Methods: A cross-sectional study was performed using 225 subjects with type 2 diabetes. Sensitivity to alcohol was surveyed by a questionnaire on facial flushing. Subjects were divided into three groups by average amount of alcohol drinking (non-drinkers; light drinkers: <140 g/week; heavy drinkers: 140 g/week or more). Results: Systolic blood pressure and blood HDL cholesterol were significantly higher in heavy drinkers than in non-drinkers. There were no significant differences in body mass index, blood pressure, blood total cholesterol, HDL cholesterol, uric acid, fibrinogen and sialic acid levels in flushers and non-flushers. In alcohol flushers, diastolic blood pressure and HDL cholesterol in heavy drinkers were significantly higher than those in non-drinkers, and systolic blood pressure was significantly higher in heavy drinkers than in non-drinkers and light drinkers. On the other hand, blood pressure and HDL cholesterol in non-flushers were not significantly different among non-, light and heavy drinkers. Serum total cholesterol was not significantly different among the three drinking groups both in flushers and non-flushers. Conclusions: Blood pressure and HDL cholesterol are more prone to be affected by drinking in flushers than in non-flushers, suggesting that alcohol sensitivity evaluated by flushing response due to drinking alcohol should be taken into account when the effects of alcohol drinking on atherosclerotic risk factors are considered in oriental patients with type 2 diabetes mellitus.
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INTRODUCTION |
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It is well known that there is a negative correlation between alcohol intake and incidence of ischaemic heart disease (Wannamethee and Shaper, 1998
). The major mechanism underlying this proposed protective effect of alcohol on ischaemic heart disease is the action of ethanol on lipid metabolism: blood HDL cholesterol and LDL cholesterol levels are increased and decreased, respectively, by alcohol drinking (Castelli et al., 1977; Langer et al., 1992). In addition, alcohol drinking is also known to decrease blood fibrinogen level (Krobot et al., 1992) and to inhibit platelet function (Meade et al., 1985), resulting in retardation of atherosclerotic progression, and to suppress thrombus formation. On the other hand, alcohol drinking induces hypertension (Klatsky, 1996), and the incidence of cerebrovascular diseases, particularly cerebral haemorrhage and subarachinoid haemorrhage, is known to be higher in moderate-to-heavy drinkers than in non-drinkers (Hillbom, 1998). Thus, alcohol drinking has both preventive and accelerating effects on atherosclerotic vascular diseases.
The sensitivity to alcohol is higher in Orientals than in Caucasians, mainly due to genetic difference in alcohol-metabolizing enzymes (Mizoi et al., 1979; Harada et al., 1981). Facial flushing due to drinking alcohol is a typical symptom of high sensitivity to alcohol. It has been reported that 
83% of Orientals were alcohol flushers (Wolff, 1972). However, there have been only a few studies on the relationships between alcohol drinking and atherosclerotic risk factors, such as blood pressure, in flushers and non-flushers. Prevalence of hypertension has been reported to be higher in flushers than that in non-flushers (Itoh et al., 1997). Our recent study using healthy people has shown that blood pressure of people with high sensitivity to alcohol was higher in drinkers than in non-drinkers but was not different in drinkers and non-drinkers who showed low sensitivity to alcohol (Wakabayashi, 2005). However, it is still to be elucidated whether sensitivity to alcohol affects the relationship between alcohol drinking and atherosclerotic risk factors in patients with diabetes. Thus, the aim of the present study was to determine whether the relationships between drinking alcohol and atherosclerotic risk factors in diabetes are affected by sensitivity to alcohol, evaluated using a questionnaire on facial flushing due to drinking alcohol.
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METHODS |
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Subjects
The subjects of this study were 225 consecutive diabetic outpatients (134 men and 91 women) who had been diagnosed as having type 2 diabetes based on the criteria of the American Diabetes Association (Anonymous, 1997
). No selection criteria were used for enrolment of subjects. The purpose of the present study was explained to the subjects, and informed consent for participation in the study was obtained from all subjects. This study was approved by the Ethics Committee of Yamagata University School of Medicine and was carried out in accordance with the declaration of Helsinki.
