R. Paul Robertson

Red Wine and Diabetes Health:Getting Skin in the GameDiabetes 2014;63:31–38 | DOI: 10.2337/db13-1318

It was an unexpected pleasure to be invited to writea Perspectives in Diabetes article considering the propo-sition that moderate consumption of red wine provideshealth benefits for people with diabetes. At the outset,I want to make clear that since Perspectives in Diabetesare not review articles in the conventional sense, this onedoes not exhaustively analyze the effects of beer, hardliquor, or alcohol per se on health. This one is all aboutwine, especially red wine. This is an important pointbecause of the intrinsic psychic influences of wine. Beer isassociated with boisterous behavior at sporting events.Hard liquor is associated with serious drinking and darkmoods. Wine, on the other hand, is associated with re-laxation, reflection, celebration, conviviality, toasting,and a certain amount of dry humor. So, in this spirit,I will lace this article with a modicum of these wine-related characteristics.

Archeologists tell us that humans made and drankwine in the Middle East (Fig. 1) beginning in ~7000BCE—well before recorded time. During its 9,000-yearhistory, wine has been used for many purposes, includingreligious (Fig. 2) and medical ones. The scientific litera-ture over the past half century does not explicitly warnagainst drinking wine in moderate amounts, exceptduring pregnancy. Yet, in the U.S. there continues to bea lurking hesitancy in some social circles about its use forrelaxation or recreational purposes. Some religious faithsspecifically proscribe wine, which also makes it in-teresting that some other religious faiths include wine intheir services. Beyond use of moderate amounts, it isclear that drinking wine excessively leads to inebriation andlikely endangerment of self and others, just as with anyalcohol-containing beverage. In view of this spectrum of

opinion and in keeping with the fashion of the day, it seemsappropriate at the outset of this Perspectives in Diabetesand in the spirit of full disclosure to state that my mother,a full-blooded Italian from Vinchiaturo in Molise, alwaystold her sons that a day without wine is a day withoutsunshine. Being a Seattle resident, I relish a sunny day.

In preparing to write, I submitted three topics toPubMed: wine and diabetes, wine and mental health, andwine and social health. Note that I purposely did not in-clude beer, liquor, or alcohol in my search. These searchesgarnered 265 references from 1963–2013, 58 referencesfrom 1967–2013, and 200 references from 1970–2013,respectively. After reading titles and abstracts, I excludedarticles that were not peer reviewed or original work, didnot specifically address drinking wine in moderate quan-tities in humans, or did not consider the impacts on healthin people with diabetes or cardiovascular disease. I read thefull manuscripts for the remainder. This Perspectives inDiabetes is organized to consider 1) epidemiologic andmetabolic studies of the consequences of red wine drinkingfor people with type 2 diabetes (T2D), 2) the question ofwhether the health effects of wine are intrinsic to grapes ora function of the alcohol in wine, and 3) potential mech-anism(s) of action for the beneficial effects of red wine.

EPIDEMIOLOGICAL STUDIES

French Paradox, Cardiovascular Disease, and T2D

The term French paradox appears to have been popu-larized in the early 1990s by 60 Minutes, the CBS newsmagazine (1), and an epidemiological article in The Lancet(2), which point out that high intake of saturated fat ispositively related to high mortality from coronary heart

Pacific Northwest Diabetes Research Institute and the Division of Metabolism,Endocrinology, and Nutrition, Departments of Medicine and Pharmacology,University of Washington, Seattle, WA

Corresponding author: R. Paul Robertson, rpr@pnri.org.

Received 26 August 2013 and accepted 15 October 2013.

© 2014 by the American Diabetes Association. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

Diabetes Volume 63, January 2014 31

PERSPECTIVESIN

DIA

BETES

disease (CHD) except in France, where there is high wineconsumption. This observation was made as early as1979 by St. Leger et al. (3). CHD has important linkage tothe issue of the effects of wine use on T2D because of themarked increased risk for CHD in people with T2D.A steady accumulation of articles reporting an associationof moderate alcohol use and protection against CHD in-dependent of T2D has appeared over the past few decades.At the current time, a PubMed search for the terms“alcohol” and “coronary heart disease” yields 11,980 cita-tions. Rather than trying to digest this unwieldy number,I will concentrate on a more refined and more manageablegroup of reports focused on the impact of red winedrinking on the health of people with T2D (4–23).

