Insulin sensitivity and regular alcohol consumption: large, prospective, cross sectional population study (Bruneck study)
=========================================================================================================================

* Stefan Kiechl
* Johann Willeit
* Werner Poewe
* Georg Egger
* Friedrich Oberhollenzer
* Michele Muggeo
* Enzo Bonora

## Abstract

**Objectives**: To assess the relation between regular alcohol consumption and insulin sensitivity, and to estimate the importance of insulin in the association of alcohol with multiple vascular risk factors and cardiovascular disease.

**Design**: Prospective and cross sectional study of a large randomly selected population sample.

**Setting**: Part of the Bruneck study 1990–5 (Bolzano province, Italy).

**Subjects**: 820 healthy non-diabetic women and men aged 40–79 years.

**Main outcome measure**: Concentrations of fasting and post-glucose insulin, cholesterol, apolipoproteins, triglycerides, Lp(a) lipoprotein, glucose, fibrinogen, and antithrombin III; blood pressure; insulin resistance estimated by the homeostasis model assessment.

**Results**: Fasting insulin concentrations in those who did not drink alcohol and subjects reporting low (1–50 g/day), moderate (51–99 g/day), and heavy (>/=100 g/day) alcohol intake were 12.4, 10.0, 8.7, and 7.1 mU/l (P<0.001). Likewise, post-glucose insulin concentrations and estimates for insulin resistance assessed by the homeostasis model assessment decreased significantly with increasing amounts of regular alcohol consumption. These trends were independent of sex, body mass index, physical activity, cigarette smoking, medication, and diet (P<0.001). Regular alcohol intake predicted multiple changes in vascular risk factors over a five year period including increased concentrations of high density lipoprotein cholesterol and apolipoprotein A I; higher blood pressure; and decreased concentration of antithrombin III. These associations were in part attributable to the decrease in insulin concentrations observed among alcohol consumers.

**Conclusions**: Low to moderate amounts of alcohol, when taken on a regular basis, improve insulin sensitivity. Insulin is a potential intermediate component in the association between alcohol consumption and vascular risk factors (metabolic syndrome).

#### Key messages

*   Regular alcohol consumption predicted multiple changes of vascular risk factors over a five year period

*   This alcohol associated metabolic syndrome is in part attributable to the decline in insulin concentrations

## Introduction

Insulin resistance and hyperinsulinaemia are prominent predictors of risk for the development of diabetes mellitus1 and may promote atherosclerotic diseases because of the association with multiple vascular risk factors and direct atherogenic effects.2 3 4 5 6 For preventive purposes precise knowledge of environmental determinants of insulin sensitivity is mandatory. Obesity and insufficient physical activity rank among these factors. With regard to alcohol consumption, a further widespread and potentially modifiable behaviour, epidemiological evidence is sparse and restricted to low amounts of alcohol and to women.7 8 We investigated the relation between insulin concentrations and regular alcohol consumption (in the range 0–210 g/day) in a large population sample of men and women.

## Methods

### SURVEY AREA AND STUDY SUBJECTS

The town of Bruneck is located in an alpine region in the north of Italy (Bolzano province). The study population was recruited as a random sample stratified for age and sex of all inhabitants aged 40 to 79 years (n = 4793) in such a way that 125 women and 125 men of each decade were invited to participate.9 10 11 The baseline examination was performed from July to November 1990 and the first follow up from July to October 1995. Participation and follow up rates were high at 93.6% and 96.5%. Subjects with cerebrovascular disease, incomplete data collection, unavailable insulin measurements, and diabetes mellitus (n = 60; World Health Organisation criteria12) were considered ineligible, which left 820 (1990) and 771 (1995) men and women for analysis.

