OBJECTIVE

Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes. This reduced risk might be explained by improved insulin sensitivity or improved glycemic status, but results of intervention studies on this relation are inconsistent. The purpose of this study was to conduct a systematic review and meta-analysis of intervention studies investigating the effect of alcohol consumption on insulin sensitivity and glycemic status.

RESEARCH DESIGN AND METHODS

PubMed and Embase were searched up to August 2014. Intervention studies on the effect of alcohol consumption on biological markers of insulin sensitivity or glycemic status of at least 2 weeks' duration were included. Investigators extracted data on study characteristics, outcome measures, and methodological quality.

RESULTS

Fourteen intervention studies were included in a meta-analysis of six glycemic end points. Alcohol consumption did not influence estimated insulin sensitivity (standardized mean difference [SMD] 0.08 [−0.09 to 0.24]) or fasting glucose (SMD 0.07 [−0.11 to 0.24]) but reduced HbA1c (SMD −0.62 [−1.01 to −0.23]) and fasting insulin concentrations (SMD −0.19 [−0.35 to −0.02]) compared with the control condition. Alcohol consumption among women reduced fasting insulin (SMD −0.23 [−0.41 to −0.04]) and tended to improve insulin sensitivity (SMD 0.16 [−0.04 to 0.37]) but not among men. Results were similar after excluding studies with high alcohol dosages (>40 g/day) and were not influenced by dosage and duration of the intervention.

CONCLUSIONS

Although the studies had small sample sizes and were of short duration, the current evidence suggests that moderate alcohol consumption may decrease fasting insulin and HbA1c concentrations among nondiabetic subjects. Alcohol consumption might improve insulin sensitivity among women but did not do so overall.

Moderate alcohol consumption, compared with abstaining and heavy drinking, is related to a reduced risk of type 2 diabetes (1,2). Although the risk is reduced with moderate alcohol consumption in both men and women, the association may differ for men and women. In a meta-analysis, consumption of 24 g alcohol/day reduced the risk of type 2 diabetes by 40% among women, whereas consumption of 22 g alcohol/day reduced the risk by 13% among men (1).

The association of alcohol consumption with type 2 diabetes may be explained by increased insulin sensitivity, anti-inflammatory effects, or effects of adiponectin (3). Several intervention studies have examined the effect of moderate alcohol consumption on these potential underlying pathways. A meta-analysis of intervention studies by Brien et al. (4) showed that alcohol consumption significantly increased adiponectin levels but did not affect inflammatory factors. Unfortunately, the effect of alcohol consumption on insulin sensitivity has not been summarized quantitatively. A review of cross-sectional studies by Hulthe and Fagerberg (5) suggested a positive association between moderate alcohol consumption and insulin sensitivity, although the three intervention studies included in their review did not show an effect (68). Several other intervention studies also reported inconsistent results (9,10). Consequently, consensus is lacking about the effect of moderate alcohol consumption on insulin sensitivity. Therefore, we aimed to conduct a systematic review and meta-analysis of intervention studies investigating the effect of alcohol consumption on insulin sensitivity and other relevant glycemic measures.

This study was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews) Statement guidelines for the reporting of systematic reviews and meta-analysis of intervention studies. The PRISMA checklist and the protocol for this study are provided in the Supplementary Data.

Data Sources and Searches

A literature search was conducted in PubMed MEDLINE and Embase for relevant intervention studies published up to August 2014. A prespecified search string including search terms on alcohol, consumption, and glycemic measures was used for PubMed and Embase (Supplementary Data). References and related citations of articles were screened to identify other relevant articles. The exposure of interest was (moderate) alcohol consumption and the primary outcome measure, insulin sensitivity. All estimates of insulin sensitivity were included, which were indices from direct measures (e.g., hyperinsulinemic-euglycemic glucose clamp [HEGC]) and indirect measures of insulin sensitivity (e.g., the frequently sampled intravenous glucose tolerance test [FSIVGTT] and oral glucose tolerance test [OGTT]). HOMA of insulin resistance (HOMA-IR) was also included, which is based on fasting insulin and glucose levels and, therefore, primarily reflects hepatic insulin resistance (11). Other relevant outcome measures taken into account were fasting insulin, fasting glucose, and hemoglobin A1c (HbA1c). HbA1c reflects average plasma glucose levels over the past 8–12 weeks and is therefore used as a measure of glycemic status (12).

Study Selection

Relevant studies were selected by two researchers (A.L.J.H., J.W.J.B.) during a multiphase process on the basis of the following inclusion criteria: trials with an alcohol intervention, relevant outcome measures as previously described, intervention period of at least 2 weeks, and written in English or Dutch. We excluded studies of individuals with (a history of) alcoholism or heavy drinkers (individuals consuming ≥60 g alcohol for at least 1 day per week) and animal studies. No publication date or status restrictions were imposed. In the first phase, titles of all retrieved studies were screened to select articles with a relevant subject; the abstracts of these articles were judged on relevance in the next phase. If judged relevant, the full text was studied in the third phase to determine whether the article was eligible for inclusion. When discrepancies occurred about the inclusion of a particular article, a third author (K.J.M. or I.C.S.) was consulted.

Data Extraction and Quality Assessment

From the included studies, sample size, participant characteristics, inclusion and exclusion criteria, study design, duration of intervention, and specific outcome measures were extracted on a prespecified form. Detailed information about the alcohol intervention (e.g., dosage, type, frequency, duration) was described. If a study did not report the grams of alcohol per unit, this was calculated based on the amount in milliliters given to the subjects and the alcohol volume of the beverage [g alcohol = (mL × %v/v) × 0.8, where %v/v is the percentage of alcohol volume per total volume]. Authors of included articles were contacted if further information was required (1315).

To assess the quality of the studies, aspects such as randomization procedures, compliance with the intervention, and dropout rates were extracted. Randomization and the inclusion of an alcohol-free control group were regarded as the most important criteria to decide whether a study had sufficient quality. If these criteria were not met, the studies were excluded from further meta-analyses. Because randomization of crossover studies may be less important than randomization of parallel studies, we also conducted a sensitivity analysis including nonrandomized crossover studies. Because blinding of participants to the alcohol intervention is of uncertain effectiveness, this criterion was not regarded as essential for inclusion. To assess the quality of the included studies, the 5-point Jadad scale was used (16).