Not so long ago, there was concern that drinking al-cohol might raise blood glucose levels. Stampfer et al. (4)(Table 1) evaluated this hypothesis in 1988 by examiningthe status of 85,051 women participating in the Nurses’Health Study who were 34–59 years of age in 1980 withno history of diabetes. A dietary questionnaire was used togather information about the consumption of beer, wine,and liquor. Follow-up questionnaires were sent in 1982and 1984. Ninety-eight percent responded to at least onefollow-up. A total of 526 incident cases of T2D wereconfirmed. The risk of diabetes decreased with increasing

moderate alcohol consumption. However, decreases inbody weight were also associated with increasing alcoholuse. The authors concluded that there was no support forthe notion that moderate alcohol intake independent ofweight loss increases or decreases the risk of T2D.

Four large epidemiological studies were reported fromAustralia (5), Sweden (6), a European consortium (7),and Denmark (8) in the past decade (Table 1). Hodgeet al. (5) studied 36,527 adults aged 40–69 years atbaseline, and incident cases of T2D were identified byquestionnaire 4 years later. Eighty-seven and eighty-fivepercent of the women and men, respectively, respondedto the questionnaires. Of women, 44% consumed noalcohol. Women with the highest consumption wereyounger, leaner, more active, and more educated, smokedmore, and were less likely to have a family history ofdiabetes. Of men, 15% consumed no alcohol. Men withthe highest consumption consumed less fat and weremore likely to have gained weight. A total of 454 par-ticipants reported a diagnosis of diabetes after baseline.Of 397 who followed up with doctors, 76% were con-firmed to have T2D. For women and men, after adjust-ment for BMI and waist-to-hip ratio, there were noassociations between general alcohol consumption anda diagnosis of T2D. However, particularly pertinent forthis Perspectives in Diabetes, wine was the most com-monly consumed beverage (92% of total alcohol intakefor women and 57% for men), and it was associatedwith lower risk of T2D for both women and men.Cullmann et al. (6) used oral glucose tolerance tests atbaseline 8–10 years later to study the development of

Figure 1—A Persian woman pouring a Persian red wine (mey) inthe ancient world (17th century, Persia). From a wall painting insidethe Chehel Sotoun palace, Isfahan, Iran. Photo by Zereshk.

Figure 2—A monk cellarer keeping track of the progress of hissacramental wine (probably white) in the Middle Ages (late 13thcentury, France). Source: From Li Livres dou Santé byAldobrandino of Siena.

32 Red Wine and Diabetes Health Diabetes Volume 63, January 2014

prediabetes or T2D in a group of 2,070 men and 3,058women with normal glucose tolerance. The devel-opment of T2D was determined in this same groupafter enrichment with other subjects who had pre-diabetes, yielding groups of 2,217 men and 3,176women with either normal glucose tolerance or pre-diabetes. Of the group with normal glucose tolerance,105 men and 57 women developed T2D and 240 menand 174 women developed prediabetes. Data were ex-amined before and after adjustment for confoundingvariables (age, BMI, tobacco use, physical activity,family history of diabetes, and education). Wine con-sumption by men was not associated with either pre-diabetes or T2D. In women with normal glucosetolerance at baseline, a reduced risk of prediabetes wasseen in the high–wine intake group compared withoccasional drinkers. Beulens et al. (7) investigated theassociation between alcohol consumption and T2D anddetermined whether it is modified by sex, BMI, andbeverage type. They analyzed 455,680 subjects aged35–70 years from the European Investigation intoCancer and Nutrition Consortium (26 centers in Den-mark, France, Germany, Italy, the Netherlands, Spain,Sweden, and the U.K.). They were studied with an av-erage follow-up of 9.9 years. The authors reported thatmoderate alcohol consumption was associated witha reduced risk of T2D; wine and fortified wine weremost clearly associated with this reduced risk. Rasouliet al. (8) used data from the Nord-Trøndelag HealthSurvey to determine the incidence of T2D in 90,296adults in relation to alcohol consumption, includingquantity and frequency of drinking, type of drink, bingedrinking, and alcohol use disorders. Consumption ofwine rather than beer and spirits was associated withrisk reduction of T2D.

Comparing the results of these epidemiology stud-ies is difficult at best because they varied widely indesign, size, definition of moderate alcohol drinking,and emphasis on weight change. Nonetheless, theirmessage in common is uniform and very clear. Mod-erate drinking of alcohol was not associated with in-creased risk of T2D. Wine drinking specifically was

associated with protection against the development ofT2D. À votre santé!