### CLINICAL EVALUATION AND LABORATORY METHODS

Alcohol consumption was assessed by a standardised interview based on a questionnaire.11 Subjects were instructed to indicate their customary frequency of drinking (days a week) and the average amount of alcoholic beverages ingested on a typical occasion or during a typical day (500 ml bottles of beer and 250 ml glasses of wine equivalent to 25 g alcohol, standard drinks of spirits 8–10 g alcohol each). Additionally, self administered prospective diet records including the same alcohol items were collected over an extended period of seven days in a representative subsample (n = 404; participation rate 91%11). In both evaluations average alcohol consumption was quantified in terms of grams a day (g/day) and classified in four categories: abstainers (0 g/day) and light (1–50 g/day), moderate (51–99 g/day), and heavy drinkers (>/=100 g/day). Advantages and validation of this categorisation, including the high reproducibility ((kappa) coefficient 0.87), have been described previously.11

Subjects were coded as non-smokers or light (1–10 cigarettes), moderate (11–20), or heavy (>20) smokers on the basis of usual smoking habits. Social class was defined by the education of the subject and the occupation of the person with the highest income in the household.9 Systolic and diastolic blood pressures were assessed as means of two independent measurements, each of which was taken after at least 10 minutes of rest. The activity score consisted of the average of the scores for work (three categories) and sports or leisure activities (0, </=2, >2 hours a week). Blood samples were collected between 7 30 and 9 30 am after 12 hours of fasting and abstinence from smoking and two hours after a standardised oral glucose challenge.9 Concentrations of laboratory variables were determined as follows: triglycerides (interassay coefficient of variation 4.3-5.4% for different standards) and total and high density lipoprotein cholesterol were determined enzymatically (by the cholesterol oxidase-4-phenyl-2, 3-dimethyl-4-amino-5-pyrazolone and the glycerol phosphate oxidase-4-phenyl-2, 3-dimethyl-4-amino-5-pyrazolone (CHOD-PAP and GPO-PAP) methods, Merck; coefficient of variation 2.2-2.4%); Lp(a) lipoprotein with an enzyme linked immunosorbent assay (ELISA) (Immuno, Vienna; 3.5-6.3%), insulin according to Hales and Randle (3.2-4.8%)13 and by a human insulin specific radioimmunoassay (Linco Research, 3.9%); apolipoproteins by a nephelometric fixed time method (apolipoprotein A I 5.7%; apolipoprotein B 2.4%); and antithrombin III with a chromogenic assay (3.9-4.9%). Concentrations of low density lipoprotein cholesterol were calculated with the Friedewald formula and corrected for Lp(a) lipoprotein cholesterol. Insulin resistance and ß cell deficit were estimated by the homoeostasis model assessment (coefficients of variation 31% and 32%).14 Normal weight, healthy subjects aged <35 who did not drink alcohol or smoke, who had normal glucose tolerance, and who were not taking any drug treatment were assumed to have 100% ß cell function and an insulin resistance of 1.

### STATISTICAL ANALYSIS

Multiple regression analysis was applied to assess relations of alcohol consumption with insulin and vascular risk attributes (SPSS-X version 4.015 and BMDP software16). Levels of alcohol intake were modelled as a set of categories or as a trend. Confidence intervals and P values presented were mainly derived from the latter approach as most results showed clear (linear) trends with alcohol intake. To evaluate the consistency of these associations by sex first order interaction terms were added to the models. Variables with a skewed distribution of serum concentrations were normalised by ln (natural log) transformation. Quantitive changes in vascular risk factors expected for the variation of insulin concentration across alcohol categories were estimated from linear regression equations (of the variable on insulin and covariates) and expressed as proportions of the differences actually observed.

## Results

A total of 114 women (28%) and 314 men (76%) reported regular alcohol consumption. In the population as a whole, fasting and post-glucose insulin concentrations steadily decreased with increasing daily consumption, as did ratios of insulin resistance estimated by the homeostasis model assessment (table 1). When alcohol intake was modelled as a continuous variable an increase in daily alcohol consumption of 50 g predicted changes in insulin resistance and fasting and post-glucose insulin of −10% (95% confidence interval −5% to −14%), −14% (−4% to −22%), and −10% (−3% to −15%), respectively. These findings were consistent by sex and independent of age, body mass index, smoking, social status, and physical activity.