Data Synthesis and Analysis

The mean and SD of the outcome variables at the end of the alcohol intervention period and control period were extracted from the articles. If SEs were reported, we used the equation SD = SE × square root of the number of subjects. The mean effects of the various studies measuring the insulin sensitivity index (ISI), HOMA-IR, insulin, glucose, or HbA1c were pooled in a meta-analysis and shown in a forest plot. To combine the studies measuring ISI and HOMA-IR in one meta-analysis, the inverted HOMA-IR (1/HOMA-IR) was calculated using the delta method.

Heterogeneity between studies was tested using χ2 and I2 statistics. If χ2 and I2 showed no evidence for heterogeneity (I2 < 30%) (17), analyses were conducted using the inverse variance fixed-effects model for pooling the studies. Otherwise, the DerSimonian and Laird random-effects model was used. The mean outcomes for insulin, glucose, and insulin sensitivity were assessed using different methods and needed to be standardized. Therefore, Cohen d was used to calculate the standardized mean difference (SMD), which is the mean difference between the intervention and control group divided by the pooled SD.

In sensitivity analyses, the effect of moderate alcohol consumption on the reported outcomes was determined by excluding studies with high alcohol dosages (>40 g/day). Furthermore, if more than one intervention arm was tested in a study, we combined the outcomes (17). Additionally, analyses were performed excluding studies potentially causing heterogeneity to determine their effect on the results.

In a meta-regression, the influences of alcohol dosage and duration of the intervention on the results were tested. The influence of type of alcoholic beverage was not assessed due to too few studies to stratify by alcoholic beverage. Because only two studies used the gold standard HEGC to estimate insulin sensitivity (11), we tested with a meta-regression whether the effect of alcohol on insulin sensitivity differed between these studies.

Because the association of alcohol consumption with type 2 diabetes differs for men and women, we conducted sex-stratified analyses. Effect modification by sex was tested in a meta-regression for insulin sensitivity.

Potential publication bias was examined by visual inspection of the funnel plot and by the Egger and Begg statistical tests. In case evidence of publication bias was found, we used the trim and fill method by Duval and Tweedie (18) to calculate a pooled SMD based on filled data to adjust for publication bias. The level of significance was set at P < 0.05. Analyses were performed with the STATA meta-procedure (Stata 10.0).

In total, 4,991 titles were found through the database searches and 24 through additional methods (Supplementary Fig. 1). After screening of titles and abstracts, 46 articles remained eligible and the full text was assessed. Finally, 22 articles met criteria for inclusion in the qualitative synthesis.

Study Characteristics

Descriptive data of the included studies are summarized in Table 1. Of the 22 studies, 15 used a crossover design and 7 a parallel design. The intervention duration of the studies ranged from 2 to 12 weeks, with an average duration of 5.6 weeks for ISI, 4.2 weeks for HOMA-IR, 7.2 weeks for insulin, 5.9 weeks for glucose, and 4.3 weeks for HbA1c. Two studies did not use an alcohol-free control group (14,19). The dosage of alcohol varied from 10 to 70 g/day of which one study used >40 g/day (20). ISI was measured by six studies, of which two used the gold standard HEGC (10,21) and four used indirect measures of insulin sensitivity (based on OGTT, FSIVGTT, or fasting levels) (8,9,22,23). HOMA-IR was measured by four studies (15,2426). Seven studies were performed by the same institute (10,2126), but they were treated as independent because they included different subjects.

Table 1

Characteristics of studies included in this systematic review and meta-analysis on the effect of alcohol consumption on insulin sensitivity