Measurements
Blood was sampled from each subject in the morning after a fast of at least 10 h. Serum total cholesterol and triglyceride were measured by the standard enzymatic methods. Serum HDL cholesterol was assayed enzymatically in combination with an inhibition assay. Serum uric acid was measured by the uricase method. Haemoglobin A1c (HbA1c) was assayed using high-performance liquid chromatography with a cation exchange column. The normal reference limits of HbA1c measured by this method are 4.3–5.8%. Serum sialic acid concentration was assayed by an enzymatic method using neuraminidase. Plasma fibrinogen concentration was assayed by an enzymatic method using thrombin. The normal reference limits of sialic acid and fibrinogen are as follows: sialic acid, 44–71 mg/dl; fibrinogen, 170–410 mg/dl.
Arterial pressure of the right brachial artery was recorded using a mercury sphygmomanometer after each subject had rested quietly in a sitting position. Korotkoff's fifth phase was used to define diastolic pressure. The body mass index (BMI) was calculated as weight in kilograms divided by the square of height in metres.
Average alcohol consumption per week of each subject was reported on questionnaires in which subjects were instructed to indicate their customary drinking frequency (days/week) and the average amount (ml) of alcoholic beverages ingested on a typical occasion or during a typical day. Alcoholic beverages included beer, sake (rice wine), wine and whisky. Usual weekly alcohol consumption (g/week) was then calculated. For analyses of effects of drinking on atherosclerotic risks, the subjects were divided into three groups according to mean ethanol consumption per week (non-drinkers; light drinkers, <140 g per week; heavy drinkers, 140 g or more per week). The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (the JNC 7) recommends drinking <1 ounce of ethanol/day for most men and 0.5 ounce of ethanol/day for women and lighter-weight persons to prevent hypertension (Chobanian et al., 2003). We used 20 g/day (140 g/week) of ethanol for separation of light and heavy drinkers. Smoking history was also reported on questionnaires. A survey on sensitivity to alcohol drinking was performed using a self-administered questionnaire on a symptom (facial flushing) that appears when drinking alcohol. The symptom was classified by its frequency as follows: always occurs, sometimes occurs or never occurs. The subjects were classified as subjects with low sensitivity and those with high sensitivity to alcohol when facial flushing always occurs and never occurs, respectively. Facial flushing sometimes occurred in 14.7% of the subjects, and data for these subjects were not included in further analysis about the effects of alcohol sensitivity on the relationships between alcohol drinking and atherosclerotic risk factors.
Statistical analyses
The data are expressed as means with standard errors. Statistical analyses were performed using computer software (SPSS version 14.0 J for Windows). The mean levels of each item were compared between the groups using ANOVA and then Student's t-test after Bonferroni correction. The frequencies of each item between the groups were compared using 
2-test for independence. Probability (P) values <0.05 were defined as significant.
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RESULTS |
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Effects of alcohol drinking on atherosclerotic risk
Table 1 shows profiles of subjects divided by amount of alcohol drinking into three groups. In non-drinkers and light drinkers, the mean ages were significantly higher and the percentages of males were significantly lower than those in heavy drinkers. The percentage of males in non-drinkers was significantly lower than that in light drinkers. Thus, comparison of atherosclerotic risk among the drinking groups was performed after adjustment for age and sex. The percentage of flushers in heavy drinkers was significantly lower than those in non-drinkers and light drinkers. The percentage of subjects receiving therapy for dyslipidaemia in heavy drinkers was significantly lower than that in non-drinkers. The percentage of smokers in heavy drinkers was significantly higher than those in non-drinkers and light drinkers, and the percentage of smokers in light drinkers was significantly higher than that in non-drinkers.