View this table:
[Table 1](https://www.bmj.com/content/313/7064/1040/T1)

Table 1 
Mean values of surrogates for insulin resistance and haemoglobin A1c, and glucose concentrations by daily alcohol consumption (n = 820)

Of the variability of serum insulin concentration in the entire population sample, 3.9% was attributable to alcohol consumption as compared with 9.4% for obesity and 4.1% for differences in physical activity. According to the high incidence of regular alcohol consumption, the attributable fraction for men amounted to 5.8% (25% of totally explained variability of insulin).

The prevalence of impaired glucose tolerance was low and consistent in the four categories of alcohol consumption (10.2, 8.8, 10.1, and 7.9%). Exclusion of these subjects did not affect changes in insulin concentration with increasing alcohol consumption (insulin 11.7 mU/l (0 g/day) to 7.1 mU/l (>/=100 g/day); P<0.001). Separate analyses that excluded or recategorised former drinkers11 yielded similar results (insulin 12.1 mU/l (0 g/day) to 7.1 mU/l (>/=100 g/day); P<0.001), as did models that adjusted for dietary differences, drugs known to interfere with insulin and glucose metabolism (corticosteroids, thyroid hormones, diuretics, oral contraceptives, ß blockers, etc17), and markers of liver function including (gamma)-glutamyl-transferase, the transaminases, prothrombin time, and albumin concentrations.

Finally, all analyses were supplemented and consistently confirmed by calculations on the basis of alcohol quantities derived from the prospective diet records (data not presented).

Regular alcohol consumption may produce considerable changes in lipoprotein metabolism and blood clotting. In our population sample concentrations of high density lipoprotein cholesterol and apolipoprotein A I linearly increased across categories of alcohol consumption, whereas antithrombin III, fibrinogen, and triiodothyronine concentrations exhibited opposite trends (table 2). The pattern of related risk factors did not differ between sexes except for a preferential enhancement of concentration of high density lipoprotein cholesterol in the men (P<0.05 for effect modification). In a second stage we prospectively assessed changes of risk factors over five years, dependent on the average amount of daily alcohol consumption in this period. Except for the association between alcohol intake and fibrinogen concentration the trends observed correspond with the cross sectional data (table 3). Varying concentrations of insulin and insulin resistance (homoeostasis model assessment) among drinkers might explain 9–35% of changes in concentrations of high density lipoprotein cholesterol, apolipoprotein A I, and antithrombin III associated with alcohol.

View this table:
[Table 2](https://www.bmj.com/content/313/7064/1040/T2)

Table 2 
Mean values of potential cardiovascular risk factors and selected laboratory variables by daily alcohol consumption (n = 820)

View this table:
[Table 3](https://www.bmj.com/content/313/7064/1040/T3)

Table 3 
Changes in cardiovascular risk factors and laboratory variables between 1990 and 1995 by daily alcohol consumption (n = 771)

## Discussion

### REGULAR ALCOHOL CONSUMPTION AND INSULINAEMIA

In both sexes we found a strong tendency of serum insulin concentrations to decrease with increasing chronic alcohol consumption. This trend emerged independent of obesity, physical activity, smoking habits, social status, and drug use. The few previous reports on the relation between regular alcohol consumption and insulin concentrations were restricted to low amounts of average alcohol intake in women. In the Kaiser permanent women twins study median daily alcohol consumption amounted to 4 g a day.7 An increment of 12 g a day (highest category of drinking) was associated with 8% lower post-glucose insulin concentrations. In a study of women in Bristol, those consuming up to 30 g a day had lower fasting insulin concentrations than did non-drinkers.8 Consistent epidemiological evidence of lower insulin concentrations among drinkers7 8 18 19 was further substantiated by results from an experimental animal model. In obese rats prone to atherosclerosis insulin concentration and ß cell hyperplasia were reduced after long term alcohol intake.20

