Diabetes Volume 63, January 2014 31

R. Paul Robertson

Red Wine and Diabetes Health: Getting Skin in the Game

Diabetes 2014;63:31–38 | DOI: 10.2337/db13-1318

It was an unexpected pleasure to be invited to write opinion and in keeping with the fashion of the day, it seems a Perspectives in Diabetes article considering the propo- appropriate at the outset of this Perspectives in Diabetes sition that moderate consumption of red wine provides and in the spirit of full disclosure to state that my mother, health benefits for people with diabetes. At the outset, a full-blooded Italian from Vinchiaturo in Molise, always I want to make clear that since Perspectives in Diabetes told her sons that a day without wine is a day without DIABETES IN PERSPECTIVES are not review articles in the conventional sense, this one sunshine. Being a Seattle resident, I relish a sunny day. does not exhaustively analyze the effects of beer, hard In preparing to write, I submitted three topics to liquor, or alcohol per se on health. This one is all about PubMed: wine and diabetes, wine and mental health, and wine, especially red wine. This is an important point wine and social health. Note that I purposely did not in- because of the intrinsic psychic influences of wine. Beer is clude beer, liquor, or alcohol in my search. These searches associated with boisterous behavior at sporting events. garnered 265 references from 1963–2013, 58 references Hard liquor is associated with serious drinking and dark from 1967–2013, and 200 references from 1970–2013, moods. Wine, on the other hand, is associated with re- respectively. After reading titles and abstracts, I excluded laxation, reflection, celebration, conviviality, toasting, articles that were not peer reviewed or original work, did and a certain amount of dry humor. So, in this spirit, not specifically address drinking wine in moderate quan- I will lace this article with a modicum of these wine- tities in humans, or did not consider the impacts on health related characteristics. in people with diabetes or cardiovascular disease. I read the Archeologists tell us that humans made and drank full manuscripts for the remainder. This Perspectives in wine in the Middle East (Fig. 1) beginning in ~7000 Diabetes is organized to consider 1) epidemiologic and BCE—well before recorded time. During its 9,000-year metabolic studies of the consequences of red wine drinking history, wine has been used for many purposes, including for people with type 2 diabetes (T2D), 2) the question of religious (Fig. 2) and medical ones. The scientific litera- whether the health effects of wine are intrinsic to grapes or ture over the past half century does not explicitly warn a function of the alcohol in wine, and 3) potential mech- against drinking wine in moderate amounts, except anism(s) of action for the beneficial effects of red wine. during pregnancy. Yet, in the U.S. there continues to be a lurking hesitancy in some social circles about its use for EPIDEMIOLOGICAL STUDIES relaxation or recreational purposes. Some religious faiths specifically proscribe wine, which also makes it in- French Paradox, Cardiovascular Disease, and T2D teresting that some other religious faiths include wine in The term French paradox appears to have been popu- their services. Beyond use of moderate amounts, it is larized in the early 1990s by 60 Minutes, the CBS news clear that drinking wine excessively leads to inebriation and magazine (1), and an epidemiological article in The Lancet likely endangerment of self and others, just as with any (2), which point out that high intake of saturated fat is alcohol-containing beverage.Inviewofthisspectrumof positively related to high mortality from coronary heart

Pacific Northwest Diabetes Research Institute and the Division of Metabolism, Corresponding author: R. Paul Robertson, [email protected]. Endocrinology, and Nutrition, Departments of Medicine and Pharmacology, Received 26 August 2013 and accepted 15 October 2013. University of Washington, Seattle, WA © 2014 by the American Diabetes Association. See http://creativecommons .org/licenses/by-nc-nd/3.0/ for details. 32 Red Wine and Diabetes Health Diabetes Volume 63, January 2014

Figure 2—A monk cellarer keeping track of the progress of his sacramental wine (probably white) in the Middle Ages (late 13th century, France). Source: From Li Livres dou Santé by Aldobrandino of Siena.

