1
2
Review
Department of Medicine, Nova Gradiška General Hospital
Strossmayerova 17, HR-35400 Nova Gradiška, Croatia
Vuk Vrhovac University Clinic
Dugi dol 4a, HR-10000 Zagreb, Croatia
CARDIOVASCULAR BENEFITS AND RISKS OF MODERATE
ALCOHOL CONSUMPTION IN DIABETES MELLITUS
Damir Japund‘iæ1, @eljko Metelko2, Franjka Po‘gaj1
Key words: alcohol, ethanol, diabetes mellitus, atherosclerosis,
coronary disease
SUMMARY
Many reports show a 20% decrease in the risk of coronary
disease in people taking small amounts of alcohol (5-14 drinks
per week), i.e. less than 30 g alcohol per day for men and 15 g
alcohol per day for women. On the other hand, diabetes mellitus
is associated with the highest rate and earlier development of
atherosclerotic changes as compared with the general
population, diabetes mellitus being one of the risk factors for
coronary disease. Alcohol has an antiatherogenic effect, the
possible mechanisms implying alcohol metabolism into
acetaldehyde that inhibits the formation of glycosylation
endproducts and lipoprotein oxidation, reduces platelet
aggregation, and influences vascular relaxation depending on
the endothelium mediated by the NO-cyclic guanosine 5monophosphate system. Thus, moderate alcohol consumption in
diabetics does not interfere with normotriglyceridemia if taken at
meals. The recommended alcohol intake is 1-2 drinks daily or 514 drinks weekly.
basal membranes of various tissues. DM is the most
common metabolic disorder with a prevalence in
Croatia of 2.37%. DM is associated with the highest
rate and earlier onset of atherosclerotic changes as
compared with the general population. This is one of
the reasons for the higher mortality in diabetic
population. Framingham study has proved the risk of
cardiovascular disorders to be increased by DM twofold
in men and threefold in women as compared with the
general population. Coronary disease develops in 55%
of diabetic population and is the most important cause
of morbidity and mortality (1). On the other hand,
moderate alcohol consumption can diminish the
mortality from coronary disease. Alcohol has an
antiatherogenic effect, however, excessive alcohol
intake is associated with a higher mortality from other
diseases.
Should alcohol intake be recommended in diabetic
individuals, and if so, when and in what amounts?
SOME CHARACTERISTICS OF ETHANOL
Ethyl alcohol (C2H5OH) has wide usage, such as a
INTRODUCTION
Diabetes mellitus (DM) is a disease characterized by
absolute or relative insulin deficiency that results in
hyperglycemia. Chronic complications develop with
time involving small and large blood vessels, nerves and
Diabetologia Croatica 32-4, 2003
disinfectant, in industry, in alcohol drinks and in
household. Various alcohol drinks contain different
concentrations of ethanol, e.g., beer 2%-6%, wine 10%20%, and strong drinks up to 50%. Medical and
cosmetic products contain ethanol in concentrations of
0.3% to 68%.
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D. Japund‘iæ, @. Metelko, F. Po‘gaj / CARDIOVASCULAR BENEFITS AND RISKS OF MODERATE ALCOHOL CONSUMPTION
IN DIABETES MELLITUS
Alcohol is a small molecule of 46 daltons, small
volume of distribution (0.6 l/kg), and boiling point at
78 °C. It is soluble in water and lipids.
in the accumulation of acetaldehyde in the liver and
circulation, manifested by the symptoms of flushing,
tachycardia and circulatory collapse.
Lethal dose for adults is 5-6 g/kg body mass, or 300400 ml of 100% ethanol, which is about 1L of 30%
strong drink taken within one hour. The highest
concentration in air is 100 ppm.
Alcohol conversion to acetaldehyde and then to
acetyl-CoA is accompanied by the release of hydrogen,
its acceptor being NAD (nicotine adenine
dinucleotide). Hydrogen changes fatty acids as fuel,
which results in the accumulation of fatty acid and
potential reduction in fatty acid oxidation. All these
steps lead to the accumulation of triglycerides in the
liver and an increased synthesis of lipoproteins. The
increased concentration of hydrogen acceptors
(NADH) has some consequences.
Alcohol cannot be eliminated from the body but has
to undergo oxidation in the liver. Healthy people can
metabolize more than 160-180 g ethanol per day.
Drinking 30 mL of whisky, 100 mL of wine or 250 mL
of beer results in body intake of 10 g alcohol.
Energy value of 1g ethanol is 7 kcal. Drinks contain
about 70-100 kcal from ethanol and other
carbohydrates. So, 8-10 alcohol drinks per day provide
more than 1000 kcal, however, the components such as
vitamins, minerals and proteins are then lacking (2,3).