METABOLIC STUDIES

As we know, epidemiology is the study of associationsand not ascertainment of cause-effect relationships.However, these associations have stimulated prospectivemetabolic research in humans. Dietary and metabolicapproaches were used to ascertain whether consumptionof alcohol and wine causes deterioration of carbohydratetolerance (Table 2). Compared with epidemiologic stud-ies, the metabolic studies I found were comprised ofmuch smaller groups of subjects. Christiansen et al. (9)(Table 2) studied T2D subjects who consumed a lightmeal containing 300 mL tap water, dry white wine, sweetwhite wine with ethanol added, or dry white wine withglucose added. No deterioration of glycemic control wasnoted. Gin et al. (10) studied a group of T2D subjects,one-third of whom received red wine, tannic acid, orethanol with their midday meal. Meals with wine ortannic acid (a component of wine) were associated withlower glucose levels after eating compared with mealswith ethanol. The authors concluded that the beneficialeffects of wine might not be mediated by alcohol. Bantleet al. (11) assessed the acute effects of wine in T2Dsubjects over 2 days during which they received 240 mLwine or grape juice with their evening meals. They alsostudied in random order the chronic effects of wine for30 days and abstaining from alcohol for 30 days.Drinking wine had no effects on fasting glycemia. Theauthors concluded that people with T2D should not bediscouraged from drinking wine in moderation. Napoliet al. (12) performed euglycemic-hyperinsulinemicclamps in T2D subjects before and after 2 weeks of redwine consumption (360 mL daily) and in T2D subjectswho did not drink wine. Insulin-mediated whole-bodyglucose disposal improved by 43% after red wine con-sumption but did not change in the control group, sug-gesting that red wine attenuates insulin resistance.Ceriello et al. (13) explored the possibility that red wineconsumption reduces oxidative stress produced by meals.T2D males in random order ingested a standard meal

Table 1—Epidemiologic studies of the association between moderate alcohol consumption and the development of T2D

Author (ref.)Association between all alcohol drinking

and risk of T2DAssociation between wine vs. beer/spirits drinking

and risk of T2D

Stampfer et al. (4) Wine equally associated with weight loss and less T2D

Hodge et al. (5) All alcohol associated with loss of weightand less T2D

Wine more strongly associated with weight lossand less T2D

Cullmann et al. (6) All alcohol associated with less T20in women only

All alcohol associated with less prediabetesin women only

Wine associated with less T20 in women only

Wine associated with less prediabetes in women only

Beulens et al. (7) All alcohol associated with less T2D Wine most strongly associated with less T2D

Rasouli et al. (8) All alcohol associated with less T2D in men Wine most strongly associated with less T2D

diabetes.diabetesjournals.org Robertson 33

without wine, 300 mL red wine without a meal, or 300 mLred wine with the meal. Plasma total radical-trappingantioxidant parameter (TRAP) was used to evaluateplasma antioxidant capacity. TRAP decreased with themeal alone, increased with red wine alone, and did notchange when red wine was combined with the meal. Theauthors concluded that the meal caused oxidative stress,that red wine reduced oxidative stress, and that winewith meals neutralized meal-induced oxidative stress.Marfella et al. (14) randomized subjects with diabeteswho had sustained a first nonfatal myocardial infarction(MI) to receive or not receive a moderate daily amount ofred wine for 1 year. At the end of a year, the groupdrinking red wine had lower levels of nitrosine,C-reactive protein (CRP), tumor necrosis factor-a(TNF-a), interleukin-6 (IL-6), and IL-8, and improvedcardiac function. They concluded that moderate red wineaccompanying meals may prevent complications after MIin T2D. Koivisto et al. (15) studied the effect of alcohol(1 g/kg as an aperitif before, wine during, and a drinkafter a meal) in T2D using mineral water as a compara-tor. They found that alcohol was associated with higherpostprandial insulin levels with no effect on postprandialglucose levels but with slightly lower fasting glucoselevels the next morning.

Taken together, these metabolic studies stronglysuggest that drinking moderate amounts of wine withmeals does not cause adverse effects on glycemia and

may improve several measures of carbohydrate andoxidative metabolism. Some of the information indi-cates that it is not the alcohol but something else in redwine that provides the beneficial effects. However, animportant caveat is the possibility of hypoglycemia,especially in elderly people taking oral hypoglycemicdrugs or insulin (16). It is well-known that use of al-cohol can be hazardous, especially if used excessively,because of the adverse effects of alcohol on counter-regulation (17) and symptom awareness of hypoglyce-mia, particularly at night while sleeping. This problemwas recently revisited in an article by Turner et al. (18),who studied men with T1D who drank dry white wine(0.75 g/kg) or mineral water at 9:00 P.M. after eatinga meal at 8:00 P.M. In the morning, fasting and post-prandial glucose levels were significantly lower afterconsumption of wine the night before, and some sub-jects required treatment for hypoglycemia after break-fast the following morning. This finding was associatedwith reduced nocturnal growth hormone levels, whichmight have contributed to increased insulin sensitivity.