Figure 1—A Persian woman pouring a Persian red wine (mey)in moderate alcohol consumption. However, decreases in the ancient world (17th century, Persia). From a wall painting inside body weight were also associated with increasing alcohol the Chehel Sotoun palace, Isfahan, Iran. Photo by Zereshk. use. The authors concluded that there was no support for the notion that moderate alcohol intake independent of weight loss increases or decreases the risk of T2D. Four large epidemiological studies were reported from disease (CHD) except in France, where there is high wine Australia (5), Sweden (6), a European consortium (7), consumption. This observation was made as early as and Denmark (8) in the past decade (Table 1). Hodge 1979 by St. Leger et al. (3). CHD has important linkage to et al. (5) studied 36,527 adults aged 40–69 years at the issue of the effects of wine use on T2D because of the baseline, and incident cases of T2D were identified by marked increased risk for CHD in people with T2D. questionnaire 4 years later. Eighty-seven and eighty-five A steady accumulation of articles reporting an association percent of the women and men, respectively, responded of moderate alcohol use and protection against CHD in- to the questionnaires. Of women, 44% consumed no dependent of T2D has appeared over the past few decades. alcohol. Women with the highest consumption were At the current time, a PubMed search for the terms younger, leaner, more active, and more educated, smoked “alcohol” and “coronary heart disease” yields 11,980 cita- more, and were less likely to have a family history of tions. Rather than trying to digest this unwieldy number, diabetes. Of men, 15% consumed no alcohol. Men with I will concentrate on a more refined and more manageable the highest consumption consumed less fat and were group of reports focused on the impact of red wine more likely to have gained weight. A total of 454 par- drinking on the health of people with T2D (4–23). ticipants reported a diagnosis of diabetes after baseline. Not so long ago, there was concern that drinking al- Of 397 who followed up with doctors, 76% were con- cohol might raise blood glucose levels. Stampfer et al. (4) firmed to have T2D. For women and men, after adjust- (Table 1) evaluated this hypothesis in 1988 by examining ment for BMI and waist-to-hip ratio, there were no the status of 85,051 women participating in the Nurses’ associations between general alcohol consumption and Health Study who were 34–59 years of age in 1980 with a diagnosis of T2D. However, particularly pertinent for no history of diabetes. A dietary questionnaire was used to this Perspectives in Diabetes, wine was the most com- gather information about the consumption of beer, wine, monly consumed beverage (92% of total alcohol intake and liquor. Follow-up questionnaires were sent in 1982 for women and 57% for men), and it was associated and 1984. Ninety-eight percent responded to at least one with lower risk of T2D for both women and men. follow-up. A total of 526 incident cases of T2D were Cullmann et al. (6) used oral glucose tolerance tests at confirmed. The risk of diabetes decreased with increasing baseline 8–10 years later to study the development of diabetes.diabetesjournals.org Robertson 33

Table 1—Epidemiologic studies of the association between moderate alcohol consumption and the development of T2D Association between all alcohol drinking Association between wine vs. beer/spirits drinking Author (ref.) and risk of T2D 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 weight Wine more strongly associated with weight loss and less T2D and less T2D Cullmann et al. (6) All alcohol associated with less T20 Wine associated with less T20 in women only in women only All alcohol associated with less prediabetes Wine associated with less prediabetes in women only 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