Study referenceDesignParticipantsParticipant characteristicsInterventionAlcohol dosage (g/day)Intervention period (weeks)Outcome measureIn meta-analysis
Bantle 2008 (31Randomized crossover 17 diabetic men and women Age 64 (45–82) years
BMI 31.7 (21.3–41.2) kg/m2 Abstinence or white/red wine during dinner 18 Insulin, glucose, HbA1c No* 
Beulens 2006 (21Randomized crossover 17 healthy men with waist circumference >94 cm Age 53 (9) years
BMI 29.1 (4.2) kg/m2
Insulin 10.7 (5.6) units/L Red wine or dealcoholized red wine with dinner 40 ISI (HEGC) Yes 
Beulens 2007 (23Randomized crossover 19 healthy lean or overweight men Lean:
Age 21 (2) years
BMI 21.4 (2.0) kg/m2
Insulin 4.7 (1.2) units/L
Overweight:
Age 28 (6) years
BMI 30.1 (3.4) kg/m2
Insulin 11.0 (5.4) units/L Whisky or mineral water 32 ISI (OGTT), HbA1c Yes 
Beulens 2008 (22Randomized crossover 20 healthy lean or overweight men Lean:
Age 19 (2) years
BMI 20.1 (1.0) kg/m2
Overweight:
Age 21 (2) years
BMI 31.3 (3.9) kg/m2 Beer or alcohol-free beer during dinner 40 ISI (OGTT) Yes 
Bhathena 1995 (27Randomized crossover 37 healthy premenopausal women Age 30 (7) years
BMI 24.4 (4.6) kg/m2 Ethanol mixed with fruit juice or soft drink after dinner 30 12 Insulin Yes 
Cesena 2011 (28Parallel (one arm) 42 healthy men and women Age 46 (9) years
BMI 25.1 (2.8) kg/m2 Abstinence or red wine during dinner 24 Glucose No 
Chiva-Blanch 2013 (15Randomized crossover 52 healthy and 15 diabetic men Age 60 (8) years
BMI 29.6 (3.9) kg/m2 Gin, red wine, or dealcoholized red wine 30 HOMA-IR, insulin, glucose Yes 
Contaldo 1989 (20Randomized crossover 8 healthy men BMI 25.4 (1.4) kg/m2 Abstinence or red wine during dinner 75 Insulin, glucose Yes 
Cordain 1997 (13Randomized crossover 14 healthy men Age 32 (9) years Abstinence or wine 28 Insulin, glucose No 
Cordain 2000 (8Randomized crossover 20 sedentary and overweight premenopausal women BMI 29.8 (2.2) kg/m2
Insulin 8.6 (3.3) units/L Abstinence or red wine 20 10 ISI (FSIVGTT), insulin, glucose Yes 
Davies 2002 (9Randomized crossover 51 healthy postmenopausal women Age 60 (8) years
BMI 27.4 (5.7) kg/m2
Insulin 6.5 (5.7) units/L Alcohol or isocaloric beverage 15 or 30 ISI (MFFM), insulin, glucose Yes 
Flechtner-Mors 2004 (52Randomized parallel 40 overweight men and women Age 48 (11) years
BMI 34.2 (6.4) kg/m2 Grape juice or white wine during meals 17 12 Insulin, glucose Yes 
Joosten 2008 (24Randomized crossover 36 healthy postmenopausal women Age 57 (4) years
BMI 25.4 (3.3) kg/m2
Insulin 37.4 (12.6) pmol/L White wine or white grape juice daily during dinner 25 HOMA-IR, insulin, glucose, HbA1c Yes 
Joosten 2011 and 2014 (25,26Randomized crossover 24 healthy premenopausal women Age 24 (4) years
BMI 22.2 (1.6) kg/m2
Insulin 41.7 (16.0) pmol/L Beer or alcohol-free beer during dinner 26 HOMA-IR, insulin, glucose, HbA1c Yes 
Joosten 2012 and 2014 (53,26Randomized crossover 24 healthy men Age 26 (3) years
BMI 24 (3) kg/m2 Vodka and orange juice or orange juice during dinner 30 HOMA-IR, insulin, glucose Yes 
Kim 2009 (29Parallel 20 nondiabetic, insulin-resistant men and women Age 54 (7) years
BMI 32 (5) kg/m2 Abstinence or vodka or red wine during dinner 30 Steady-state plasma glucose, glucose No 
Lavy 1994 (14Randomized parallel 20 healthy men — Red or white wine 40 Glucose No 
Queipo-Ortuño 2012 (33Randomized crossover 10 healthy men Age 48 (2) years
BMI 27.6 (3.2) kg/m2 Gin, red wine, or dealcoholized red wine 30 Glucose Yes 
Romeo 2008 (30Parallel (one arm) 57 healthy women and men  Women:
Age 38 (9) years
BMI 24.4 (3.5) kg/m2
Men:
Age 35 (6) years
BMI 25.5 (2.4) kg/m2 Abstinence or beer during the meal 11 (women), 22 (men) Glucose No 
Shai 2007 (32Randomized parallel (multicenter) 91 diabetic men and women Age 62 (6) years
BMI 30.1 (4.6) kg/m2 Wine or nonalcoholic beer during dinner 13 12 Glucose, HbA1c No* 
Sierksma 2004 (10Randomized crossover 23 healthy men Age 52 (5) years
BMI 26.7 (3.0) kg/m2
Insulin 8.9 (8.8) units/L Whisky or tap water during dinner 40 2.5 ISI (HEGC) Yes 
Zheng 2012 (19Randomized parallel 45 healthy men and women TFL:
Age 24 (2) years
BMI 21.3 (1.6) kg/m2
TCL:
Age 24 (1) years
BMI 21.1 (2.2) kg/m2 TFL or TCL 10 HOMA-IR, insulin, glucose No 
Study referenceDesignParticipantsParticipant characteristicsInterventionAlcohol dosage (g/day)Intervention period (weeks)Outcome measureIn meta-analysis
Bantle 2008 (31Randomized crossover 17 diabetic men and women Age 64 (45–82) years
BMI 31.7 (21.3–41.2) kg/m2 Abstinence or white/red wine during dinner 18 Insulin, glucose, HbA1c No* 
Beulens 2006 (21Randomized crossover 17 healthy men with waist circumference >94 cm Age 53 (9) years
BMI 29.1 (4.2) kg/m2
Insulin 10.7 (5.6) units/L Red wine or dealcoholized red wine with dinner 40 ISI (HEGC) Yes 
Beulens 2007 (23Randomized crossover 19 healthy lean or overweight men Lean:
Age 21 (2) years
BMI 21.4 (2.0) kg/m2
Insulin 4.7 (1.2) units/L
Overweight:
Age 28 (6) years
BMI 30.1 (3.4) kg/m2
Insulin 11.0 (5.4) units/L Whisky or mineral water 32 ISI (OGTT), HbA1c Yes 
Beulens 2008 (22Randomized crossover 20 healthy lean or overweight men Lean:
Age 19 (2) years
BMI 20.1 (1.0) kg/m2
Overweight:
Age 21 (2) years
BMI 31.3 (3.9) kg/m2 Beer or alcohol-free beer during dinner 40 ISI (OGTT) Yes 
Bhathena 1995 (27Randomized crossover 37 healthy premenopausal women Age 30 (7) years
BMI 24.4 (4.6) kg/m2 Ethanol mixed with fruit juice or soft drink after dinner 30 12 Insulin Yes 
Cesena 2011 (28Parallel (one arm) 42 healthy men and women Age 46 (9) years
BMI 25.1 (2.8) kg/m2 Abstinence or red wine during dinner 24 Glucose No 
Chiva-Blanch 2013 (15Randomized crossover 52 healthy and 15 diabetic men Age 60 (8) years
BMI 29.6 (3.9) kg/m2 Gin, red wine, or dealcoholized red wine 30 HOMA-IR, insulin, glucose Yes 
Contaldo 1989 (20Randomized crossover 8 healthy men BMI 25.4 (1.4) kg/m2 Abstinence or red wine during dinner 75 Insulin, glucose Yes 
Cordain 1997 (13Randomized crossover 14 healthy men Age 32 (9) years Abstinence or wine 28 Insulin, glucose No 
Cordain 2000 (8Randomized crossover 20 sedentary and overweight premenopausal women BMI 29.8 (2.2) kg/m2
Insulin 8.6 (3.3) units/L Abstinence or red wine 20 10 ISI (FSIVGTT), insulin, glucose Yes 
Davies 2002 (9Randomized crossover 51 healthy postmenopausal women Age 60 (8) years
BMI 27.4 (5.7) kg/m2
Insulin 6.5 (5.7) units/L Alcohol or isocaloric beverage 15 or 30 ISI (MFFM), insulin, glucose Yes 
Flechtner-Mors 2004 (52Randomized parallel 40 overweight men and women Age 48 (11) years
BMI 34.2 (6.4) kg/m2 Grape juice or white wine during meals 17 12 Insulin, glucose Yes 
Joosten 2008 (24Randomized crossover 36 healthy postmenopausal women Age 57 (4) years
BMI 25.4 (3.3) kg/m2
Insulin 37.4 (12.6) pmol/L White wine or white grape juice daily during dinner 25 HOMA-IR, insulin, glucose, HbA1c Yes 
Joosten 2011 and 2014 (25,26Randomized crossover 24 healthy premenopausal women Age 24 (4) years
BMI 22.2 (1.6) kg/m2
Insulin 41.7 (16.0) pmol/L Beer or alcohol-free beer during dinner 26 HOMA-IR, insulin, glucose, HbA1c Yes 
Joosten 2012 and 2014 (53,26Randomized crossover 24 healthy men Age 26 (3) years
BMI 24 (3) kg/m2 Vodka and orange juice or orange juice during dinner 30 HOMA-IR, insulin, glucose Yes 
Kim 2009 (29Parallel 20 nondiabetic, insulin-resistant men and women Age 54 (7) years
BMI 32 (5) kg/m2 Abstinence or vodka or red wine during dinner 30 Steady-state plasma glucose, glucose No 
Lavy 1994 (14Randomized parallel 20 healthy men — Red or white wine 40 Glucose No 
Queipo-Ortuño 2012 (33Randomized crossover 10 healthy men Age 48 (2) years
BMI 27.6 (3.2) kg/m2 Gin, red wine, or dealcoholized red wine 30 Glucose Yes 
Romeo 2008 (30Parallel (one arm) 57 healthy women and men  Women:
Age 38 (9) years
BMI 24.4 (3.5) kg/m2
Men:
Age 35 (6) years
BMI 25.5 (2.4) kg/m2 Abstinence or beer during the meal 11 (women), 22 (men) Glucose No 
Shai 2007 (32Randomized parallel (multicenter) 91 diabetic men and women Age 62 (6) years
BMI 30.1 (4.6) kg/m2 Wine or nonalcoholic beer during dinner 13 12 Glucose, HbA1c No* 
Sierksma 2004 (10Randomized crossover 23 healthy men Age 52 (5) years
BMI 26.7 (3.0) kg/m2
Insulin 8.9 (8.8) units/L Whisky or tap water during dinner 40 2.5 ISI (HEGC) Yes 
Zheng 2012 (19Randomized parallel 45 healthy men and women TFL:
Age 24 (2) years
BMI 21.3 (1.6) kg/m2
TCL:
Age 24 (1) years
BMI 21.1 (2.2) kg/m2 TFL or TCL 10 HOMA-IR, insulin, glucose No 