BENEFITS OF RED WINE: IS IT THE ALCOHOL ORTHE GRAPES?

If, based on these epidemiologic and metabolic data, weaccept the proposition that drinking red wine can behealthful, the next step is to ask what in red wine is re-sponsible for its beneficial effects. Is it the alcohol, the

Table 2—Metabolic studies of the effects of moderate alcohol consumption on fasting glucose, glucose tolerance, andoxidative stress

Author (ref.) T2D subjects (n) Study design and results

Christiansen et al. (9) 12 Comparison of a meal with 300 mL water, dry white wine, sweet white winewith ethanol added, or dry white wine with glucose added. No differences.

Gin et al. (10) 30 Ten each drank 200 mL red wine, 150 mL tannic acid, or 16 g ethanol withmidday meal. Red wine and tannic acid associated with better glucosetolerance compared with water and ethanol.

Bantle et al. (11) 18 Acute: subjects drank either 240 mL wine or grape juice with evening meal.No differences. Chronic: Subjects drank 120–240 mL wine daily for 30 daysand also abstained from alcohol for 30 days. No effect on fasting glucoseor HbA1c.

Napoli et al. (12) 17 Nine T2D subjects studied before and after 2 weeks of drinking 360 mL/dayred wine; eight T2D subjects studied before and after not drinking wine;euglycemic clamps. Red wine decreased insulin resistance by 43%.

Ceriello et al. (13) 10 Randomized study of meal vs. fasting plus 300 mL red wine vs. meal plus300 mL red wine. Study of antioxidant activity (TRAP). Meal decreased TRAP;red wine while fasting increased TRAP; red wine with meal negated TRAPdecrease.

Marfella et al. (14) 115 Subjects who had sustained a first nonfatal MI were randomized to 118 mLred wine or no alcoholic beverage for 1 year. Nitrotyrosine, TNF-a,IL-6, IL-18, and CRP were lower and myocardial performance washigher in red wine group.

Koivisto et al. (15) 10 Alcohol (1 g/kg) was given as an apertif before, wine during, and a drinkafter a meal or an equal amount of mineral water was given with a meal.Drinking alcohol with a meal the evening before slightly but significantlylowered glucose the morning after; no overt hypoglycemia.

34 Red Wine and Diabetes Health Diabetes Volume 63, January 2014

grapes, or both? And if it is the grapes, what is in grapesthat might be beneficial for people with or at risk for T2D?

To address these questions, Alberti-Fidanza et al. (19)examined the acute effects of lyophilized red wine aftera meal on plasma oxygen radical absorbance capacity(ORAC), a measure of antioxidant capacity, in healthysubjects. The control was a meal without drinking wineafterward. The meal without wine decreased ORAC for360 min, whereas the meal plus drinking red wine fromwhich alcohol had been removed increased ORAC for 360min. This suggests that meals decrease antioxidant ca-pacity, whereas red wine ingredients in the absence ofalcohol increase antioxidant capacity. Noguer et al. (20)studied whether red wine affects antioxidant enzymeactivity in blood or blood products. Subjects consumeda low phenolic diet (to avoid interference from dietarypolyphenols) while drinking or not drinking 300 mL redwine every day for a week. The low-polyphenol diet re-duced enzyme activities for superoxide dismutase, cata-lase, and glutathione reductase; the same diet combinedwith red wine increased the activities of these enzymes.The authors posited that the increase in antioxidantenzyme activity was due to the polyphenolic compositionof wine and not its alcohol content. Chiva-Blanch et al.(21) took this line of research important steps further bystudying a much larger group of subjects and includingthe control of a nongrape alcoholic beverage. Men withhigh cardiovascular risk were randomized in a crossovertrial during which all received red wine (272 mL, 30 galcohol, 798 mg polyphenols/day), the equivalentamount of dealcoholized red wine (272 mL, 1.14 galcohol, 733 mg polyphenols/day), and gin (100 mL, 30 galcohol) for 4-week periods. Fasting glucose levelsremained constant throughout the study. Comparedwith baseline values, fasting insulin levels decreasedslightly but significantly during the periods of drinkingred wine and dealcoholized red wine but not gin. Theinsulin data were used to calculate homeostasis modelassessment of insulin resistance values, which led theauthors to conclude that the nonalcoholic fraction ofred wine contains polyphenols, which decrease insulinresistance. Nakamura et al. (24) studied subjects withT2D and nephropathy who were randomly assigned todrink 118 mL red wine or white wine daily for 6months. A third group with T2D and nephropathy didnot drink wine. Urinary 8-hydroxydeoxyguanosine wasmeasured as a marker of oxidative stress, and urinaryliver-type fatty acid–binding protein was measured asa marker for deteriorating renal function. The subjectswho drank red wine had a reduction of these twomarkers at 3 and 6 months of study, whereas the groupdrinking white wine did not. The authors concludedthat the renoprotective effect of red wine may be due inpart to its ability to reduce oxidative stress.