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Mean systolic blood pressure and serum HDL cholesterol were significantly higher in heavy drinkers than in non-drinkers. The mean levels of blood total cholesterol and fibrinogen were slightly but not significantly lower in light and heavy drinkers than in non-drinkers. The mean level of serum uric acid was slightly but not significantly higher in heavy drinkers than in non-drinkers and light drinkers. The above tendencies of the relationships of alcohol drinking with blood pressure, HDL cholesterol, total cholesterol, fibrinogen and uric acid in the present subjects with type 2 diabetes are similar to the results of the effects of alcohol drinking on atherosclerotic risk factors reported in the Japanese general population. There were no significant differences in the mean levels of BMI, diastolic blood pressure, HbA1c and sialic acid among the three groups.
Comparison of atherosclerotic risk in alcohol flushers and non-flushers
Comparison of the profiles of alcohol flushers and non-flushers is shown in Table 2. The mean amount of alcohol drinking in non-flushers was significantly greater than that in flushers. Atherosclerotic risk factors, including smoking, BMI, blood pressure, HbA1c, total cholesterol, HDL cholesterol, uric acid, fibrinogen and sialic acid, were not significantly different in non-flushers and flushers.
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Comparison of alcohol-drinking effects on atherosclerotic risk in alcohol flushers and non-flushers
The mean blood pressure and lipid levels after adjustment for age, sex and therapy for hypertension or dyslipidaemia were compared among the three different drinking groups in flushers and non-flushers separately. In flushers, the mean systolic blood pressure of heavy drinkers was significantly higher than those in non-drinkers and light drinkers, and the mean diastolic blood pressure of heavy drinkers was significantly higher than that in non-drinkers, while the mean systolic and diastolic blood pressure of non-flushers was not significantly different among non-, light and heavy drinkers (Fig. 1A,B). The mean serum total cholesterol levels in both the flusher group and non-flusher group were not significantly different among non-, light and heavy drinkers (Fig. 2A). In flushers, the mean serum HDL cholesterol level of heavy drinkers was significantly higher than that in non-drinkers, while the mean serum HDL cholesterol level in non-flushers was not significantly different among non-, light and heavy drinkers (Fig. 2B). The above results for blood pressure and HDL cholesterol were not influenced by inclusion of smoking in factors for adjustment (data not shown). In flushers, dose-dependent effects of alcohol drinking on diastolic blood pressure and HDL cholesterol were shown (Figs 1B and 2B), while a linear relationship was not shown between systolic blood pressure and alcohol drinking (Fig. 1A). There were tendencies that systolic and diastolic blood pressure and HDL cholesterol after adjustment for age, sex and therapy for hypertension or dyslipidaemia in heavy drinkers were higher in flushers than those in non-flushers, but their differences were not significant [systolic blood pressure (mm Hg): 131.7 ± 2.2 (non-flushers) vs 136.6 ± 2.4 (flushers); diastolic blood pressure (mm Hg): 75.6 ± 1.3 (non-flushers) vs 79.6 ± 1.5 (flushers); HDL cholesterol (mg/dl): 51.9 ± 3.2 (non-flushers) vs 57.4 ± 3.5 (flushers)].
