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Nutrition and Prevention of Diseases
Topic 20
Module 20.6
Moderate Alcohol and Cardiometabolic Risk in Type 2 Diabetes
(T2D)
Iris Shai, RD, PhD
Professor of Nutrition and Epidemiology,
Department of Public Health, Faculty of Health Sciences,
Ben-Gurion University of the Negev, Israel
Learning Objectives
• Addressing the risks and benefits of alcohol consumption;
• Examining the associations and effects of moderate alcohol consumption in type 2
diabetes (T2D);
• Introducing the 2-year CArdiovaSCulAr
Randomized Controlled Trial.
Diabetes
and
Ethanol
(CASCADE)
Contents
1. Risks and benefits of alcohol consumption
2. The associations and effects of moderate alcohol consumption in type 2 diabetes
(T2D)
3. The 2-year CArdiovaSCulAr Diabetes and Ethanol (CASCADE) randomized
controlled trial
4. Summary
5. References
Key Messages
•
•
•
•
•
Alcohol is a toxic substance which risk-benefit balance depends on numerous
factors;
Heavy alcohol consumption has deleterious health effects, while drinking alcohol in
moderation was demonstrated to have beneficial influence on cardio-metabolic
health;
Moderate alcohol consumption is defined as 10–30 g of alcohol per day, which is
equivalent to ~0.5–2 drinks per day (up to 1 drink a day for women and up to 2
drinks/day for men);
Beneficial effects of moderate alcohol on human health are documented in healthy
populations as well as amongst patients with type 2 diabetes;
Genetic polymorphisms in alcohol metabolizing genes may interact with the
alcohol-health effects.
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1. Risks and Benefits of Alcohol Consumption
The relationship between alcohol intake and alcohol-related health effects is a complex
subject, since alcohol is associated with both, harmful and beneficial effects on health.
Mounting evidence demonstrates a J-shape association for alcohol intake. It is well
known that heavy alcohol drinking is positively associated with various social problems
and adverse medical conditions. High alcohol consumption is associated with increased
risk for numerous deleterious health outcomes, such as liver cirrhosis, dementia, and
several types of cancers. Moreover, overall mortality is higher amongst individuals with a
high alcohol intake compared with moderate consumers. High alcohol intake may result
in acute cardiovascular damage (such as arterial hypertension and transitory ischaemic
cerebral attack) as well as in harmful chronic effects on the heart (such as coronary heart
disease, atrial dysfunction, ventricular dysfunction, and chronic arrhythmias), brain (such
as ischaemic stroke, haemorrhagic stroke and subdural haemorrhage) and the vascular
system (such as systemic atherosclerosis, arterial hypertension, peripheral artery
disease, and adverse changes in inflammatory endothelial markers) (1,2).
On the contrary, moderate alcohol consumption decreases the overall mortality and has
numerous health benefits. It was demonstrated to decrease the risk of type 2 diabetes
and the cardiovascular risk, prevent thrombosis and plaques, and improve lipid profile (3,
4, 5, 6). These favorable effects were observed both in healthy populations as well as
amongst patients with type 2 diabetes.
2. The Associations and Effects of Moderate Alcohol Consumption
in Type 2 Diabetes (T2D)
With regard to diabetes and its complications, a J-shape association was suggested for
alcohol intake (7, 8, 9), implying that moderate drinkers may benefit from a protective
effect of alcohol on the risk of developing diabetes and its complications. Consistently,
prospective studies confirmed an inverse relationship between moderate alcohol
consumption and diabetes incidence, with moderate drinkers having a 43% to 46%
reduction in risk for new-onset diabetes compared with abstainers.
In diagnosed type 2 diabetic patients, alcohol in moderation is linked to lower
cardiovascular risk (10). Meta-analysis of observational studies (11) shows that among
type 2 diabetics who reported alcohol consumption, a 21–36% lower total mortality rate,
and a 25–66% lower rate of total and fatal CHD were observed, compared with
abstainers. Intriguingly, the magnitude of these associations is even stronger than
reported in observational studies in the general, non-diabetic population (12). However,
the question whether it is acceptable to recommend patients start drinking to reduce the
risk for cardiovascular disorders remains controversial issue.
The apparent beneficial effects of alcohol on cardiovascular disease have been proposed
to be mediated via effects on lipid metabolism (13), coagulation, fibrinolysis (14), and
insulin sensitivity (15, 16). We have previously shown in an observational study among
over 700 men with type 2 diabetes (17), that moderate alcohol intake was associated
with decreasing levels of inflammatory biomarkers (sTNFr-2, sICAM-1, fibrinogen), as
well as with elevated circulating levels of adiponectin. However, although these
parameters may be regarded as good surrogate markers, it is unknown whether alcohol
has direct effects on the atherosclerotic plaque.
Independent of the favorable biological effects of alcohol on the lipid profile, on
homeostatic factors, and in reducing insulin resistance (18), phenolic compounds (19)
(mostly resveratrol and quercetin) (20) of red wine appear to also exert beneficial effects
(21, 22, 23). The mechanisms include antiplatelet actions, increases in high-density
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lipoprotein, antioxidative function, reduced endothelin-1 production, and increased
endothelial nitric oxide synthase expression. Comparison studies suggest (24) that wine
is more protective against coronary disease than liquor or beer. However, others suggest
that favorable traits or drinking patterns of wine drinkers might explain the comparative
findings. As opposed to the experimental studies, epidemiological studies demonstrate a
beneficial effect of alcohol consumption independent of the specific kind of alcoholic
beverage consumed (25), suggesting that small doses (1-2 drinks a day) of wine, beer,
or spirits are equally beneficial (26). In-vivo study suggests that both wine and ethanol
alone reduce myocardial ischemic reperfusion injury. However, the mechanisms utilized
by the various beverages in exerting their cardio-protective effect(s) differ (27). Thus,
long-term intervention trials are needed to determine the net beneficial effect, of ethanol
per se.