These four studies point toward the beneficial effectsof red wine being provided not by its alcoholic contentbut by something else. Is it the polyphenolic acid

content? If so, which polyphenols, and are they modu-lators of oxidative stress? And where in the grape arepolyphenols found? However, before we move on tomore information about polyphenols, the definition ofmoderate drinking and how it relates to a glassful ofwine needs to be addressed. Obviously, the size of theglass is a huge variable. Some red wine glasses can holdan entire bottleful of wine! The majority of studies de-fine a moderate quantity as 300 cc or 2 glasses of redwine. This is a little less than one-half of a conventional750-cc bottle of wine, which makes one wonder whybottle makers chose five as the number glasses a bottlecan fill. However, this no doubt is the origin of the well-known gambit in which one diverts one’s dinner part-ner’s attention elsewhere in the restaurant while cadg-ing the remaining 150 cc.

GRAPES HAVE SKIN IN THE GAME OF DIABETESHEALTH CARE

What are polyphenolic acid and polyphenols? Poly-phenols are found in plants, especially grapes and berries,and can be defined as macromolecules generally con-taining ,12 phenolic hydroxyl groups with five to sixaromatic rings per 1,000 daltons. Polyphenols sport ex-otic names, such as (in no particular order) phytoalexins,gallic acid, syningic acid, protocatechuric acid, caffeicacid, ferulic acid, stilbenes, flavonoids, quercetin,myricetin, kamempferol, rutin, catechin, delphinidin,malvidin, etc. Processing these names is challengingenough to tempt one to reach for a glass of sangiovese.One of these names that you will readily recognize isresveratrol of the stilbene group, commonly discussedin newspapers and on television shows. According toWikipedia, this less-than-intuitive name comes from thefact that resveratrol is a resorcinol derivative comingfrom a Veratrum species (25). If you are in the mood toread an incredibly large amount of information aboutplants and polyphenols, I refer you to several reviewsI thought were encyclopedic (26) or succinct (1,27).Many mechanisms of actions of polyphenols have beenproposed, but the one that recurrently appears in thescientific literature is the role of polyphenols asantioxidants. Paganga et al. (22) reported that theantioxidant activities of 1 glass (150 mL) red wine isequivalent to 2 cups of tea, 3.5 glasses of black currantjuice, 3.5 (500 ml) glasses of beer, 4 apples, 5 portionsof onion, 5.5 portions of eggplant, 7 glasses of orangejuice, 12 glasses of white wine, and 20 glasses ofapple juice. Hence, the often-heard comment that redwine provides excellent protection against oxidativestress.

Tomé-Carneiro et al. (28) studied subjects undergoingprimary prevention of cardiovascular disease in a triple-blinded, randomized, parallel, dose-response, placebo-controlled, 1-year follow-up trial of placebo versus grapesupplement containing 8 mg resveratrol (a polyphenol)versus grape supplement lacking resveratrol. They