prediabetes or T2D in a group of 2,070 men and 3,058 associated with protection against the development of women with normal glucose tolerance. The devel- T2D. Àvotresanté! opment of T2D was determined in this same group after enrichment with other subjects who had pre- METABOLIC STUDIES diabetes, yielding groups of 2,217 men and 3,176 As we know, epidemiology is the study of associations women with either normal glucose tolerance or pre- and not ascertainment of cause-effect relationships. diabetes. Of the group with normal glucose tolerance, However, these associations have stimulated prospective 105menand57womendevelopedT2Dand240men metabolic research in humans. Dietary and metabolic and 174 women developed prediabetes. Data were ex- approaches were used to ascertain whether consumption amined before and after adjustment for confounding of alcohol and wine causes deterioration of carbohydrate variables (age, BMI, tobacco use, physical activity, tolerance (Table 2). Compared with epidemiologic stud- family history of diabetes, and education). Wine con- ies, the metabolic studies I found were comprised of sumption by men was not associated with either pre- much smaller groups of subjects. Christiansen et al. (9) diabetes or T2D. In women with normal glucose (Table 2) studied T2D subjects who consumed a light tolerance at baseline, a reduced risk of prediabetes was meal containing 300 mL tap water, dry white wine, sweet seen in the high–wine intake group compared with white wine with ethanol added, or dry white wine with occasional drinkers. Beulens et al. (7) investigated the glucose added. No deterioration of glycemic control was association between alcohol consumption and T2D and noted. Gin et al. (10) studied a group of T2D subjects, determined whether it is modified by sex, BMI, and one-third of whom received red wine, tannic acid, or beverage type. They analyzed 455,680 subjects aged ethanol with their midday meal. Meals with wine or 35–70 years from the European Investigation into tannic acid (a component of wine) were associated with Cancer and Nutrition Consortium (26 centers in Den- lower glucose levels after eating compared with meals mark, France, Germany, Italy, the Netherlands, Spain, with ethanol. The authors concluded that the beneficial Sweden, and the U.K.). They were studied with an av- effects of wine might not be mediated by alcohol. Bantle erage follow-up of 9.9 years. The authors reported that et al. (11) assessed the acute effects of wine in T2D moderate alcohol consumption was associated with subjects over 2 days during which they received 240 mL a reduced risk of T2D; wine and fortified wine were wine or grape juice with their evening meals. They also most clearly associated with this reduced risk. Rasouli studied in random order the chronic effects of wine for et al. (8) used data from the Nord-Trøndelag Health 30 days and abstaining from alcohol for 30 days. Survey to determine the incidence of T2D in 90,296 Drinking wine had no effects on fasting glycemia. The adults in relation to alcohol consumption, including authors concluded that people with T2D should not be quantity and frequency of drinking, type of drink, binge discouraged from drinking wine in moderation. Napoli drinking, and alcohol use disorders. Consumption of et al. (12) performed euglycemic-hyperinsulinemic wine rather than beer and spirits was associated with clamps in T2D subjects before and after 2 weeks of red risk reduction of T2D. wine consumption (360 mL daily) and in T2D subjects Comparing the results of these epidemiology stud- who did not drink wine. Insulin-mediated whole-body iesisdifficult at best because they varied widely in glucose disposal improved by 43% after red wine con- design, size, definition of moderate alcohol drinking, sumption but did not change in the control group, sug- and emphasis on weight change. Nonetheless, their gesting that red wine attenuates insulin resistance. message in common is uniform and very clear. Mod- Ceriello et al. (13) explored the possibility that red wine erate drinking of alcohol was not associated with in- consumption reduces oxidative stress produced by meals. creased risk of T2D. Wine drinking specifically was T2D males in random order ingested a standard meal 34 Red Wine and Diabetes Health Diabetes Volume 63, January 2014

Table 2—Metabolic studies of the effects of moderate alcohol consumption on fasting glucose, glucose tolerance, and oxidative 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 wine with 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 with midday meal. Red wine and tannic acid associated with better glucose tolerance 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 days and also abstained from alcohol for 30 days. No effect on fasting glucose

or HbA1c. Napoli et al. (12) 17 Nine T2D subjects studied before and after 2 weeks of drinking 360 mL/day red 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 plus 300 mL red wine. Study of antioxidant activity (TRAP). Meal decreased TRAP; red wine while fasting increased TRAP; red wine with meal negated TRAP decrease. Marfella et al. (14) 115 Subjects who had sustained a first nonfatal MI were randomized to 118 mL red wine or no alcoholic beverage for 1 year. Nitrotyrosine, TNF-a, IL-6, IL-18, and CRP were lower and myocardial performance was higher in red wine group. Koivisto et al. (15) 10 Alcohol (1 g/kg) was given as an apertif before, wine during, and a drink after a meal or an equal amount of mineral water was given with a meal. Drinking alcohol with a meal the evening before slightly but significantly lowered glucose the morning after; no overt hypoglycemia.