Several mechanisms for beneficial effects of ethanol uniquely in diabetic patients can be
envisioned, and include improved glycemia and decrease in cardiovascular risk. Ethanol
metabolism increases the hepatic cytosolic NADH/NAD+ ratio, thereby inhibiting
gluconeogenesis which is abnormally elevated in type 2 diabetes, thus contributing
particularly to fasting hyperglycemia. Current therapy of type 2 diabetes, including nighttime long-acting insulin and metformin, improves glucose homeostasis largely by
addressing this abnormally-elevated metabolic pathway. However, just as hepatic
glucose production can be over inhibited by excessive night-time insulin, alcohol can
provoke hypoglycemia. This is particularly true when ingested in the fasting state (28).
Since ethanol does not appear to significantly affect insulin secretion or glucose disposal,
a hypoglycemic effect of ethanol is likely to be highly dependent on the nutritional status
and fed-fast state of the person ingesting it (29). Several small short-term studies, of 520 patients with type 2 diabetes, reported a decrease in plasma glucose concentrations
(30, 31) with moderate alcohol administration. However, other studies found no effect of
alcohol on glycemic control (32, 33). Thus, the potential impact of moderate alcohol
consumption on glycemic control in diabetics remains intriguing, but largely unproven.
The beneficial effects of moderate alcohol consumption inferred by observational studies
form the need to test the hypothesis that initiating regular moderate alcohol consumption
would be beneficial in patients with type 2 diabetes. Yet, as summarized in an editorial
commentary, (34) proving the beneficial effect of moderate alcohol intake awaits results
of randomized controlled intervention trials. To date, few such studies have been
performed. In a randomized controlled crossover trial (35) of 63 healthy (non-diabetic)
postmenopausal women over 8 weeks, consumption of 30 g/d of alcohol (2 drinks per
day) reduced insulin and triglyceride concentrations and improved insulin sensitivity, but
fasting glucose concentrations were not significantly affected. In a trial among young
patients with diabetes after a first myocardial infarction (36), red wine, taken with meals,
significantly reduced oxidative stress and pro-inflammatory cytokines. These important,
but still anecdotal studies, provide proof-of-principle consistent with the hypothesis
driving the present proposal, however, they are insufficient to determine whether
initiating moderate alcohol intake, as a medically-prescribed long-term treatment, should
be regarded as a safe therapeutic intervention for the general population of type 2
diabetic people.
To address these questions, we completed a three-month randomized controlled
intervention pilot study (37) of alcohol (13 g/day) or a control nonalcoholic beer among
109 alcohol-abstainers with type 2 diabetes, and assessed the effect on fasting and
postprandial glycemia. Within the alcohol intervention group, mean FPG decreased from
139.6 mg/dL to 118.0 after 3 months compared to 136.7 to 138.6 in the controls (p =
0.015). The effect was more pronounced among patients with higher baseline HbA1c
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levels, consistent with the proposition that elevated hepatic glucose production may be
an important contributor to hyperglycemia in advanced diabetes.
3. The 2-year CArdiovaSCulAr Diabetes and Ethanol (CASCADE)
Randomized Controlled Trial
Currently there are only a few randomized controlled trials (RCT) examining the possible
beneficial cardio-metabolic health effects of chronic moderate alcohol consumption.
Moreover, long-term large-scale RCTs in type 2 diabetes patients are virtually lacking.
Therefore, we conducted a 2-year RCT assessing whether initiating moderate alcohol
intake in patients with type-2 diabetes is beneficial and, moreover, safe. 224 wellcontrolled alcohol-abstaining diabetics were randomized to mineral-water, white-wine or
red-wine (150ml/dinner) groups. Wines and water were provided. All groups followed a
Mediterranean diet without caloric restriction. Retention was 94% after one year and
87% after two. Overall, red wine was superior in improving cardiometabolic risk . While
both wines were beneficial for glycemic control, the effect was mainly dependent on their
polymorphism in alcohol-dehydrogenase 1B (ADH1B) gene. ADH1B is the main enzyme
that metabolizes the first step of ethanol metabolism - catalytically oxidizing the ethanol
into acetaldehyde. In the wine groups, slow-ethanol-metabolizers [homozygotic for the
alcohol-dehydrogenase variants (ADH)1B*1] had favorable changes in glycemic control
parameters as compared to fast-ethanol-metabolizers [carrying ADH1B*2 (Arg48His;
rs1229984)]. Other parameters as blood pressure, liver function, adiposity, medications
intake, and specific symptoms were not altered across groups. To summarize, initiating
moderate wine intake among well-controlled type-2 diabetes patients as part of healthy
diet is apparently safe. Wine induces modest improvements in several metabolic
parameters. The significant interactions with genetic polymorphisms in alcohol
metabolizing genes lend further support for a causal role of ethanol (38).
4. Summary
A complex interplay exists between alcohol and human health. To complicate the picture
even more, not only the alcohol-related factors, such as drinking pattern with regard to
alcohol dose consumed and the frequency of alcohol drinking, but also several additional
features, such as age, gender, genetic factors, ethnicity, and the current health status,
all have an influence on the effect of alcohol on health parameters. Therefore, alcohol
consumption should be subject to careful consideration.
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5.
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