Fasting and post-glucose insulin are well established surrogate measures for insulin resistance in nondiabetic subjects,21 22 with low concentrations of insulin as observed in alcohol consumers indicating higher insulin sensitivity. Theoretically, impaired secretion or enhanced hepatic degradation of insulin could interfere with this assumption: The latter mechanism, however, may not apply to alcohol drinking given the experimental observation of an unchanged or even reduced liver uptake of insulin after acute or chronic intake of alcohol.23 24 Likewise, inhibition of ß cell secretion was observed only after administration of high doses of ethanol,25 26 27 whereas low to moderate intake of alcohol tended to enhance insulin release (“priming effect”) in an experimental setting.25 28 The homoeostasis model assessment permits differentiation between insulin resistance and ß cell deficit in epidemiological surveys with the limitations of high variability in measurement and uncertain estimates of ß cell function at normal glucose concentrations.14 When we used this method we observed a significant decrease in insulin resistance across all alcohol categories. Besides, ß cell deficiency as indicated by the coincidence of fasting hyperglycaemia (>6.4 mmol/l) with clearly reduced ß cell activity and insulin concentrations was demonstrated in 13% of heavy drinkers.

Direct experimental evaluations of insulin sensitivity in alcohol consumers have dealt mainly with immediate effects of acute alcohol loading25 29 30 rather than consequences of long term alcohol consumption.31

### ASSOCIATION OF ALCOHOL CONSUMPTION WITH MULTIPLE VASCULAR RISK FACTORS

Our population study confirmed previous reports in that it assessed an increase in concentrations of high density lipoprotein cholesterol and apolipoprotein A I and higher blood pressure among alcohol consumers, extended the metabolic complex associated with drinking by a decline in antithrombin III concentration, and provided first prospective confirmation of these findings. Several mechanisms have been proposed that link regular alcohol intake and changes in vascular risk attributes. Enhanced insulin sensitivity as postulated for alcohol consumers in our study may rank among these pathways because of the broad overlap of the alcohol associated metabolic complex with components of the “syndrome X.”32 33 This hypothesis could partly explain alcohol associated variations in concentrations of high density lipoprotein cholesterol, apolipoprotein A I, and antithrombin III. With regard to systolic blood pressure, however, changes across alcohol categories (+3.6 mm Hg) were contrary to those expected (−1.1 mm Hg), probably because of an alcohol induced activation of the autonomous nervous system or enhancement of renal tubular sodium reabsorption.25

### LIMITATIONS AND SELECTED METHODOLOGICAL PROBLEMS IN QUANTITIVE ALCOHOL RESEARCH

The insulin assay used in the current study cross reacts with pro-insulin and pro-insulin split products. In a subsample of the Bruneck cohort (n = 200), however, insulin concentration was additionally measured with a specific assay (cross reactivity <0.2%). Both assessments were strongly correlated (r = 0.85; mean difference −8.4%; −0.8 to −15.8%) and showed an analogous inverse association with regular alcohol intake (“specific” insulin 11.0 mU/l (0 g/day) to 6.6 mU/l (>/=100 g/day); P<0.001). Likewise, Haffner and coworkers reported that both types of tests perform equally well for the purpose of analysing the associations between vascular risk factors and insulin.34

The quality of alcohol research primarily relies on the accuracy of assessing alcohol consumption. In our survey, the non-differential response error which is believed to be the major source of incorrect ascertainment of alcohol consumption35 was dealt with by the application of diet records in a representative subsample. Prospective assessment of daily food records over an extended period is the best possible method to minimise error in recall and overcome fluctuation in drinking behaviour and inadequate self estimation of alcohol intake.11 36 Analysis of these data further substantiated results derived from point estimates of alcohol intake. The second important type of error, the deliberate denial of alcohol use or selective non-responding by heavy drinkers, may also be regarded as low because of a participation rate over 93% and the fairly high boundaries of socially accepted drinking in the survey area.