withoutwine,300mLredwinewithoutameal,or300mL may improve several measures of carbohydrate and red wine with the meal. Plasma total radical-trapping oxidative metabolism. Some of the information indi- antioxidant parameter (TRAP) was used to evaluate catesthatitisnotthealcoholbutsomethingelseinred plasma antioxidant capacity. TRAP decreased with the wine that provides the beneficial effects. However, an meal alone, increased with red wine alone, and did not importantcaveatisthepossibilityofhypoglycemia, change when red wine was combined with the meal. The especially in elderly people taking oral hypoglycemic authors concluded that the meal caused oxidative stress, drugs or insulin (16). It is well-known that use of al- that red wine reduced oxidative stress, and that wine cohol can be hazardous, especially if used excessively, with meals neutralized meal-induced oxidative stress. because of the adverse effects of alcohol on counter- Marfella et al. (14) randomized subjects with diabetes regulation (17) and symptom awareness of hypoglyce- who had sustained a first nonfatal myocardial infarction mia, particularly at night while sleeping. This problem (MI) to receive or not receive a moderate daily amount of was recently revisited in an article by Turner et al. (18), red wine for 1 year. At the end of a year, the group who studied men with T1D who drank dry white wine drinking red wine had lower levels of nitrosine, (0.75 g/kg) or mineral water at 9:00 P.M. after eating C-reactive protein (CRP), tumor necrosis factor-a amealat8:00P.M.Inthemorning,fastingandpost- (TNF-a), interleukin-6 (IL-6), and IL-8, and improved prandial glucose levels were significantly lower after cardiac function. They concluded that moderate red wine consumption of wine the night before, and some sub- accompanying meals may prevent complications after MI jects required treatment for hypoglycemia after break- in T2D. Koivisto et al. (15) studied the effect of alcohol fast the following morning. This finding was associated (1 g/kg as an aperitif before, wine during, and a drink with reduced nocturnal growth hormone levels, which after a meal) in T2D using mineral water as a compara- might have contributed to increased insulin sensitivity. tor. They found that alcohol was associated with higher postprandial insulin levels with no effect on postprandial BENEFITS OF RED WINE: IS IT THE ALCOHOL OR glucose levels but with slightly lower fasting glucose THE GRAPES? levels the next morning. If, based on these epidemiologic and metabolic data, we Taken together, these metabolic studies strongly accept the proposition that drinking red wine can be suggestthatdrinkingmoderateamountsofwinewith healthful, the next step is to ask what in red wine is re- meals does not cause adverse effects on glycemia and sponsible for its beneficial effects. Is it the alcohol, the diabetes.diabetesjournals.org Robertson 35 grapes, or both? And if it is the grapes, what is in grapes content? If so, which polyphenols, and are they modu- that might be beneficial for people with or at risk for T2D? lators of oxidative stress? And where in the grape are To address these questions, Alberti-Fidanza et al. (19) polyphenols found? However, before we move on to examined the acute effects of lyophilized red wine after more information about polyphenols, the definition of a meal on plasma oxygen radical absorbance capacity moderate drinking and how it relates to a glassful of (ORAC), a measure of antioxidant capacity, in healthy wine needs to be addressed. Obviously, the size of the subjects. The control was a meal without drinking wine glassisahugevariable.Someredwineglassescanhold afterward. The meal without wine decreased ORAC for an entire bottleful of wine! The majority of studies de- 360 min, whereas the meal plus drinking red wine from fine a moderate quantity as 300 cc or 2 glasses of red which alcohol had been removed increased ORAC for 360 wine.Thisisalittlelessthanone-halfofaconventional min. This suggests that meals decrease antioxidant ca- 750-cc bottle of wine, which makes one wonder why pacity, whereas red wine ingredients in the absence of bottle makers chose five as the number glasses a bottle alcohol increase antioxidant capacity. Noguer et al. (20) can fill. However, this no doubt is the origin of the well- studied whether red wine affects antioxidant enzyme known gambit in which one diverts one’s dinner part- activity in blood or blood products. Subjects consumed ner’s attention elsewhere in the restaurant while cadg- a low phenolic diet (to avoid interference from dietary ing the remaining 150 cc. polyphenols) while drinking or not drinking 300 mL red wine every day for a week. The low-polyphenol diet re- GRAPES HAVE SKIN IN THE GAME OF DIABETES duced enzyme activities for superoxide dismutase, cata- HEALTH CARE lase, and glutathione reductase; the same diet combined What are polyphenolic acid and polyphenols? Poly- with red wine increased the activities of these