Data are mean (SD) or (range) unless otherwise indicated. MFFM, whole-body glucose disposal rate normalized to fat-free mass; TCL, traditional Chinese liquor; TFL, tea-flavor liquor.

Reason for exclusion from meta-analysis:

*

participants with type 2 diabetes,

no randomized design,

no control group.

Quality Assessment

The results of the quality assessment are shown in Supplementary Table 1. Of the 22 studies included in the qualitative synthesis, 4 did not report the measurement of compliance to the intervention (9,14,20,27). Blinding of the researcher was not reported or not conducted in any of the studies. Dropout rates were described in 18 studies. The studies scored between 1 and 3 points on the Jadad scale (range 0–5). Of the 22 studies, 2 were excluded from the meta-analysis because they did not include an alcohol-free control group (14,19), and 4 were excluded because they did not have a randomized design (13,2830). Because only two studies included subjects with type 2 diabetes, these studies were excluded as well (31,32). One study included both healthy and type 2 diabetic subjects, and from this study, only data from healthy subjects were included (15). Overall, 14 studies were included in the meta-analysis (Table 1 and Supplementary Table 1).

Meta-analysis

The number of included studies in the analysis was 7 for ISI, 5 for HOMA-IR, 9 for insulin, 10 for glucose, and 3 for HbA1c. The forest plots on insulin sensitivity and glycemic status are shown in Figs. 13.

Figure 1

Forest plot of meta-analysis of the effect of alcohol consumption on insulin sensitivity. Data are pooled SMDs with 95% CIs and are calculated with exclusion of the results of the two study arms of Chiva-Blanch et al. (15) because they induced heterogeneity.

Figure 1

Forest plot of meta-analysis of the effect of alcohol consumption on insulin sensitivity. Data are pooled SMDs with 95% CIs and are calculated with exclusion of the results of the two study arms of Chiva-Blanch et al. (15) because they induced heterogeneity.

Close modal
Figure 2

Forest plots of meta-analysis of the effect of alcohol consumption on fasting insulin (A) and fasting glucose (B). Data are pooled SMDs with 95% CIs. RW, red wine.

Figure 2

Forest plots of meta-analysis of the effect of alcohol consumption on fasting insulin (A) and fasting glucose (B). Data are pooled SMDs with 95% CIs. RW, red wine.

Close modal
Figure 3

Forest plot of meta-analysis of the effect of alcohol consumption on HbA1c. Data are pooled SMDs with 95% CIs.

Figure 3

Forest plot of meta-analysis of the effect of alcohol consumption on HbA1c. Data are pooled SMDs with 95% CIs.

Close modal

Pooled analysis showed no difference in ISI after a period of alcohol consumption compared with no alcohol consumption (SMD 0.06 [−0.13 to 0.26], P = 0.53, test for heterogeneity P = 0.76, I2 = 0%). For HOMA-IR, both the χ2 (P < 0.01) and I2 (97%) statistics demonstrated heterogeneity. In a random-effects model, the pooled SMD was 0.35 [−0.90 to 1.59], indicating no effect of alcohol consumption on HOMA-IR (P = 0.59). Similar results were observed when studies measuring ISI and HOMA-IR were combined (SMD −0.12 [−0.61 to 0.39], P = 0.65). A random-effects model was used because heterogeneity was present (P < 0.01, I2 = 91%). The funnel plot indicated that the results of the intervention arms (i.e., red wine, gin) of Chiva-Blanch et al. (15) were largely responsible for this heterogeneity. Exclusion of this study resulted in an SMD of 0.08 (−0.09 to 0.24, P = 0.35), with no evidence of heterogeneity (P = 0.90, I2 = 0%). Sex-stratified analysis showed different effects in men and women (Psex = 0.018) (Fig. 1). Alcohol consumption tended to increase insulin sensitivity in women (SMD 0.16 [−0.04 to 0.37], P = 0.12) but not in men (SMD −0.30 [−1.23 to 0.64], P = 0.54). In men, heterogeneity was present (P < 0.01, I2 = 95%), and exclusion of the study by Chiva-Blanch et al. resulted in a pooled SMD of −0.07 (−0.34 to 0.20, P = 0.61). However, after exclusion of Chiva-Blanch et al., the pooled SMDs in men and women were no longer significantly different (P = 0.18).