diabetes.diabetesjournals.org Robertson 35

observed at 1 year that the resveratrol-rich grape supple-ment decreased high-sensitivity CRP, TNF-a, plasminogenactivator inhibitor type 1, and IL-6–to–IL-10 ratio. Theysuggested that grape-derived resveratrol as a dietary in-tervention could complement methods conventionally usedin the primary prevention of cardiovascular disease.However, one should not assume that resveratrol is theonly or even the principal antioxidant in red wine. Germanand Walzem (1) reported that the total phenolic acids andpolyphenols in red wine is 900–2,500 mg/L. Of these, theconcentration of flavonoids is 750–1,060 mg/L and con-sists of flavonols, flavanols, and anthrocyanins. Thehighest polyphenol concentrations in these three sub-groups are, respectively, quercetin, procyanidins, andmalvidin 3-monoglucaside. The nonflavonoids have a con-centration of 240–500 mg/L and include hydroxybenzoicacids, hydroxycinnamic acids, and stilbene. The highestconcentrations in these three subgroups, respectively, areprotocatechuric acid, cis-/trans-caftaric acid, and trans-resveratrol. But resveratrol is at the bottom of the entirelist in terms of concentration in red wine . . . a pitiful 1.0mg/L (1,23), which makes one wonder why it gets all theattention. One review (27) suggests that it may be due toinformation published in the last decade suggesting thatresveratrol is an inhibitor of cyclooxygenase and an acti-vator of sirtuin enzymes. Regarding this point, Poulsenet al. (29) reported a study in which 24 obese men wererandomized in a double-blinded, placebo-controlled fashionto receive either high-dose oral resveratrol or placebo for4 weeks. They found no significant effect of resveratrol ona host of physical and metabolic parameters. However,Timmers et al. (30) and Brasnyó et al. (31) reported thatresveratrol supplementation was associated with an im-proved homeostasis model assessment index, sug-gesting increased insulin sensitivity. Bhatt et al. (32)studied 62 subjects with T2D subjects using oral hy-poglycemic agents who were randomized into an in-tervention group receiving resveratrol and a controlgroup not receiving resveratrol. The former groupexperienced a slight but statistically significant de-crease in mean HbA1c level. Rytter et al. (33) reporteda study in which 47 subjects with T2D were random-ized in a double-blind, placebo-controlled study of theeffects of antioxidant supplements (unfortunately,resveratrol was not included) on blood levels of glucoseand HbA1c and found no differences. Importantly, theyalso observed no effects of the supplements on markersof oxidative stress, which raises the question ofwhether the concentrations of supplements they usedwere sufficiently high to have effects on metabolicparameters. I did not find reports of comprehensivebiochemical comparisons of the antioxidant potenciesof the various polyphenolic acids found in red wine,which could be a more important factor than their totalconcentrations.

Finally, where in red grapes are polyphenols found?Here’s the skinny: Wine is composed of yeast

fermentation products of the “must,” which is the juicepressed from the grape, the fruit of the genus Vitis.Fermentation produces a variety of chemical changes inthe must, so wine is not a simple grape juice withethanol added. Red wine is left in contact with the mustfor longer periods of time than white wine. The longerthe must is exposed to the skins, seeds, and stems ofthe grapes, the more polyphenols are extracted into thejuice and the more antioxidant activity is contained inthe wine. This no doubt is why many wine drinkersbelieve choosing red is a must.

WHAT DOES PROTECTION AGAINST OXIDATIVESTRESS HAVE TO DO WITH PROTECTIONAGAINST DIABETES?

Oxidative stress is a topic that chemists, especially foodchemists, love. They find moieties like O2

2, $OH, H2O2,and ONOO2 fascinating, if not endearing. They teach usthat reactive oxygen species (ROS), such as the ones justlisted, are two-edged swords. In small concentrations,ROS are good things because they enhance physiologicaland cellular function. In excess concentrations, however,they cause havoc in cells. This is termed oxidative stress,which, as its name implies, is not a good thing. Thecomplications of T2D have long been associated withchronic oxidative stress. Excessive circulating glucoseconcentrations spilling over into a variety of metabolicpathways form increasing amounts of ROS, which inexcess destroy membranes and compartments in thetissues in which they are formed. This risky state ofaffairs is particularly true in the b-cell, which for un-known reasons does not contain two major antioxidants(catalase and glutathione peroxidase) (34,35). Thus, theb-cell is left without the major protection that othertissues have against accumulation of H2O2 and in-tracellular peroxides. b-Cells do contain superoxide dis-mutases (SODs), but this doesn’t help much becauseSODs, although classified as antioxidant enzymes, ca-tabolize superoxide into the oxidant H2O2, thereby act-ing like a pro-oxidant enzyme.

In T2D, this all comes down to the issue of excessglycemia bathing tissues and creating ROS, which inexcess can damage organs, including retina, kidney,nerves, vascular tissue, and b-cells (36,37). The patho-genesis of T2D by consensus originates as a polygenicdisease amplified by epigenetic influences, such as en-vironmental oxidants and obesity with associated in-sulin resistance, to damage b-cells, thereby causingimpaired glucose tolerance and early diabetes. The glu-cose toxicity hypothesis holds that continual exposureto high postprandial glucose levels over time steadilygenerates excess ROS that constantly nibble away atcells and their normal function (38). Red wine comesinto the picture of T2D because it contains antioxidantsthat can be used as an ancillary buffer against the oxi-dative stress caused by the ingestion of a meal or en-vironmental toxins.

