Moderate Alcohol Consumption,
Insulin Resistance and Cardiovascular Disease

Address by Gerald Reaven, M.D., to The Society of Medical Friends of Wine at their Quarterly Dinner Meeting at the Atrium Restaurant, San Francisco, August 9,  2000

Introduction

Epidemiological studies (1-6) have repeatedly demonstrated that mild to moderate alcohol consumption is associated with a decrease in cardiovascular disease (CVD). Despite these  observations, the relationship between alcohol and CVD has received relatively little attention, presumably because of the obvious disastrous consequences of excessive alcohol consumption. However, the untoward effects of too much alcohol should not prevent consideration of the beneficial effects described in individuals consuming amounts of alcohol below the levels of intake leading to liver disease, pancreatitis, etc.

The  goal of this presentation will be to review the metabolic changes identified in light to moderate drinkers that might account for their decreased risk of CVD. In particular, attention will be focused on the possibility that insulin sensitivity is enhanced in individuals consuming light to moderate amounts of alcohol, and this effect contributes to the decrease in CVD risk.

Alcohol Consumption, Dyslipidemia, And CVD

A low high density lipoprotein (HDL) cholesterol concentration is a well-recognized CVD risk factor (7,8), and there is evidence that the beneficial effect of moderate alcohol consumption on CVD is  mediated via its ability to raise HDL cholesterol concentrations (5,6,9-16). Although differences of opinion exist as to whether alcohol consumption is associated with increases in HDL2(14), or HDL3(11,13), or both (15,16), there is general agreement that there is a direct relationship between HDL cholesterol concentration and alcohol intake. In general, high HDL cholesterol concentrations tend to be accompanied by lower plasma  triglyceride (TG) concentrations. However, this inverse relationship doesn't seem to be the case as regards the changes in HDL cholesterol concentration associated with alcohol consumption. Indeed, it is generally assumed that the greater the intake of alcohol, the higher the plasma TG concentration. However, the generalization may not apply to individuals consuming <30g of alcohol per day, in which case plasma TG  concentrations may be similar, or lower, than in abstainers (15-17).

Alcohol and HDL Cholesterol Metabolism

Given evidence of a direct relationship between alcohol intake and HDL cholesterol concentration, it is surprising how little information is available concerning the effect of alcohol intake on HDL metabolism. For example, there is evidence from kinetic studies that the fractional catabolic rate (FCR) of apoA-I/HDL is accentuated in individuals with endogenous hypertriglyceridemia (18-20), type 2 diabetes (21) or essential hypertension (22). Furthermore, it appears that the more rapid the FCR of apoA-1/HDL, the lower  the HDL cholesterol concentration (21-23). Thus, it could be speculated that the increase in HDL cholesterol concentrations associated with mild to moderate alcohol consumption is due to a decrease in the FCR of  apoA-1/HDL. Unfortunately, there does not appear to be published data to support, or rule out, this possibility.

If it is assumed that higher HDL cholesterol concentrations in users of alcohol are due to decreases in the FCR of apoA-1/HDL, it is necessary to ask why this is the case. In this context it should be noted that syndromes associated with increases in the FCR of apoA-1/HDL, i.e., hypertension, hypertriglyceridemia, and  type 2 diabetes (18-22), are associated with insulin resistance and compensatory hyperinsulinemia (24). And there is evidence of a direct relationship between plasma insulin concentrations and the FCR of apoA-1/HDL (21-23). Thus, it is possible that insulin sensitivity is enhanced in association with alcohol intake, and this change leads to a decrease in the FCR of apoA-1/HDL, and higher HDL cholesterol concentrations.

Alcohol and Insulin Sensitivity

To evaluate the possibility that mild to moderate alcohol intake is associated with enhanced insulin sensitivity, we compared plasma lipid and lipoprotein concentrations, plasma glucose and insulin responses to an oral glucose challenge, and insulin-mediated glucose disposal rates in 40 healthy volunteers - 20 individuals light to moderate consumers of alcohol and 20 non-drinkers. Habitual intake of alcohol was estimated by questionnaire, based on an average estimated alcohol content of 10,4,40, and 20% (weight), respectively, for wine, beer, spirits, and mixed. Light to  moderate drinking was defined as consumption of 10-30g of alcohol per day, an amount roughly equivalent to 1-3 drinks/day.

The 20 nondrinkers were healthy volunteers who stated that they never consumed alcohol  (n=14), or only used it on rare occasions (n=6). They were otherwise identical to the 20 drinkers in terms of gender distribution, age, body mass index, ratio of waist to hip girth, family history of hypertension or type 2 diabetes, and estimates of habitual physical activity. Finally, only 2 of the 40 participants smoked.