Fasting insulin concentrations were lower after alcohol consumption compared with abstinence, as shown by a pooled SMD of −0.19 (−0.35 to −0.02, P = 0.03) and the test for heterogeneity (P = 0.92, I2 = 0%). Sex-stratified analysis showed that alcohol consumption decreased insulin concentrations in women (SMD −0.23 [−0.41 to −0.04], P = 0.02). Only two studies measured insulin concentrations in men, showing a decrease in insulin levels (SMD −0.13 [−0.62 to 0.36], P = 0.59) (Fig. 2A).

For fasting glucose concentrations, the pooled SMD was 0.07 [−0.11 to 0.24], indicating no effect of alcohol consumption on glucose concentration among individuals without diabetes (P = 0.45, Pheterogeneity = 0.94, I2 = 0%). Similar results were observed when men and women were analyzed separately (Fig. 2B). In women, the SMD was 0.01 (−0.20 to 0.21, P = 0.94); in men, the SMD was 0.14 (−0.24 to 0.53, P = 0.48).

For HbA1c, a random-effects model was used because the I2 statistic indicated evidence for some heterogeneity (I2 = 30%). The pooled SMD was −0.62 (−1.01 to −0.23), showing lower HbA1c concentrations after alcohol consumption compared with no alcohol consumption (P < 0.01) (Fig. 3).

Sensitivity Analyses and Meta-regression

Only the study by Contaldo et al. (20) used a high alcohol dosage (70 g/day) and measured insulin and glucose concentrations. Exclusion of this study from the meta-analysis resulted in generally similar results for insulin (SMD −0.18 [−0.36 to −0.01]) and glucose (SMD 0.06 [−0.12 to 0.23]).

Combining the two intervention arms of the studies by Davies et al. (9) with 15 and 30 g alcohol/day and those of Queipo-Ortuño et al. (33) with red wine and gin resulted in generally similar outcomes. The pooled SMD for insulin sensitivity (ISI and HOMA-IR) was 0.06 (−0.11 to 0.24) overall and 0.15 (−0.08 to 0.38) in women. For insulin, SMD was −0.18 (−0.38 to −0.01) overall and −0.22 (−0.43 to −0.02) in women. Including the nonrandomized crossover study by Cordain et al. (13) resulted in generally similar results for insulin (SMD −0.17 [−0.33 to 0.00]) and glucose (SMD 0.08 [−0.09 to 0.25]).

The meta-regression showed no influence of duration (all Ptrend > 0.60) and/or alcohol dosage (all Ptrend > 0.67) on the pooled SMD of ISI and HOMA-IR and of insulin and glucose. Additionally, the meta-regression showed no differences between results from the studies using the HEGC to measured insulin sensitivity and the other studies (SMD −0.03 for HEGC studies vs. 0.09 for other studies, P = 0.64).

Publication Bias

Results of the Egger and Begg tests showed publication bias for the outcomes of ISI, ISI and HOMA-IR, and glucose (Supplementary Table 2). Visual inspection of the funnel plots showed some asymmetry, which was due to missing results in favor of alcohol treatment from smaller studies (Supplementary Fig. 2). For ISI and HOMA-IR, we calculated an adjusted pooled SMD by using the trim and fill approach by Duval and Tweedie (18). This resulted in four extra study estimates (linear method used) and an adjusted pooled SMD of 0.17 (0.02–0.31, P = 0.03). The trim and fill method shows that without publication bias, the pooled SMD would probably indicate a positive effect of alcohol consumption on insulin sensitivity, whereas the unadjusted SMD did not show an effect (SMD 0.08 [−0.09 to 0.24], P = 0.35). The adjusted results and funnel plot are shown in Supplementary Table 2 and Supplementary Fig. 2.

This meta-analysis shows that moderate alcohol consumption did not affect estimates of insulin sensitivity or fasting glucose levels, but it decreased fasting insulin concentrations and HbA1c. Sex-stratified analysis suggested that moderate alcohol consumption may improve insulin sensitivity and decrease fasting insulin concentrations in women but not in men. The meta-regression suggested no influence of dosage and duration on the results. However, the number of studies may have been too low to detect influences by dosage and duration.

Comparison With Other Studies

The primary finding that alcohol consumption does not influence insulin sensitivity concords with the intervention studies included in the review of Hulthe and Fagerberg (5). This is in contrast with observational studies suggesting a significant association between moderate alcohol consumption and improved insulin sensitivity (34,35). However, the results of these studies might be biased through residual confounding because of their observational nature. Moreover, in contrast to intervention studies, observational studies are not designed to detect a causal relationship. On the other hand, we cannot exclude the possibility that the intervention studies in this review had an insufficient sample size or too short a duration to detect an effect of alcohol consumption on insulin sensitivity (10,21,23,24).

We found lower fasting insulin levels after alcohol consumption. This finding agrees with the inverse relation between alcohol consumption and insulin levels observed in observational studies (3639). However, in the DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort, a longitudinal study, no relation between the average or a change in alcohol consumption and fasting insulin levels was found, but this may be a result of the inclusion of subjects with type 2 diabetes (40). Fasting insulin level is a surrogate marker of insulin sensitivity in healthy subjects, with lower insulin levels indicating higher insulin sensitivity (11,41). Conversely, low insulin levels are a common phenomenon in subjects with type 2 diabetes due to impaired insulin secretion by β-cells. Because we excluded studies in subjects with type 2 diabetes, the results of lower fasting insulin levels may indicate higher insulin sensitivity. Additionally, we observed no change in glucose levels by alcohol consumption, and lower insulin levels coinciding with unchanged glucose levels suggest an improved insulin sensitivity.

The current meta-analysis suggests that men and women might respond differently to a period of alcohol consumption with regard to insulin sensitivity. Subgroup analysis showed that the effect of alcohol consumption on insulin sensitivity was only present among women, but the pooled effects in men and women were not significantly different. These results generally concord with observational studies showing a larger risk reduction of moderate alcohol consumption on risk of type 2 diabetes in women than in men (40% vs. 13%) (1) and with the study by Beulens et al. (42). The studies included in the review by Hulthe and Fagerberg (5), which were mainly cross-sectional, did not find sex differences in alcohol effects.

We observed lower levels of HbA1c in subjects consuming moderate amounts of alcohol compared with abstainers. This has also been shown in several observational studies (39,43,44). Alcohol may decrease HbA1c by suppressing the acute rise in blood glucose after a meal and increasing the early insulin response (45). This would result in lower glucose concentrations over time and, thus, lower HbA1c concentrations. Unfortunately, the underlying mechanism of glycemic control by alcohol is not clearly understood.