36 Red Wine and Diabetes Health Diabetes Volume 63, January 2014

CONCLUSIONS

From my perspective, the articles that I have readstrongly suggest that drinking red wine in moderationhas no adverse effects on people with T2D. Moreover,red wine may have a preventive effect for people at riskfor T2D. Overall, the metabolic studies of humans areconsistent with the epidemiologic data, i.e., no harmfuleffects and possibly beneficial effects of red wine. In-terestingly, the skin of the grape, rather than the alcoholor juice in red wine, is the source of polyphenols, andtheir antioxidant effects may play a role in the beneficialeffects of red wine. Red wine has 12-fold higher levels ofpolyphenols than white wine and so has a clear edge onantioxidant potency. The actual mechanism of action ofred wine has been popularly suggested to involveresveratrol, but the contention that this polyphenol isexclusively involved does not stand up to scientific ev-idence. This intriguing health-related area is ripe forclinical and basic research efforts designed to moreprecisely identify which of the many polyphenolic acidsin red wine may be playing a role in the protectivemechanism(s) involved and, beyond that, the full elu-cidation of these mechanism(s). You may want to getyour own skin in this game. While thinking about it, sitback and relax with two glassfuls of your favorite redwine without fear. It may be that one significant mech-anism of wine’s beneficial effects is just that.relaxing with good friends during a savory meal witha great cabernet.

Duality of Interest. No potential conflicts of interest relevant to thisarticle were reported.

References1. German JB, Walzem RL. The health benefits of wine. Annu Rev Nutr 2000;

20:561–593

2. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradoxfor coronary heart disease. Lancet 1992;339:1523–1526

3. St. Leger AS, Cochrane AL, Moore F. Factors associated with cardiacmortality in developed countries with particular reference to the con-sumption of wine. Lancet 1979;1:1017–1020

4. Stampfer MJ, Colditz GA, Willett WC, et al. A prospective study of moderatealcohol drinking and risk of diabetes in women. Am J Epidemiol 1988;128:549–558

5. Hodge AM, English DR, O’Dea K, Giles GG. Alcohol intake, consumptionpattern and beverage type, and the risk of type 2 diabetes. Diabet Med2006;23:690–697

6. Cullmann M, Hilding A, Östenson CG. Alcohol consumption and risk of pre-diabetes and type 2 diabetes development in a Swedish population. DiabetMed 2012;29:441–452

7. Beulens JW, van der Schouw YT, Bergmann MM, et al.; InterAct Consor-tium. Alcohol consumption and risk of type 2 diabetes in European menand women: influence of beverage type and body size. The EPIC-InterActstudy. J Intern Med 2012;272:358–370

8. Rasouli B, Ahlbom A, Andersson T, et al. Alcohol consumption is associ-ated with reduced risk of type 2 diabetes and autoimmune diabetes in

adults: results from the Nord-Trøndelag Health Study. Diabet Med 2013;30:56–64

9. Christiansen C, Thomsen C, Rasmussen O, et al. Wine for type 2 diabeticpatients? Diabet Med 1993;10:958–961

10. Gin H, Rigalleau V, Caubet O, Masquelier J, Aubertin J. Effects of red wine,tannic acid, or ethanol on glucose tolerance in non-insulin-dependent di-abetic patients and on starch digestibility in vitro. Metabolism 1999;48:1179–1183

11. Bantle AE, Thomas W, Bantle JP. Metabolic effects of alcohol in the form ofwine in persons with type 2 diabetes mellitus. Metabolism 2008;57:241–245

12. Napoli R, Cozzolino D, Guardasole V, et al. Red wine consumption improvesinsulin resistance but not endothelial function in type 2 diabetic patients.Metabolism 2005;54:306–313

13. Ceriello A, Bortolotti N, Motz E, et al. Meal-generated oxidative stress indiabetes. The protective effect of red wine. Diabetes Care 1999;22:2084–2085

14. Marfella R, Cacciapuoti F, Siniscalchi M, et al. Effect of moderate red wineintake on cardiac prognosis after recent acute myocardial infarction ofsubjects with type 2 diabetes mellitus. Diabet Med 2006;23:974–981

15. Koivisto VA, Tulokas S, Toivonen M, Haapa E, Pelkonen R. Alcohol witha meal has no adverse effects on postprandial glucose homeostasis indiabetic patients. Diabetes Care 1993;16:1612–1614

16. Burge MR, Zeise TM, Sobhy TA, Rassam AG, Schade DS. Low-dose ethanolpredisposes elderly fasted patients with type 2 diabetes to sulfonylurea-induced low blood glucose. Diabetes Care 1999;22:2037–2043