The total integrated glucose response to a 75g oral glucose challenge was significantly lower in light to moderate drinkers (17.8±0.8 vs 19.8±0.9mM/h, p<0.02). The difference in the total integrated plasma insulin response between the two groups was greater, and was significantly lower (p<0.01) in light  to moderate drinkers (600±65pM/h) than in nondrinkers (1,075±160 pM/h).

Insulin-mediated glucose uptake was estimated by a modification (25) of the insulin suppression test originally described by our research group (26). This approach is based on the continuous intravenous infusion for 180 min of somatostatin (5µg/min), insulin (25mU·/m2/min) and glucose (240 mg/m2/min). Venous blood samples were taken  every 10 minutes during the last 30 minutes for measurement of plasma glucose and insulin concentrations, and the mean value for these four measurements were used to calculate the steady-state plasma insulin (SSPI) and steady-state plasma glucose (SSPG) concentrations.

Despite the similarity of the SSPI concentrations in the two groups (~ 300 pmol/L), the SSPG concentrations were significantly higher in non-drinkers as compared  to light to moderate drinkers (10.7±1.2 vs 6.7±0.8mmol/L, p<0.01). Thus, individuals who abstain from the alcohol were less able to dispose of the infused glucose load, i.e., they were relatively insulin  resistant as compared to light to moderate consumers of alcohol.

In addition to being more insulin sensitive, light to moderate drinkers had significantly higher (p<0.02) HDL cholesterol concentrations (1.46±0.08 vs 1.25±0.08mmol/L) than non-drinkers. However, there was no increase in either LDL cholesterol ( 2.56±0.18 vs 2.49±0.15mmol/L) or triglyceride (1.18± 0.12±1.21±0.11mmol/L) concentrations in those consuming alcoholic beverages.

These results show that light to moderate drinkers are relatively more insulin sensitive, and have lower plasma insulin levels, than do nondrinkers. Because  the two experimental groups were well-matched in age, sex distribution, and degree of obesity and habitual physical activity, i.e., variables known to affect insulin action and insulin concentration, it seems reasonable to conclude that the difference in alcohol intake was responsible for the observed changes in insulin metabolism. These results are also quite consistent with published information that plasma insulin concentrations are lower in population-based studies of both men and women (15-17,27). Thus, there is substantial evidence that light to moderate consumers of alcohol are more insulin sensitive than are individuals who do not use alcoholic beverages.

The conclusion that light to moderate drinkers are more insulin sensitive than abstainers is not in conflict with previous publications showing that the acute administration of large amounts  of alcohol decreased insulin-mediated glucose disposal (28-30). These studies were performed in a relatively small number of individuals (7, 10, and 6 in references 28-30, respectively), and large amounts of alcohol  were administered intravenously over quite short time periods, i.e., total doses ranging from 22g in 7h to ~60g in 30 minutes. Obviously, the amounts are greatly in excess of the daily 10-30g of alcohol consumed by the light to moderate drinkers in this study.

Evidence that enhanced insulin sensitivity was present in light to moderate drinkers does not mean that alcohol consumption should be encouraged to improve insulin-mediated glucose disposal; the dangers of excessive alcohol intake are well-appreciated and need not be repeated. Furthermore, the changes in insulin-mediated glucose disposal and plasma insulin concentration  noted in light to moderate drinkers are not necessarily caused by alcohol consumption, per se. Although we tried to take into account all relevant variables known to affect insulin action and glucose tolerance, some other variable, present in drinkers and not nondrinkers, was possibly responsible for the changes noted. However, even if this were the case, it would not alter the fact that nondrinkers were relatively insulin  resistant, glucose intolerant, and hyperinsulinemic compared to light to moderate drinkers.

Conclusion

There is substantial evidence that light to moderate alcohol consumption is associated with: 1)  decreased risk of CVD; 2) higher HDL cholesterol concentrations; 3) enhanced insulin sensitivity and lower plasma insulin concentrations. It is possible with this information to construct a coherent formulation that links the four variables together in the following manner. As a group, light to moderate drinkers are more insulin sensitive and have lower insulin concentrations than nondrinkers. The more insulin sensitive an individual, the lower their insulin concentration, the higher their HDL cholesterol (31,32). In the case of light to moderate drinkers, this is presumably related to a decrease in the FCR of apoA-1/HDL. However whatever the mechanism responsible for the relationship between insulin and HDL cholesterol metabolism, the higher HDL cholesterol concentrations in light to moderate drinkers should decrease their risk of CVD.

Finally, although the hypothesis outlined above links mild to moderate alcohol consumption to decreased risk of CVD by modulation of HDL cholesterol concentration, it should be remembered that the lower glucose and insulin  concentrations seen in light to moderate drinkers have also been identified as decreasing risk of CVD in nondiabetic individuals (33-37). Thus, there are multiple reasons why CVD risk is lower in individuals consuming mild to moderate amounts of alcohol. It seems reasonable to suggest that we need to learn much more about this relationship, and how this information could be used to reduce CVD risk.

References

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