Strengths and Weaknesses of the Study

A major strength of this meta-analysis is the inclusion of studies with a randomized controlled design and the inclusion of several complementary end points, providing a comprehensive overview of the evidence on this topic. There are also limitations that warrant consideration. As in any meta-analysis, the strength of the current study is largely determined by the quality and number of the included studies. The results of the quality assessment show that the larger part of the included studies did not report or did not take into account some important aspects, such as blinding. Nevertheless, randomization and the inclusion of an alcohol-free control group were the most important quality factors for this review, and only six studies did not satisfy those criteria. Compliance was measured in most studies (17 of 22) but was only reported in 13. However, of these 13 studies, 11 reported good or excellent compliance, suggesting that low compliance did not influence the results of the studies. Second, the analysis of several different outcomes resulted in inclusion of a small number of studies for certain end points, such as HbA1c. Third, only two studies used the gold standard HEGC to estimate insulin sensitivity (11). Because this may lead to inconsistency in the results, we standardized the results of the different studies using Cohen d. However, the results from the studies using HEGC were similar to the other intervention studies, and no significant heterogeneity was present except for the combined meta-analysis of ISI and HOMA-IR. This was due to the study of Chiva-Blanch et al. (15), who reported a relatively small variation in HOMA-IR, causing a relatively large SMD. Exclusion of this study removed heterogeneity without changing the effect. Fourth, because most studies used a crossover design, a carryover effect might have influenced the outcomes. Another limitation was the short duration and small sample sizes of the included studies. The average duration of 5.4 weeks may not have been long enough to show detectable differences in insulin sensitivity or glucose status. In addition, effects may change after longer-term intake of alcohol. Therefore, the short-term nature of the included studies does not allow us to draw conclusions on longer-term alcohol consumption.

It is important to note evidence for publication bias for certain outcomes in the current study. The publication bias unexpectedly suggests that smaller studies with positive results are missing. After adjustment for publication bias using the trim and fill method, even a significant increase in insulin sensitivity by alcohol consumption was shown. However, statistical tests for publication bias may yield biased results with small numbers of studies and are prone to heterogeneity (17).

Finally, the results of this research may not be generalizable to all healthy subjects because the selected studies included mainly light to moderate alcohol consumers. Therefore, the period of abstaining from alcohol might also be seen as an intervention, and subjects might have responded differently than alcohol abstainers.

Implications

To draw implications from the current research, the findings need to be placed in a clinical context. In this meta-analysis, we observed that alcohol consumption decreased fasting insulin levels by 0.19, which translates to an ∼11% decrease in insulin (−20 pmol/L) in people with impaired glucose tolerance, as calculated from data of the Diabetes Prevention Program study (46), and a 13% decrease in insulin (−5.2 pmol/L) in normoglycemic people, as calculated from data of the Multiethnic Study of Atherosclerosis (MESA) (47). For comparison, metformin treatment results in a 14% decrease in fasting insulin levels and a 40% lower risk of diabetes versus a control group (48). An 11% reduction of fasting insulin levels after alcohol consumption would result in an ∼30% reduced risk of diabetes, which is in line with the 40% risk reduction observed among women.

The reduced HbA1c concentration found in the current study by alcohol consumption (SMD −0.62) is equal to a 5% reduction in HbA1c concentration in both the MESA and the Diabetes Prevention Program studies (from 5.4% [36 mmol/mol] to 5.1% [33 mmol/mol] and from 5.9% [41 mmol/mol] to 5.6% [38 mmol/mol], respectively) (46,49). The Diabetes Prevention Program study showed that 4 years of metformin medication and a lifestyle intervention both resulted in a reduction in HbA1c of ∼3% (50). Because type 2 diabetes is characterized by hyperglycemia, HbA1c could be seen as a surrogate end point of the disease rather than an intermediate factor in the pathway toward type 2 diabetes. The World Health Organization indeed suggests that a level >6.5% (48 mmol/mol) be used as a cutoff point for diagnosing diabetes (51). In this respect, the current results for HbA1c match with the reduced risk of type 2 diabetes with moderate alcohol consumption. Results of alcohol intake on HbA1c should be carefully interpreted because we included only three intervention studies in the analysis. However, the results suggest that drinking a moderate amount of alcohol is not harmful with regard to insulin sensitivity and glycemic status in healthy adults without type 2 diabetes.

Conclusion

This systematic review and meta-analysis showed that moderate alcohol consumption decreased fasting insulin and HbA1c concentrations among nondiabetic subjects. Alcohol consumption might improve insulin sensitivity among women but did not do so overall. These results may partly explain the lower risk of type 2 diabetes with moderate alcohol consumption found in observational studies. However, more intervention studies with a longer intervention period are necessary to confirm the results.

Funding. I.C.S. and H.F.J.H. were supported by both the Dutch Ministry of Economic Affairs, Agriculture and Innovation and the Dutch Foundation for Alcohol Research, representing Dutch producers of and traders in beer, wine, and spirits and The Netherlands Organization for Applied Scientific Research. Their joint aim is to independently study the health effects of moderate alcohol consumption.

The funding sources had no role in conducting the study, in analyzing or interpreting the study results, or in the decision to submit the manuscript for publication.

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

Author Contributions. I.C.S. contributed to the data extraction and analysis, data interpretation, and writing of the manuscript. A.L.J.H. contributed to the study design, article search and data extraction, data analysis, and data interpretation. H.F.J.H. contributed to the data interpretation. K.J.M. contributed to the study design and data interpretation. J.W.J.B. contributed to the study design, search and data extraction, data analysis, data interpretation, and writing of the manuscript.

Prior Presentation. Parts of this study were presented in abstract form at the Epidemiology and Prevention/Nutrition, Physical Activity and Metabolism 2014 Scientific Sessions of the American Heart Association, San Francisco, CA, 18–21 March 2014, and were presented orally at the 7th European Beer and Health Symposium, Brussels, Belgium, 30 September 2014.