enzymes. phenols are found in plants, especially grapes and berries, The authors posited that the increase in antioxidant and can be defined as macromolecules generally con- enzyme activity was due to the polyphenolic composition taining ,12 phenolic hydroxyl groups with five to six of wine and not its alcohol content. Chiva-Blanch et al. aromatic rings per 1,000 daltons. Polyphenols sport ex- (21) took this line of research important steps further by otic names, such as (in no particular order) phytoalexins, studying a much larger group of subjects and including gallic acid, syningic acid, protocatechuric acid, caffeic the control of a nongrape alcoholic beverage. Men with acid, ferulic acid, stilbenes, flavonoids, quercetin, high cardiovascular risk were randomized in a crossover myricetin, kamempferol, rutin, catechin, delphinidin, trial during which all received red wine (272 mL, 30 g malvidin, etc. Processing these names is challenging alcohol, 798 mg polyphenols/day), the equivalent enough to tempt one to reach for a glass of sangiovese. amount of dealcoholized red wine (272 mL, 1.14 g One of these names that you will readily recognize is alcohol, 733 mg polyphenols/day), and gin (100 mL, 30 g resveratrol of the stilbene group, commonly discussed alcohol) for 4-week periods. Fasting glucose levels innewspapersandontelevisionshows.Accordingto remained constant throughout the study. Compared Wikipedia, this less-than-intuitive name comes from the with baseline values, fasting insulin levels decreased fact that resveratrol is a resorcinol derivative coming slightly but significantly during the periods of drinking from a Veratrum species(25).Ifyouareinthemoodto red wine and dealcoholized red wine but not gin. The read an incredibly large amount of information about insulin data were used to calculate homeostasis model plants and polyphenols, I refer you to several reviews assessment of insulin resistance values, which led the I thought were encyclopedic (26) or succinct (1,27). authors to conclude that the nonalcoholic fraction of Many mechanisms of actions of polyphenols have been red wine contains polyphenols, which decrease insulin proposed, but the one that recurrently appears in the resistance. Nakamura et al. (24) studied subjects with scientificliteratureistheroleofpolyphenolsas T2D and nephropathy who were randomly assigned to antioxidants. Paganga et al. (22) reported that the drink 118 mL red wine or white wine daily for 6 antioxidant activities of 1 glass (150 mL) red wine is months. A third group with T2D and nephropathy did equivalent to 2 cups of tea, 3.5 glasses of black currant not drink wine. Urinary 8-hydroxydeoxyguanosine was juice, 3.5 (500 ml) glasses of beer, 4 apples, 5 portions measured as a marker of oxidative stress, and urinary of onion, 5.5 portions of eggplant, 7 glasses of orange liver-type fatty acid–binding protein was measured as juice, 12 glasses of white wine, and 20 glasses of a marker for deteriorating renal function. The subjects apple juice. Hence, the often-heard comment that red who drank red wine had a reduction of these two wine provides excellent protection against oxidative markers at 3 and 6 months of study, whereas the group stress. drinking white wine did not. The authors concluded Tomé-Carneiro et al. (28) studied subjects undergoing that the renoprotective effect of red wine may be due in primary prevention of cardiovascular disease in a triple- part to its ability to reduce oxidative stress. blinded, randomized, parallel, dose-response, placebo- These four studies point toward the beneficial effects controlled, 1-year follow-up trial of placebo versus grape of red wine being provided not by its alcoholic content supplement containing 8 mg resveratrol (a polyphenol) but by something else. Is it the polyphenolic acid versus grape supplement lacking resveratrol. They 36 Red Wine and Diabetes Health Diabetes Volume 63, January 2014 observed at 1 year that the resveratrol-rich grape supple- fermentation products of the “must,” which is the juice ment decreased high-sensitivity CRP, TNF-a,plasminogen pressed from the grape, the fruit of the genus Vitis. activator inhibitor type 1, and IL-6–to–IL-10 ratio. They Fermentation produces a variety of chemical changes in suggested that grape-derived resveratrol as a dietary in- the must, so wine is not a simple grape juice with tervention could complement methods conventionally used ethanol added. Red wine is left in contact with the must in the primary prevention of cardiovascular disease. for longer periods of time than white wine. The longer However, one should not assume that resveratrol is the the must is exposed to the skins, seeds, and stems of only or even the principal antioxidant in red wine. German the grapes, the more polyphenols are extracted into the and Walzem (1) reported that the total phenolic acids and juice and the more antioxidant activity is contained in polyphenols in red wine is 900–2,500 mg/L. Of