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The mean levels of HbA1c, uric acid, fibrinogen and sialic acid after adjustment for age and sex in both the flusher and non-flusher groups were not significantly different among non-, light and heavy drinkers [HbA1c (%): 7.68 ± 0.23 (non-drinkers) vs 7.42 ± 0.35 (light drinkers) vs 7.76 ± 0.35 (heavy drinkers) in flushers and 7.78 ± 0.33 (non-drinkers) vs 7.25 ± 0.42 (light drinkers) vs 7.32 ± 0.27 (heavy drinkers) in non-flushers; uric acid (mg/dl): 4.98 ± 0.17 (non-drinkers) vs 4.80 ± 0.26 (light drinkers) vs 5.16 ± 0.28 (heavy drinkers) in flushers and 4.55 ± 0.33 (non-drinkers) vs 5.20 ± 0.45 (light drinkers) vs 5.30 ± 0.27 (heavy drinkers) in non-flushers; fibrinogen (mg/dl): 298.8 ± 9.9 (non-drinkers) vs 306.0 ± 15.0 (light drinkers) vs 306.0 ± 15.4 (heavy drinkers) in flushers and 301.0 ± 17.7 (non-drinkers) vs 286.9 ± 22.7 (light drinkers) vs 296.7 ± 14.5 (heavy drinkers) in non-flushers; sialic acid (mg/dl): 58.1 ± 1.0 (non-drinkers) vs 57.5 ± 1.6 (light drinkers) vs 60.6 ± 1.7 (heavy drinkers) in flushers and 60.4 ± 2.2 (non-drinkers) vs 58.0 ± 3.1 (light drinkers) vs 60.7 ± 1.8 (heavy drinkers) in non-flushers]. There were tendencies both in flushers and non-flushers for the mean serum triglyceride levels to be lower in light drinkers than in non-drinkers and heavy drinkers and for the mean serum triglyceride levels to be higher in heavy drinkers than in non-drinkers, although there were no significant differences among the subgroups of alcohol drinking [flushers: 148.3 ± 30.9 mg/dl (non-drinkers) vs 103.7 ± 6.0 mg/dl (light drinkers) vs 170.7 ± 16.7 mg/dl (heavy drinkers); non-flushers: 146.3 ± 16.7 mg/dl (non-drinkers) vs 114.1 ± 12.2 mg/dl (light drinkers) vs 152.5 ± 17.6 mg/dl (heavy drinkers)]. In subjects who sometimes flush, there were tendencies that systolic and diastolic blood pressure and HDL cholesterol were higher in heavy drinkers than in non-drinkers (data not shown) similarly to the subjects who always flush, although the number (n = 33) of the subjects was too small to obtain a conclusion.
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DISCUSSION |
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In the present study, blood pressure and blood HDL cholesterol of heavy drinkers were significantly higher than those of non-drinkers in alcohol flushers but not in non-flushers of patients with type 2 diabetes mellitus after adjustment for age, sex and therapy for hypertension or dyslipidaemia. Thus, alcohol sensitivity evaluated by flushing response due to drinking alcohol is a crucial factor that influences alcohol action on atherosclerotic risk factors in diabetes in Orientals. The present finding on the relationship between drinking and blood pressure agrees with the finding of our previous study that sensitivity to alcohol drinking affects relationship between amount of alcohol drinking and blood pressure in healthy people (Wakabayashi, 2005
). Although prevalence of hypertension in general subjects has been reported to be higher in flushers than that in non-flushers (Itoh et al., 1997), the percentage of subjects receiving therapy for hypertension was only slightly higher in flushers than in non-flushers in the present study using patients with diabetes mellitus (Table 2). This difference may in part result from the high prevalence of hypertension due to diabetes mellitus per se (Salomaa et al., 1991; Anonymous, 1993). Similar to the results for blood pressure, HDL cholesterol level was increased by heavy drinking in flushers but not in non-flushers. The present study is the first study to show that serum HDL cholesterol level is influenced by drinking alcohol differently in flushers and non-flushers. Blood fibrinogen, one of the major risk factors for atherosclerosis, is known to be lowered by drinking alcohol (Chobanian et al., 2003). However, no significant difference in fibrinogen level was found among non-, light and heavy drinkers both in flushers and non-flushers in the present study. This may be due to the small number of subjects, and further studies using large populations are needed to clarify whether alcohol sensitivity affects the relationship between drinking and atherosclerotic risk factors other than blood pressure and HDL cholesterol.
A simple method of a self-reported questionnaire about alcohol flushing was used in the present study in order to evaluate alcohol sensitivity, and thus alcohol sensitivity is indirectly judged by the symptom. Thus, the self-reported measurement of alcohol sensitivity may have caused a bias in the present study, though we did not include border cases of ‘facial flushing sometimes occurred’ in flushers and non-flushers. There is also a possibility of a bias that abstainers, who had reduced or stopped drinking due to ageing and ill health, were included in the non-drinker group. This bias might cause an under-estimation of differences in non-drinkers and drinkers. In spite of this possible bias, there was a significant difference in blood pressure and HDL cholesterol concentration between non-drinkers and heavy drinkers of the flushing group. The bias might also cause an under-estimation in the finding that there was no significant difference in blood pressure or HDL cholesterol concentration between non-drinkers and drinkers of the non-flushing group. Unfortunately, we do not know whether the rate of abstainers was different in flushers and non-flushers. However, reduction of alcohol drinking even for a short period (3–6 weeks) reportedly showed an obvious lowering effect on blood pressure (Puddey et al., 1985; Ueshima et al., 1993). Moreover, the data from the Kaiser Permanente study suggested that the elevated blood pressure of heavy drinkers completely regressed within a week upon abstinence from alcohol (Klatsky et al., 1986). Thus, past drinking history is unlikely to alter the relationship between alcohol drinking and blood pressure in the present study.