17. Wilson NM, Brown PM, Juul SM, Prestwich SA, Sönksen PH. Glucoseturnover and metabolic and hormonal changes in ethanol-induced hypo-glycaemia. Br Med J (Clin Res Ed) 1981;282:849–853

18. Turner BC, Jenkins E, Kerr D, Sherwin RS, Cavan DA. The effect of eveningalcohol consumption on next-morning glucose control in type 1 diabetes.Diabetes Care 2001;24:1888–1893

19. Alberti-Fidanza A, Burini G, Antonelli G, Murdolo G, Perriello G. Acuteeffects of lyophilised red wine on total antioxidant capacity in healthyvolunteers. Diabetes Nutr Metab 2003;16:65–71

20. Noguer MA, Cerezo AB, Donoso Navarro E, Garcia-Parrilla MC. Intake ofalcohol-free red wine modulates antioxidant enzyme activities in a humanintervention study. Pharmacol Res 2012;65:609–614

21. Chiva-Blanch G, Urpi-Sarda M, Ros E, et al. Effects of red wine polyphenolsand alcohol on glucose metabolism and the lipid profile: a randomizedclinical trial. Clin Nutr 2013;32:200–206

22. Paganga G, Miller N, Rice-Evans CA. The polyphenolic content of fruit andvegetables and their antioxidant activities. What does a serving constitute?Free Radic Res 1999;30:153–162

23. Siemann EH, Creasy LL. Concentration of the phytoalexinn resveratrol inwine. Am J Enol Vitic 1992;43:49–52

24. Nakamura T, Fujiwara N, Sugaya T, Ueda Y, Koide H. Effect of red wine onurinary protein, 8-hydroxydeoxyguanosine, and liver-type fatty acid-bindingprotein excretion in patients with diabetic nephropathy. Metabolism 2009;58:1185–1190

25. Takaoka M. Resveratrol, a new phenolic compound, from Veratrumgrandiflorum. J Chem Soc of Japan 1939;60:1090–1100

26. Pervaiz S, Holme AL. Resveratrol: its biologic targets and functional ac-tivity. Antioxid Redox Signal 2009;11:2851–2897

27. Smoliga JM, Vang O, Baur JA. Challenges of translating basic research intotherapeutics: resveratrol as an example. J Gerontol A Biol Sci Med Sci2012;67:158–167

diabetes.diabetesjournals.org Robertson 37

28. Tomé-Carneiro J, Gonzálvez M, Larrosa M, et al. One-year consumption ofa grape nutraceutical containing resveratrol improves the inflammatory andfibrinolytic status of patients in primary prevention of cardiovascular dis-ease. Am J Cardiol 2012;110:356–363

29. Poulsen MM, Vestergaard PF, Clasen BF, et al. High-dose resveratrolsupplementation in obese men: an investigator-initiated, randomized,placebo-controlled clinical trial of substrate metabolism, insulin sensitivity,and body composition. Diabetes 2013;62:1186–1195

30. Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effectsof 30 days of resveratrol supplementation on energy metabolismand metabolic profile in obese humans. Cell Metab 2011;14:612–622

31. Brasnyó P, Molnár GA, Mohás M, et al. Resveratrol improves insulinsensitivity, reduces oxidative stress and activates the Akt pathway in type 2diabetic patients. Br J Nutr 2011;106:383–389

32. Bhatt JK, Thomas S, Nanjan MJ. Resveratrol supplementation improvesglycemic control in type 2 diabetes mellitus. Nutr Res 2012;32:537–541

33. Rytter E, Vessby B, Asgård R, et al. Supplementation with a combination

of antioxidants does not affect glycaemic control, oxidative stress or

inflammation in type 2 diabetes subjects. Free Radic Res 2010;44:

1445–1453

34. Grankvist K, Marklund SL, Täljedal IB. CuZn-superoxide dismutase,

Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic

islets and other tissues in the mouse. Biochem J 1981;199:393–398

35. Tiedge M, Lortz S, Drinkgern J, Lenzen S. Relation between antioxidant

enzyme gene expression and antioxidative defense status of insulin-

producing cells. Diabetes 1997;46:1733–1742

36. Brownlee M. Biochemistry and molecular cell biology of diabetic compli-

cations. Nature 2001;414:813–820

37. Robertson RP. Chronic oxidative stress as a central mechanism for glucose

toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 2004;279:

42351–42354

38. Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dys-

function. Endocr Rev 2008;29:351–366

38 Red Wine and Diabetes Health Diabetes Volume 63, January 2014