METABOLISM OF ETHANOL
Twenty percent of the ethanol consumed per os is
absorbed in the stomach, and 80% in the small
intestine, the absorption being very fast, i.e. 80%-90%
in 30-60 minutes. Many factors can influence the
absorption, e.g., concentration (best absorption at a
concentration of 20%), volume and characteristics of
alcohol drinks, motility of the stomach and small
intestine (attenuated in the elderly), fasting drink
intake, coadministration of some medicaments, liver
function, individual variation, and time lapse of drink
consumption. Depending on these conditions, the
absorption can be prolnged by up to 2-6 h.
Three enzyme systems are involved in the hepatic
oxidation of ethanol to acetate: alcohol dehydrogenase
(ADH), microsomal system of oxidation (MEOS), and
catalase. ADH system is most important in the
condition of low blood and tissue concentration of
ethanol, and is responsible for 80%-85% of oxidation.
ADH turns ethanol into acetaldehyde in the cytosol.
Acetaldehyde is a highly reactive and toxic compound
that can cause membrane injury in the cytosol and
mitochondria, and thus lead to cell necrosis. Therefore,
acetaldehyde metabolizing to acetate is of utmost
importance. Acetaldehyde oxidation to acetate occurs
through acetyl-CoA, primarily by the action of aldehyde
dehydrogenase (ALDH) in hepatocyte mitochondria.
The function of ALDH may decline, which can result
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The redox potential of hepatocytes implies changes
with inhibition of protein synthesis and increased lipid
peroxidation. NADH provides hydrogen needed for
pyruvate conversion to lactate, which increases the
blood concentration of lactates and urates after alcohol
consumption. This mechanism can explain the
episodes of gout and hypoglycemia after alcohol
ingestion.
The MEOS system is responsible for the metabolism
of 10%-15% of alcohol. The critical component of
MEOS is the cytochrome P450 (CPY2E1) enzyme that
catalyzes not only ethanol oxidation but also many
drugs such as paracetamol and halothane. This explains
the higher toxicity of customary percentage of these
drugs in alcoholics. Chronic consumption of alcohol
increases the activity of CPY2E1 enzyme 5- to 10-fold,
resulting in accelerated elimination of ethanol in
chronic alcoholics. In case of fasting alcohol intake, a
high concentration of ethanol will reach liver with the
blood and alcohol metabolism will prevail in the first
passage through the liver. This in turn will result in an
increased concentration of ethanol in the blood. The
same amount of alcohol taken postprandially will slowly
pass through the liver, thus allowing for the metabolism
of ethanol to be completed by the first passage through
the liver and resulting in a lower concentration of
ethanol in the blood.
Glucose deficit entails higher concentration of
NADH, a product of ethanol oxidation. This in turn
results in reduced metabolism (pyruvate → lactate and
oxalacetate → malate). The increased lactate
production leads to lactic acidosis. A decreased
concentration of oxalacetate limits gluconeogenesis
and favors development of ketoacidosis.
D. Japund‘iæ, @. Metelko, F. Po‘gaj / CARDIOVASCULAR BENEFITS AND RISKS OF MODERATE ALCOHOL CONSUMPTION
IN DIABETES MELLITUS
CONSEQUENCES OF ALCOHOL
DRINKING
The consequences of alcohol drinking do not only
depend on the volume and frequency of alcohol intake
but also on the individual features such as sex, age,
nutritional status, genetic predisposition, and presence
of other diseases. The relations between alcohol drink
volume and its consequences are not simple, and there
is no clear border between safe and risk alcohol
consumption. The relative risk of liver cirrhosis grows
exponentially with daily volume of alcohol intake. The
relation between the risk of coronary disease and
alcohol intake has a configuration of U letter, i.e. there
is a proportionate daily intake of alcohol which
diminishes the onset of plaques in coronary arteries.
ETHANOL EFFECTS ON BODY SYSTEMS
Central nervous system
Alcohol acts as a depressor of the central nervous
system (CNS) and has effects similar to those of
anesthetics. Passing through lipid cell membranes of
the CNS alcohol compromises normal relationship
between lipid cell membranes and functional proteins
(receptors, enzymes). Among systems that can be
attacked by alcohol, implying neuron function
impairment, are the systems of neurotransmitters such
as norepinephrine, dopamine, serotonin and enkephalin. CNS can adapt to these effects and develop
tolerance. Except for its modifying effects on the
psychologic, intellectual and naturopathic features,
chronic alcohol abuse also has other effects such as
CNS lesions. The pathogenic effect of alcohol also
involves other body systems and organs.