1.
Baliunas
DO
,
Taylor
BJ
,
Irving
H
, et al
.
Alcohol as a risk factor for type 2 diabetes: a systematic review and meta-analysis
.
Diabetes Care
2009
;
32
:
2123
2132
[PubMed]
2.
Koppes
LL
,
Dekker
JM
,
Hendriks
HF
,
Bouter
LM
,
Heine
RJ
.
Moderate alcohol consumption lowers the risk of type 2 diabetes: a meta-analysis of prospective observational studies
.
Diabetes Care
2005
;
28
:
719
725
[PubMed]
3.
Hendriks HFJ. Moderate alcohol consumption and insulin sensitivity: observations and possible mechanisms. Ann Epidemiol 2007;17:S40–S42
4.
Brien
SE
,
Ronksley
PE
,
Turner
BJ
,
Mukamal
KJ
,
Ghali
WA
.
Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies
.
BMJ
2011
;
342
:
d636
[PubMed]
5.
Hulthe
J
,
Fagerberg
B
.
Alcohol consumption and insulin sensitivity: a review
.
Metab Syndr Relat Disord
2005
;
3
:
45
50
[PubMed]
6.
Zilkens
RR
,
Burke
V
,
Watts
G
,
Beilin
LJ
,
Puddey
IB
.
The effect of alcohol intake on insulin sensitivity in men: a randomized controlled trial
.
Diabetes Care
2003
;
26
:
608
612
[PubMed]
7.
Flanagan
DE
,
Pratt
E
,
Murphy
J
, et al
.
Alcohol consumption alters insulin secretion and cardiac autonomic activity
.
Eur J Clin Invest
2002
;
32
:
187
192
[PubMed]
8.
Cordain
L
,
Melby
CL
,
Hamamoto
AE
, et al
.
Influence of moderate chronic wine consumption on insulin sensitivity and other correlates of syndrome X in moderately obese women
.
Metabolism
2000
;
49
:
1473
1478
[PubMed]
9.
Davies
MJ
,
Baer
DJ
,
Judd
JT
,
Brown
ED
,
Campbell
WS
,
Taylor
PR
.
Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women: a randomized controlled trial
.
JAMA
2002
;
287
:
2559
2562
[PubMed]
10.
Sierksma
A
,
Patel
H
,
Ouchi
N
, et al
.
Effect of moderate alcohol consumption on adiponectin, tumor necrosis factor-α, and insulin sensitivity
.
Diabetes Care
2004
;
27
:
184
189
[PubMed]
11.
Muniyappa
R
,
Lee
S
,
Chen
H
,
Quon
MJ
.
Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage
.
Am J Physiol Endocrinol Metab
2008
;
294
:
E15
E26
[PubMed]
12.
Nathan DM, Turgeon H, Regan S. Relationship between glycated haemoglobin levels and mean glucose levels over time. Diabetologia 2007;50:2239–2244
13.
Cordain
L
,
Bryan
ED
,
Melby
CL
,
Smith
MJ
.
Influence of moderate daily wine consumption on body weight regulation and metabolism in healthy free-living males
.
J Am Coll Nutr
1997
;
16
:
134
139
[PubMed]
14.
Lavy
A
,
Fuhrman
B
,
Markel
A
, et al
.
Effect of dietary supplementation of red or white wine on human blood chemistry, hematology and coagulation: favorable effect of red wine on plasma high-density lipoprotein
.
Ann Nutr Metab
1994
;
38
:
287
294
[PubMed]
15.
Chiva-Blanch
G
,
Urpi-Sarda
M
,
Ros
E
, et al
.
Effects of red wine polyphenols and alcohol on glucose metabolism and the lipid profile: a randomized clinical trial
.
Clin Nutr
2013
;
32
:
200
206
[PubMed]
16.
Jadad
AR
,
Moore
RA
,
Carroll
D
, et al
.
Assessing the quality of reports of randomized clinical trials: is blinding necessary
?
Control Clin Trials
1996
;
17
:
1
12
[PubMed]
17.
Higgins JPT, Green S, Eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Oxford, U.K., The Cochrane Collaboration, 2011
18.
Duval
S
,
Tweedie
R
.
Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis
.
Biometrics
2000
;
56
:
455
463
[PubMed]
19.
Zheng J, Yang J, Huang T, Hu X, Luo M, Li D. Effects of Chinese liquors on cardiovascular disease risk factors in healthy young humans. ScientificWorldJournal 2012;2012:372143
20.
Contaldo
F
,
D’Arrigo
E
,
Carandente
V
, et al
.
Short-term effects of moderate alcohol consumption on lipid metabolism and energy balance in normal men
.
Metabolism
1989
;
38
:
166
171
[PubMed]
21.
Beulens
JW
,
van Beers
RM
,
Stolk
RP
,
Schaafsma
G
,
Hendriks
HF
.
The effect of moderate alcohol consumption on fat distribution and adipocytokines
.
Obesity (Silver Spring)
2006
;
14
:
60
66
[PubMed]
22.
Beulens
JW
,
de Zoete
EC
,
Kok
FJ
,
Schaafsma
G
,
Hendriks
HF
.
Effect of moderate alcohol consumption on adipokines and insulin sensitivity in lean and overweight men: a diet intervention study
.
Eur J Clin Nutr
2008
;
62
:
1098
1105
[PubMed]
23.
Beulens
JW
,
van Loon
LJ
,
Kok
FJ
, et al
.
The effect of moderate alcohol consumption on adiponectin oligomers and muscle oxidative capacity: a human intervention study
.
Diabetologia
2007
;
50
:
1388
1392
[PubMed]
24.
Joosten
MM
,
Beulens
JW
,
Kersten
S
,
Hendriks
HF
.
Moderate alcohol consumption increases insulin sensitivity and ADIPOQ expression in postmenopausal women: a randomised, crossover trial
.
Diabetologia
2008
;
51
:
1375
1381
[PubMed]
25.
Joosten
MM
,
Witkamp
RF
,
Hendriks
HF
.
Alterations in total and high-molecular-weight adiponectin after 3 weeks of moderate alcohol consumption in premenopausal women
.
Metabolism
2011
;
60
:
1058
1063
[PubMed]
26.
Joosten MM, Schrieks IC, Hendriks HF. Effect of moderate alcohol consumption on fetuin-A levels in men and women: post-hoc analyses of three open-label randomized crossover trials. Diabetol Metab Syndr 2014;6:24
27.
Bhathena
SJ
,
Berlin
E
,
Judd
JT
, et al
.
Selective responses of hormones involved in carbohydrate and lipid metabolism and properties of erythrocyte membranes during the menstrual cycle in premenopausal women consuming moderate amounts of alcohol
.
Am J Clin Nutr
1995
;
62
:
751
756
[PubMed]
28.
Cesena
FHY
,
Coimbra
SR
,
Andrade
ACM
,
da Luz
PL
.
The relationship between body mass index and the variation in plasma levels of triglycerides after short-term red wine consumption