Alcohol is an important constituent of the European and American diet. Our survey identified regular alcohol intake as a further determinant of insulin sensitivity in a general healthy population, even though its explanatory contribution to insulin variability was only half that of obesity. Light to moderate drinking emerged as safe regarding its effects on insulin. Conclusions on severe alcohol consumption require particular caution given the associated social and health risks, potential impairment of ß cell function, and occurrence of diabetes due to advanced pancreatitis induced by alcohol.

## Footnotes

*   Funding Pustertaler Verein zur Pravention der Herz und Hirngefaßerkrankungen, Sanitatseinheit Ost, Assessorat fur Gesundheit, province of Bozen, Italy.

*   Conflict of interest None.

## References

1.  1.Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 1993;329:1988–92.
    
    [CrossRef](https://www.bmj.com/lookup/external-ref?access_num=10.1056/NEJM199312303292703&link_type=DOI) 
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=8247074&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1993MN57300003&link_type=ISI) 

2.  2.Fontbonne A, Charles MA, Thibult N, Richard JL, Claude JR, Warnet JM, et al. Hyperinsulinaemia as a predictor of coronary heart disease mortality in a healthy population: the Paris prospective study, 15-year follow-up. Diabetologia 1991;34:356–61.
    
    [CrossRef](https://www.bmj.com/lookup/external-ref?access_num=10.1007/BF00405009&link_type=DOI) 
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=1864491&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1991FM27400012&link_type=ISI) 

3.  3.Pyorala K, Savolainen E, Kaukola S, Haapakoski J. Plasma insulin as coronary heart disease risk factor: relationship to other risk factors and predictive value during 9 1/2-year follow-up of the Helsinki policemen study population. Acta Med Scand 1985;701:38–52.
    
    

4.  4.Welborn TA, Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentration. Diabetes Care 1979;2:154–60.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiZGlhY2FyZSI7czo1OiJyZXNpZCI7czo3OiIyLzIvMTU0IjtzOjQ6ImF0b20iO3M6MjM6Ii9ibWovMzEzLzcwNjQvMTA0MC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

5.  5.Laakso M, Sarlund H, Salonen R, Suhonen M, Pyorala K, Salonen JT, et al. Asymptomatic atherosclerosis and insulin resistance. Arterioscler Thromb 1991;11:1068–76.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiYXR2YmFoYSI7czo1OiJyZXNpZCI7czo5OiIxMS80LzEwNjgiO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zMTMvNzA2NC8xMDQwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

6.  6.Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 1992;41:715–22.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiZGlhYmV0ZXMiO3M6NToicmVzaWQiO3M6ODoiNDEvNi83MTUiO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zMTMvNzA2NC8xMDQwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

7.  7.Mayer EJ, Newman B, Quesenberry CP, 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;88:2190–7.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTQ6ImNpcmN1bGF0aW9uYWhhIjtzOjU6InJlc2lkIjtzOjk6Ijg4LzUvMjE5MCI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzMxMy83MDY0LzEwNDAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

8.  8.Razay G, Heaton KW, Bolton CH, Hughes AO. Alcohol consumption and its relation to cardiovascular risk factors in British women. BMJ 1992;304:80–3.
    
    

9.  9.Willeit J, Kiechl S. Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis: a population-based study. Arterioscler Thromb 1993;13:661–8.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiYXR2YmFoYSI7czo1OiJyZXNpZCI7czo4OiIxMy81LzY2MSI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzMxMy83MDY0LzEwNDAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

10. 10.Kiechl S, Willeit J, Rungger G, Egger G, Oberhollenzer F. Quantitative assessment of carotid atherosclerosis in a healthy population. Neuroepidemiology 1994;13:314–7.
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=7800111&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1994PD89500011&link_type=ISI) 

11. 11.Kiechl S, Willeit J, Egger G, Oberhollenzer M, Aichner F. Alcohol consumption and carotid atherosclerosis: evidence of dose-dependent atherogenic and antiatherogenic effects. Results from the Bruneck study. Stroke 1994;25:1593–8.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToic3Ryb2tlYWhhIjtzOjU6InJlc2lkIjtzOjk6IjI1LzgvMTU5MyI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzMxMy83MDY0LzEwNDAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

12. 12.WHO Study Group on Diabetes Mellitus. Report. World Health Organ Tech Rep Ser 1985;727.
    