Gastrointestinal system
Oral cavity: periodontitis and caries as well as
carcinoma of the tongue, ephipharynx and larynx are
more common in alcoholics than in nonalcoholics.
Esophagus: inflammation of esophageal mucosa, lower
sphincter defects; fivefold prevalence of carcinoma
recorded in nonalcoholics, esophageal varices due to
stasis in the portal vein system.
Diabetologia Croatica 32-4, 2003
Stomach and intestine: gastritis
intestinal mucosa are the
gastrointestinal
complications
characterized by vomitus matutinus
and vomiting).
and damage of
most common
of
alcoholism
(morning nausea
Liver cirrhosis: it is a common and severe
complication of chronic alcoholism, with an incidence
of 10%-15% (4). The prevalence of liver carcinoma is
also higher in alcoholics. Besides liver cirrhosis,
alcoholic pancreatitis is a typical complication of
alcoholism.
Cardiovascular complications
Ethanol in low doses induces peripheral
vasodilatation, however, daily intake of a greater
volume of alcohol is a cause of hypertension. Alcohol
induces congestive cardiomyopathy characterized by
hypocontractility of the myocardium, arrhythmias and
dilatation of all four cardiac cavities.
Pulmonary manifestations
Hypoxia is common in patients with cirrhosis. In case
of normal physical status and radiology finding, it is
caused by ventilation-perfusion disbalance and
intrapulmonary arteriovenous shunt. Tuberculosis is
more common in alcoholics.
Muscular disease
Acute intake of a high volume of alcohol may in
chronic alcoholic lead to acute muscular damage with
injuries ranging from a mild and transitory increase in
muscle enzymes to rhabdomyolysis with myoglobulinuria. Chronic alcoholism leads to progressive muscle
atrophy and weakness, especially of proximal leg
muscles, in association with peripheral neuropathy.
Endocrine diseases
Alcohol decreases erectile capacity and leads to
testicular atrophy. In women it causes amenorrhea,
atrophy of ovaries, loss of corpora lutea with infertility
and spontaneous abortions. Sustained alcohol abuse in
pregnancy may induce fetal alcohol syndrome.
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IN DIABETES MELLITUS
Alcoholics have low gonadal hormones in plasma with
hyperestrogenism, which progresses to cutaneous
vascular changes and gynecomastia. Direct effects of
alcohol on ACTH secretion can induce development of
pseudo-Cushing’s syndrome that is clinically identical
to Cushing’s syndrome. The diagnosis is based on
regression of the disease signs after a period of alcohol
abstinence.
Hypoglycemia is a frequent and potentially fatal
disorder induced by poor nutrition in chronic alcoholics
with deficient vitamins and loss of glycogen reserve.
ALCOHOL AND CORONARY DISEASE
Many reports show a decrease in the risk of coronary
disease by 20% in people who drink alcohol in small
volume (5-14 drinks per week), i.e. less than 30 g
alcohol per day for men and 15 g alcohol per day for
women (5). It points to a conclusion that the risk of
death is higher in abstinents than in people with
moderate alcohol intake. The effect of alcohol is
antiatherogenic, and the possible mechanisms are
alcohol metabolizing to acetaldehyde, which inhibits
the production of glycosylation endproducts and
oxidation of lipoproteins, diminishes platelet
aggregation, and influences relaxation of blood vessels
dependent on endothelium mediated by the NO-cyclic
guanosine 5-monophosphate system.
Red wine contains polyphenols that exert an
antioxidative effect and are supposed to diminish
oxidation of LDL granules and their atherogenic effect
(6,7). There are reports on a higher protective effect of
white wine (8) and beer (9) when taken in moderate
volume, however, all alcohol drinks have some
protective effect.
ALCOHOL AND DIABETES MELLITUS
Reports consistently suggest that the acute effects of
alcohol induce a state of insulin resistance following
oral and/or intravenous glucose load. Contrary to the
acute alcohol studies, there is a large body of
epidemiologic evidence from cross-sectional studies
which suggest that longterm exposure to alcohol is
associated with an improvement in insulin sensitivity.
There is a nonlinear relation between alcohol intake
and the risk of type 2 diabetes. Results from the ARIC
study point to a relationship between alcohol intake
154
and risk of type 2 DM in 12,261 middle-aged subjects
of both sexes. Men who drank more than 14 alcohol
drinks weekly had a 82% higher chance to develop type
2 DM than men who did not drink alcohol habitually
(10). Serum insulin and HDL cholesterol explained a
low proportion (20%) of the reduction in the risk of
type 2 diabetes associated with moderate drinking
(11). Light to moderate alcoholic beverage
consumption may be associated with a lower risk of
type 2 DM among women aged 25 to 42, although this
benefit may not persist at higher levels (12).