.
J Clin Lipidol
2011
;
5
:
294
298
[PubMed]
29.
Kim
SH
,
Abbasi
F
,
Lamendola
C
,
Reaven
GM
.
Effect of moderate alcoholic beverage consumption on insulin sensitivity in insulin-resistant, nondiabetic individuals
.
Metabolism
2009
;
58
:
387
392
[PubMed]
30.
Romeo
J
,
González-Gross
M
,
Wärnberg
J
,
Díaz
LE
,
Marcos
A
.
Effects of moderate beer consumption on blood lipid profile in healthy Spanish adults
.
Nutr Metab Cardiovasc Dis
2008
;
18
:
365
372
[PubMed]
31.
Bantle
AE
,
Thomas
W
,
Bantle
JP
.
Metabolic effects of alcohol in the form of wine in persons with type 2 diabetes mellitus
.
Metabolism
2008
;
57
:
241
245
[PubMed]
32.
Shai
I
,
Wainstein
J
,
Harman-Boehm
I
, et al
.
Glycemic effects of moderate alcohol intake among patients with type 2 diabetes: a multicenter, randomized, clinical intervention trial
.
Diabetes Care
2007
;
30
:
3011
3016
[PubMed]
33.
Queipo-Ortuño
MI
,
Boto-Ordóñez
M
,
Murri
M
, et al
.
Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers
.
Am J Clin Nutr
2012
;
95
:
1323
1334
[PubMed]
34.
Kawamoto
R
,
Kohara
K
,
Tabara
Y
, et al
.
Alcohol consumption is associated with decreased insulin resistance independent of body mass index in Japanese community-dwelling men
.
Tohoku J Exp Med
2009
;
218
:
331
337
[PubMed]
35.
Englund Ogge
L
,
Brohall
G
,
Behre
CJ
,
Schmidt
C
,
Fagerberg
B
.
Alcohol consumption in relation to metabolic regulation, inflammation, and adiponectin in 64-year-old Caucasian women: a population-based study with a focus on impaired glucose regulation
.
Diabetes Care
2006
;
29
:
908
913
[PubMed]
36.
Mayer
EJ
,
Newman
B
,
Quesenberry
CP
 Jr
,
Friedman
GD
,
Selby
JV
.
Alcohol consumption and insulin concentrations. Role of insulin in associations of alcohol intake with high-density lipoprotein cholesterol and triglycerides
.
Circulation
1993
;
88
:
2190
2197
[PubMed]
37.
Kiechl
S
,
Willeit
J
,
Poewe
W
, et al
.
Insulin sensitivity and regular alcohol consumption: large, prospective, cross sectional population study (Bruneck study)
.
BMJ
1996
;
313
:
1040
1044
[PubMed]
38.
Lazarus
R
,
Sparrow
D
,
Weiss
ST
.
Alcohol intake and insulin levels. The Normative Aging Study
.
Am J Epidemiol
1997
;
145
:
909
916
[PubMed]
39.
Kroenke
CH
,
Chu
NF
,
Rifai
N
, et al
.
A cross-sectional study of alcohol consumption patterns and biologic markers of glycemic control among 459 women
.
Diabetes Care
2003
;
26
:
1971
1978
[PubMed]
40.
Vernay M, Balkau B, Moreau J, Sigalas J, Chesnier M, Ducimetiere P; Desir Study Group. Alcohol consumption and insulin resistance syndrome parameters: associations and evolutions in a longitudinal analysis of the French DESIR cohort. Ann Epidemiol 2004;14:209–214
41.
Laakso
M
.
How good a marker is insulin level for insulin resistance
?
Am J Epidemiol
1993
;
137
:
959
965
[PubMed]
42.
Beulens
JW
,
van der Schouw
YT
,
Bergmann
MM
, et al.;
InterAct Consortium
.
Alcohol consumption and risk of type 2 diabetes in European men and women: influence of beverage type and body size The EPIC-InterAct study [published correction appears in J Intern Med 2013;273:422]
.
J Intern Med
2012
;
272
:
358
370
[PubMed]
43.
Harding
AH
,
Sargeant
LA
,
Khaw
KT
, et al
.
Cross-sectional association between total level and type of alcohol consumption and glycosylated haemoglobin level: the EPIC-Norfolk Study
.
Eur J Clin Nutr
2002
;
56
:
882
890
[PubMed]
44.
Gulliford
MC
,
Ukoumunne
OC
.
Determinants of glycated haemoglobin in the general population: associations with diet, alcohol and cigarette smoking
.
Eur J Clin Nutr
2001
;
55
:
615
623
[PubMed]
45.
McMonagle
J
,
Felig
P
.
Effects of ethanol ingestion on glucose tolerance and insulin secretion in normal and diabetic subjects
.
Metabolism
1975
;
24
:
625
632
[PubMed]
46.
Kitabchi
AE
,
Temprosa
M
,
Knowler
WC
, et al.;
Diabetes Prevention Program Research Group
.
Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin
.
Diabetes
2005
;
54
:
2404
2414
[PubMed]
47.
Bertoni
AG
,
Wong
ND
,
Shea
S
, et al
.
Insulin resistance, metabolic syndrome, and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA)
.
Diabetes Care
2007
;
30
:
2951
2956
[PubMed]
48.
Salpeter
SR
,
Buckley
NS
,
Kahn
JA
,
Salpeter
EE
.
Meta-analysis: metformin treatment in persons at risk for diabetes mellitus
.
Am J Med
2008
;
121
:
149
157
[PubMed]
49.
McNeely
MJ
,
McClelland
RL
,
Bild
DE
, et al
.
The association between A1C and subclinical cardiovascular disease: the multi-ethnic study of atherosclerosis
.
Diabetes Care
2009
;
32
:
1727
1733
[PubMed]
50.
Knowler
WC
,
Barrett-Connor
E
,
Fowler
SE
, et al.;
Diabetes Prevention Program Research Group
.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
.
N Engl J Med
2002
;
346
:
393
403
[PubMed]
51.
World Health Organization. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. Geneva, World Health Org., 2011 (Rep. no. WHO/NMH/CHP/CPM/11.1)
52.
Flechtner-Mors
M
,
Biesalski
HK
,
Jenkinson
CP
,
Adler
G
,
Ditschuneit
HH
.
Effects of moderate consumption of white wine on weight loss in overweight and obese subjects
.
Int J Obes Relat Metab Disord
2004
;
28
:
1420
1426
[PubMed]
53.
Joosten MM, van Erk MJ, Pellis L, Witkamp RF, Hendriks HFJ. Moderate alcohol consumption alters both leucocyte gene expression profiles and circulating proteins related to immune response and lipid metabolism in men. Br J Nutr 2012;108:620–627

Supplementary data