    

13. 13.Hales CN, Randle PJ. Immunoassay of insulin with insulin-antibody precipitate. Biochem J 1963;88:137–44.
    
    [FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czoxMDoicHBiaW9jaGVtaiI7czo1OiJyZXNpZCI7czo4OiI4OC8xLzEzNyI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzMxMy83MDY0LzEwNDAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

14. 14.Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and (beta)-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9.
    
    [CrossRef](https://www.bmj.com/lookup/external-ref?access_num=10.1007/BF00280883&link_type=DOI) 
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=3899825&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1985APQ2500004&link_type=ISI) 

15. 15.Norusis MJ. User's guide SPSS-X. Version 4.0. Chicago: SPSS, 1990.
    
    

16. 16.Hill MA. BMDP user's guide. Los Angeles: BMDP Statistical Software, 1987.
    
    

17. 17.Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance. Ann Intern Med 1993;118:529–39.
    
    [CrossRef](https://www.bmj.com/lookup/external-ref?access_num=10.7326/0003-4819-118-7-199304010-00008&link_type=DOI) 
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=8442624&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1993KU07900008&link_type=ISI) 

18. 18.Manolio TA, Savage PJ, Burke GL, Liu K, Wagenknecht LE, Sidney S, et al. Association of fasting insulin with blood pressure and lipids in young adults. The CARDIA study. Arteriosclerosis 1990;10:430–6.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiYXR2YmFoYSI7czo1OiJyZXNpZCI7czo4OiIxMC8zLzQzMCI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzMxMy83MDY0LzEwNDAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

19. 19.Sevak L, McKeigue PM, Marmot MG. Relationship of hyperinsulinemia to dietary intake in South Asian and European men. Am J Clin Nutr 1994;59:1069–74.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiYWpjbiI7czo1OiJyZXNpZCI7czo5OiI1OS81LzEwNjkiO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zMTMvNzA2NC8xMDQwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

20. 20.Russell JC, Amy RM, Manickavel V, Dolphin PJ. Effects of chronic ethanol consumption in atherosclerosis-prone JCR: LA-corpulent rat. Arteriosclerosis 1989;9:122–8.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiYXR2YmFoYSI7czo1OiJyZXNpZCI7czo3OiI5LzEvMTIyIjtzOjQ6ImF0b20iO3M6MjM6Ii9ibWovMzEzLzcwNjQvMTA0MC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

21. 21.Laakso M. How good a marker is insulin level for insulin resistance? Am J Epidemiol 1993;137:959–65.
    
    

22. 22.Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocrine Rev 1985;6:45–86.
    
    [CrossRef](https://www.bmj.com/lookup/external-ref?access_num=10.1210/edrv-6-1-45&link_type=DOI) 
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=3884329&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1985ACM9200003&link_type=ISI) 

23. 23.Fawcett J, Hammond B, Smith GD. Acute effects of ethanol on hepatic endocytosis and processing of insulin in perfused rat liver. Am J Physiol 1993;264:E420–7.
    
    

24. 24.Casey CA, Camacho KB, Tuma DJ. The effects of chronic ethanol administration on the rates of internalization of various ligands during hepatic endocytosis. Biochim Biophys Acta 1992;134:96–104.
    
    

25. 25.Avogaro A, Tiengo A. Alcohol, glucose metabolism and diabetes. Diabetes Metab Rev 1993;9:129–46.
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=8258307&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1993MB89100004&link_type=ISI) 

26. 26.Patel DG, Singh SP. Effect of ethanol and its metabolite on glucose mediated insulin release from isolated islets of rats. Metabolism 1979;28:85–9.
    