Furthermore, a substantial number of prospective
studies point to a protective role of light to moderate
chronic alcohol intake against the development of
diabetes as well as a protective effect of regular mild to
moderate drinking against coronary artery disease in
type 2 diabetic subjects (13).
Three prospective cohort studies investigated the
association between alcohol consumption and risk of
coronary heart disease among diabetics. The results
indicated significant risk reductions, ranging from 34%
to 79%, associated with light to moderate alcohol
intake. The potential mechanisms include increased
HDL cholesterol, decreased coagulation, and increased
insulin sensitivity. Alcohol intake is also associated with
certain risks among diabetics. Consumption of
excessive alcohol amounts within a short period of time
is associated with hypoglycemia, lactic acidosis and
ketoacidosis. Chronic alcohol intake is associated with
higher risks of carcinoma, hypertension, liver cirrhosis
and symptomatic neuropathy (5,14,15).
However, for moderate alcohol consumption, the
benefits would likely outweigh the risks (16).
Moderate alcohol consumption is associated with a
lower risk of coronary heart disease in men with type 2
diabetes (17-19). These results of the Physician
Health Study in 87,938 subjects including 2790
diabetics free from myocardial infarction, cancer or
liver disease suggest that light to moderate alcohol
consumption is associated with similar risk reductions
in coronary heart disease among diabetic and
nondiabetic men (19).
Moderate alcohol consumption is associated with a
reduced risk of coronary heart disease in women with
type 2 diabetes and should not be routinely
discouraged. Compared to diabetic women reporting
no alcohol intake, the adjusted relative risk of nonfatal
or fatal coronary heart disease for diabetic women
D. Japund‘iæ, @. Metelko, F. Po‘gaj / CARDIOVASCULAR BENEFITS AND RISKS OF MODERATE ALCOHOL CONSUMPTION
IN DIABETES MELLITUS
reporting a daily intake of 0.1 to 4.9 g alcohol (<0.5
drinks) or ≥5 g (≥0.5 drinks) was 0.72 and 0.45,
respectively (18).
Figure 1. Mechanism of hypoglycemia, lactic acidosis
and ketoacidosis induced by ethanol
IRREGULAR DIET
ETH ANOL
↓
Alcohol dehydrogenase
↓
Glucose ↓
ACETALDEHYDE
↓
↓
NADH→NAD
NAD → NADH Aldehyde dehydrogenase
Pyruvate
→
Lactate
↓
ACETATE
↓
↓
↓
NAD → NADH
ACETYL – CoA
↓
NADH → NAD OXALATE
→ CITRATE
↓ KREBS CYCLE
MALATE
extrahepatic tissue
ACETYL CoA
↓
KREBS CYCLE
CONCLUSION
Many studies report on a decrease of mortality in the
population with moderate alcohol intake, especially in
those at a higher risk of coronary disease (14). The
effect of light to moderate alcohol consumption in
diabetic patients may be reduction in the risk of
coronary heart disease and myocardial infarction (1720). Whereas diabetes is a risk factor for coronary heart
disease, moderate alcohol consumption does not
interfere with the state of normotriglyceridemia if
Diabetologia Croatica 32-4, 2003
taken with a mixed meal. Recommendations for alcohol
intake are 1-2 drinks daily or 5-14 drinks weekly, but
not 3-5 drinks daily. Diabetics must be cautious not to
take a large amount of alcohol within a short period of
time, as it may lead to hypoglycemia, lactic acidosis and
ketoacidosis. They should be aware of the fact that
chronic alcohol intake is associated with higher risks of
carcinoma, hypertension, liver cirrhosis and
symptomatic neuropathy. They should also pay due
attention to the energy part of alcohol in their diet,
especially in obese patients and those on sulfonylureas.
If diabetic individuals take one unit of alcohol drink
as part of a mixed meal, they have reduced the intake
of some other group of food (bread, fats, or meat).
Usually one unit of fat is replaced by one unit of
alcohol. It is not the same whether the patient is on an
800, 1300 or 1800 kcal diet. We do not recommend
moderate alcohol intake for obese patients on
reduction diet.
It is not the same whether it is wine or beer. Beer and
spirit contain alcohol and sugar, therefore wine without
sugar is preferred (21).
Recommendations for diabetic patients should be
tailored individually, depending on the patient’s
characteristics, readiness for cooperation and
compliance, comorbidity, therapy, and specific
conditions (e.g., pregnancy, exercise).
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IN DIABETES MELLITUS
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