these, the the wine. This no doubt is why many wine drinkers concentration of flavonoids is 750–1,060 mg/L and con- believe choosing red is a must. sists of flavonols, flavanols, and anthrocyanins. The highest polyphenol concentrations in these three sub- WHAT DOES PROTECTION AGAINST OXIDATIVE groups are, respectively, quercetin, procyanidins, and STRESS HAVE TO DO WITH PROTECTION malvidin 3-monoglucaside. The nonflavonoids have a con- AGAINST DIABETES? centration of 240–500 mg/L and include hydroxybenzoic Oxidative stress is a topic that chemists, especially food 2 acids, hydroxycinnamic acids, and stilbene. The highest chemists, love. They find moieties like O2 , $OH, H2O2, 2 concentrations in these three subgroups, respectively, are and ONOO fascinating, if not endearing. They teach us protocatechuric acid, cis-/trans-caftaric acid, and trans- that reactive oxygen species (ROS), such as the ones just resveratrol. But resveratrol is at the bottom of the entire listed, are two-edged swords. In small concentrations, list in terms of concentration in red wine . . . a pitiful 1.0 ROS are good things because they enhance physiological mg/L (1,23), which makes one wonder why it gets all the and cellular function. In excess concentrations, however, attention. One review (27) suggests that it may be due to they cause havoc in cells. This is termed oxidative stress, information published in the last decade suggesting that which, as its name implies, is not a good thing. The resveratrol is an inhibitor of cyclooxygenase and an acti- complications of T2D have long been associated with vator of sirtuin enzymes. Regarding this point, Poulsen chronic oxidative stress. Excessive circulating glucose et al. (29) reported a study in which 24 obese men were concentrations spilling over into a variety of metabolic randomized in a double-blinded, placebo-controlled fashion pathways form increasing amounts of ROS, which in to receive either high-dose oral resveratrol or placebo for excess destroy membranes and compartments in the 4weeks.Theyfoundnosignificant effect of resveratrol on tissues in which they are formed. This risky state of a host of physical and metabolic parameters. However, affairs is particularly true in the b-cell, which for un- Timmers et al. (30) and Brasnyó et al. (31) reported that known reasons does not contain two major antioxidants resveratrol supplementation was associated with an im- (catalase and glutathione peroxidase) (34,35). Thus, the proved homeostasis model assessment index, sug- b-cell is left without the major protection that other gesting increased insulin sensitivity. Bhatt et al. (32) tissues have against accumulation of H2O2 and in- studied 62 subjects with T2D subjects using oral hy- tracellular peroxides. b-Cells do contain superoxide dis- poglycemic agents who were randomized into an in- mutases (SODs), but this doesn’t help much because tervention group receiving resveratrol and a control SODs, although classified as antioxidant enzymes, ca- group not receiving resveratrol. The former group tabolize superoxide into the oxidant H2O2, thereby act- experienced a slight but statistically significant de- ing like a pro-oxidant enzyme. crease in mean HbA1c level. Rytter et al. (33) reported In T2D, this all comes down to the issue of excess a study in which 47 subjects with T2D were random- glycemia bathing tissues and creating ROS, which in ized in a double-blind, placebo-controlled study of the excess can damage organs, including retina, kidney, effects of antioxidant supplements (unfortunately, nerves, vascular tissue, and b-cells (36,37). The patho- resveratrol was not included) on blood levels of glucose genesis of T2D by consensus originates as a polygenic and HbA1c and found no differences. Importantly, they disease amplified by epigenetic influences, such as en- also observed no effects of the supplements on markers vironmental oxidants and obesity with associated in- of oxidative stress, which raises the question of sulin resistance, to damage b-cells, thereby causing whether the concentrations of supplements they used impaired glucose tolerance and early diabetes. The glu- were sufficiently high to have effects on metabolic cose toxicity hypothesis holds that continual exposure parameters. I did not find reports of comprehensive to high postprandial glucose levels over time steadily biochemical comparisons of the antioxidant potencies generates excess ROS that constantly nibble away at of the various polyphenolic acids found in red wine, cells and their normal function (38). Red wine comes which could be a more important factor than their total into the picture of T2D because it contains antioxidants concentrations. that can be used as an ancillary buffer against the oxi- Finally, where in red grapes are polyphenols found? dative stress caused by the ingestion of a meal or en- Here’stheskinny:Wineiscomposedofyeast vironmental toxins. diabetes.diabetesjournals.org Robertson 37