    [CrossRef](https://www.bmj.com/lookup/external-ref?access_num=10.1016/0026-0495(79)90173-2&link_type=DOI) 
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=366333&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1979GF86600014&link_type=ISI) 

27. 27.Tiengo A, Valerio A, Molinari M, Meneghel A, Lapolla A. Effect of ethanol, acetaldehyde, and acetate on insulin and glucagon secretion in the perfused rat pancreas. Diabetes 1981;30:705–9.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiZGlhYmV0ZXMiO3M6NToicmVzaWQiO3M6ODoiMzAvOS83MDUiO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zMTMvNzA2NC8xMDQwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

28. 28.Metz R, Berger S, Mako M. Potentiation of the plasma insulin response to glucose by prior administration of alcohol. An apparent islet priming effect. Diabetes 1969;18:517–22.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiZGlhYmV0ZXMiO3M6NToicmVzaWQiO3M6ODoiMTgvOC81MTciO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zMTMvNzA2NC8xMDQwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

29. 29.Boden G, Chen X, Desantis R, White J, Mozzoli M. Effects of ethanol on carbohydrate metabolism in the elderly. Diabetes 1993;42:28–34.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiZGlhYmV0ZXMiO3M6NToicmVzaWQiO3M6NzoiNDIvMS8yOCI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzMxMy83MDY0LzEwNDAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

30. 30.Singh SP, Kumar Y, Snyder AK, Ellyin FE, Gilden JL. Effect of alcohol on glucose tolerance in normal and noninsulin-dependent diabetic subjects. Alcohol Clin Exp Res 1988;12:727–30.
    
    [CrossRef](https://www.bmj.com/lookup/external-ref?access_num=10.1111/j.1530-0277.1988.tb01335.x&link_type=DOI) 
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=3064631&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1988R497400001&link_type=ISI) 

31. 31.Facchini F, Chen YD, Reaven GM. Light-to-moderate alcohol intake is associated with enhanced insulin sensitivity. Diabetes Care 1994;17:115–9.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiZGlhY2FyZSI7czo1OiJyZXNpZCI7czo4OiIxNy8yLzExNSI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzMxMy83MDY0LzEwNDAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

32. 32.Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiZGlhYmV0ZXMiO3M6NToicmVzaWQiO3M6MTA6IjM3LzEyLzE1OTUiO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zMTMvNzA2NC8xMDQwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

33. 33.Moller DE, Flier JS. Insulin resistance - mechanisms, syndromes and implications. N Engl J Med 1991;325:938–48.
    
    [CrossRef](https://www.bmj.com/lookup/external-ref?access_num=10.1056/NEJM199109263251307&link_type=DOI) 
    
    [PubMed](https://www.bmj.com/lookup/external-ref?access_num=1881419&link_type=MED&atom=%2Fbmj%2F313%2F7064%2F1040.atom) 
    
    [Web of Science](https://www.bmj.com/lookup/external-ref?access_num=A1991GF85600007&link_type=ISI) 

34. 34.Haffner SM, Mykkanen L, Valdez RA, Stern MP. Evaluation of two insulin assays in insulin resistance syndrome (syndrome X). Arterioscler Thromb 1994;14:1430–7.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiYXR2YmFoYSI7czo1OiJyZXNpZCI7czo5OiIxNC85LzE0MzAiO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zMTMvNzA2NC8xMDQwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

35. 35.1.  Smart RG, 
    2.  Capell HD, 
    3.  Glaser FB
    
    Alanko T. An overview of techniques and problems in the measurement of alcohol consumption. In: Smart RG, Capell HD, Glaser FB eds. Research advances in alcohol and drug problems. New York: Plenum Publishing, 1984.
    
    

36. 36.Willett WC, Stampson L, Stampfer MJ, Rosner B, Bain C, Witschi J, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985;122:51–65.
    
    [Abstract/FREE Full Text](https://www.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiYW1qZXBpZCI7czo1OiJyZXNpZCI7czo4OiIxMjIvMS81MSI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzMxMy83MDY0LzEwNDAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9)