Moderate alcohol consumption, adiponectin, inflammation and type 2 diabetes risk : prospective cohort studies and randomized crossover trials

Background: Moderate alcohol consumption has been associated with a lower risk of type 2 diabetes in various populations. However, the underlying mechanisms are not entirely clear. The aims of this thesis were 1) to substantiate the evidence of the association between alcohol consumption and type 2 diabetes in observational research and 2) to examine physiological mechanisms in randomized trials with specific attention to adiponectin, inflammation and insulin sensitivity which may mediate the association between alcohol consumption and type 2 diabetes. Methods: Two prospective cohort studies, one among 38,031 U.S. men (age: 45-75 y) of the Health Professionals Follow up Study (HPFS) and one among 35,625 Dutch men and women (age: 20-70 y) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL cohort. Four randomized, crossover trials of eight to twelve weeks with consumption of 25-30 g alcohol/day in the form of vodka with orange juice, beer, or white wine (twice) compared to orange juice, alcohol free beer, white grape juice or water among 24 young men, 24 premenopausal and 36 and 22 postmenopausal women, respectively. Results: A 7.5 g/day increase in alcohol consumption over four years was associated with lower diabetes risk among initial non-drinkers (hazard ratio [HR]: 0.78; 95% confidence interval (CI): 0.60, 1.00) and drinkers initially consuming <15 g/d (HR: 0.89; 95% CI: 0.83, 0.96) but not among men initially drinking ≥15 g/d (HR: 0.99; 95% CI: 0.95, 1.02) (Pinteraction < 0.01) in U.S. men. Among Dutch subjects with ≥3 out of 4 low-risk lifestyle behaviors, moderate alcohol consumption was associated with a lower risk of type 2 diabetes compared with abstention (HR: 0.56; 95% CI: 0.32, 1.00). In the randomized crossover trials, alcohol consumption consistently increased circulating adiponectin levels by about 10% compared to abstention (P < 0.05) regardless of beverage type, gender or age. These increases were evident after a minimum of three weeks of alcohol consumption. Moderate alcohol consumption also increased expression of the gene encoding adiponectin in adipose tissue and lowered serum fasting insulin and triglyceride levels (all P < 0.05). An integrated approach of large-scale profiling of proteins and genes revealed that moderate alcohol consumption for four weeks altered gene expression profiles of white blood cells and circulating markers related to inflammation in men (all P < 0.05). However, we did not observe an attenuated inflammatory response after a low-dose in vivo endotoxin bolus, despite increased high-density lipoprotein cholesterol and apolipoprotein levels after four weeks of alcohol consumption compared to abstention. Six minutes of oral white wine exposure without swallowing substantially (-20%; P < 0.05) and temporarily (~20 min) decreased circulating free fatty acid concentrations compared with oral water exposure. Conclusions: Moderate alcohol consumption was associated with a lower risk of type 2 diabetes compared with abstention. The association persisted among subjects already at low risk based on combined favorable lifestyle behaviors. Also, increases in alcohol consumption among initially rare and light drinking men were associated with higher adiponectin levels and lower risk of type 2 diabetes. Increased adiponectin levels, anti-inflammatory effects and decreased insulin and triglyceride levels, may partially explain the inverse association between moderate alcohol consumption and type 2 diabetes.