Atherosclerotic macroangiopathy is a major complication of diabetes that determines its prognosis (Sakamoto et al., 1996). Moderate drinking is known to prevent atherosclerotic progression in patients with diabetes (Valmadrid et al., 1999; Ajani et al., 2000; Solomon et al., 2000), but it is not clear whether heavy drinking also has a preventive effect on atherosclerotic progression in patients with diabetes similar to non-diabetic people (Cooper et al., 2002). In diabetic patients with high sensitivity to alcohol, blood pressure and HDL cholesterol are elevated by heavy drinking. Thus, both harmful and beneficial effects of alcohol on the pathophysiology of atherosclerosis are increased by drinking alcohol in flushers with diabetes. This may explain why no significant effect of drinking on serum sialic acid level was found in flushers, since blood inflammatory markers, such as sialic acid, are known to reflect atherosclerotic progression (Lindberg et al., 1992).
Previous studies have shown that there was no significant relationships of blood pressure and HDL cholesterol with ALDH2 genotype (Okayama et al., 1994; Tsuritani et al., 1995; Nakamura et al., 2002), which strongly affects circulatory response, such as skin flushing and palpitation, induced by acetoaldehyde when drinking alcohol in Orientals (Mizoi et al., 1979; Harada et al., 1981). ADH is also known to be involved in sensitivity to alcohol (Takeshita et al., 1996). However, it is not clear whether genotypes of ADH, such as ADH1B and ADH1C, affect blood pressure, HDL cholesterol and incidence of atherosclerotic diseases (Hines et al., 2001; Hashimoto et al., 2002; Yamada et al., 2002; Saito et al., 2003; Whitfield et al., 2003; Marques-Vidal et al., 2006). Our previous and present studies have shown that sensitivity to alcohol, which was evaluated by self-reporting of facial flushing, affected the action of alcohol on blood pressure in healthy subjects and diabetic subjects. The reason for the discrepancy in the results of studies using genotypes and studies using alcohol-induced symptoms, such as flushing, is unknown. However, one possible explanation is that more than one gene is involved in the mechanism of alcohol flushing. In fact, two types of flushing responses after drinking have been proposed, and it has been shown that deficiency of ALDH2 caused fast-onset flushing induced by a small amount of alcohol (one drink of alcohol or less) but was not associated with slow-onset flushing induced by larger amount of alcohol (two drinks or more) (Higuchi et al., 1992). Thus, further studies are needed to elucidate the relations of genotypes of alcohol-metabolizing enzymes to flushing response and atherosclerotic risks. More detailed analysis on time-dependent flushing response based on questionnaires is also needed.
In conclusion, alcohol sensitivity evaluated by flushing response due to drinking alcohol influences the relationships of drinking with atherosclerotic risk factors in diabetes, and blood pressure and HDL cholesterol are more prone to be increased by drinking alcohol in flushers than in non-flushers. The findings of the present study suggest that sensitivity to alcohol should be taken into account when the effects of alcohol drinking on atherosclerotic risk factors are considered in Oriental patients with type 2 diabetes mellitus. Since there have been only a few studies on the relationships of alcohol sensitivity with atherosclerotic risk factors, future investigations, including prospective studies, are needed to confirm the present findings.
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ACKNOWLEDGEMENTS |
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This work was supported by a grant for scientific research from the Ministry of Education, Science and Culture of Japan (No. 17590533) and the Grant of the Yamagata University 21st Century COE program.
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