CONCLUSIONS adults: results from the Nord-Trøndelag Health Study. Diabet Med 2013; – From my perspective, the articles that I have read 30:56 64 strongly suggest that drinking red wine in moderation 9. Christiansen C, Thomsen C, Rasmussen O, et al. Wine for type 2 diabetic – has no adverse effects on people with T2D. Moreover, patients? Diabet Med 1993;10:958 961 red wine may have a preventive effect for people at risk 10. Gin H, Rigalleau V, Caubet O, Masquelier J, Aubertin J. Effects of red wine, for T2D. Overall, the metabolic studies of humans are tannic acid, or ethanol on glucose tolerance in non-insulin-dependent di- consistent with the epidemiologic data, i.e., no harmful abetic patients and on starch digestibility in vitro. Metabolism 1999;48: – effects and possibly beneficial effects of red wine. In- 1179 1183 terestingly, the skin of the grape, rather than the alcohol 11. Bantle AE, Thomas W, Bantle JP. Metabolic effects of alcohol in the form of – or juice in red wine, is the source of polyphenols, and wine in persons with type 2 diabetes mellitus. Metabolism 2008;57:241 their antioxidant effects may play a role in the beneficial 245 effects of red wine. Red wine has 12-fold higher levels of 12. Napoli R, Cozzolino D, Guardasole V, et al. Red wine consumption improves polyphenols than white wine and so has a clear edge on insulin resistance but not endothelial function in type 2 diabetic patients. – antioxidant potency. The actual mechanism of action of Metabolism 2005;54:306 313 red wine has been popularly suggested to involve 13. Ceriello A, Bortolotti N, Motz E, et al. Meal-generated oxidative stress in – resveratrol, but the contention that this polyphenol is diabetes. The protective effect of red wine. Diabetes Care 1999;22:2084 exclusively involved does not stand up to scientificev- 2085 idence. This intriguing health-related area is ripe for 14. Marfella R, Cacciapuoti F, Siniscalchi M, et al. Effect of moderate red wine clinical and basic research efforts designed to more intake on cardiac prognosis after recent acute myocardial infarction of – preciselyidentifywhichofthemanypolyphenolicacids subjects with type 2 diabetes mellitus. Diabet Med 2006;23:974 981 in red wine may be playing a role in the protective 15. Koivisto VA, Tulokas S, Toivonen M, Haapa E, Pelkonen R. Alcohol with mechanism(s) involved and, beyond that, the full elu- a meal has no adverse effects on postprandial glucose homeostasis in – cidation of these mechanism(s). You may want to get diabetic patients. Diabetes Care 1993;16:1612 1614 yourownskininthisgame.Whilethinkingaboutit,sit 16. Burge MR, Zeise TM, Sobhy TA, Rassam AG, Schade DS. Low-dose ethanol back and relax with two glassfuls of your favorite red predisposes elderly fasted patients with type 2 diabetes to sulfonylurea- – wine without fear. It may be that one significant mech- induced low blood glucose. Diabetes Care 1999;22:2037 2043 anism of wine’sbeneficial effects is just that. 17. Wilson NM, Brown PM, Juul SM, Prestwich SA, Sönksen PH. Glucose relaxing with good friends during a savory meal with turnover and metabolic and hormonal changes in ethanol-induced hypo- – a great cabernet. 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 evening alcohol consumption on next-morning glucose control in type 1 diabetes. Duality of Interest. No potential conflicts of interest relevant to this Diabetes Care 2001;24:1888–1893 article were reported. 19. Alberti-Fidanza A, Burini G, Antonelli G, Murdolo G, Perriello G. Acute effects of lyophilised red wine on total antioxidant capacity in healthy References volunteers. Diabetes Nutr Metab 2003;16:65–71 1. German JB, Walzem RL. The health benefits of wine. Annu Rev Nutr 2000; 20. 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