Chronic heavy alcohol consumption influences the association between genetic variants of GCK or INSR and the development of diabetes in men: A 12-year follow-up study

Abstract

Chronic heavy alcohol consumption is a risk factor for diabetes, which is characterized by impaired β-cell function and insulin resistance. We aimed to determine whether the longitudinal associations between genetic variants of glucokinase (GCK) and insulin receptor (INSR) and the risk of developing diabetes were influenced by chronic heavy alcohol consumption. Data were obtained from the Korean Genome and Epidemiology Study. To identify candidate variants, 1,520 subjects (726 non-drinkers and 794 heavy drinkers) were included in the baseline cross-sectional study. After excluding patients with diabetes at baseline and those with insufficient data on diabetes incidence, prospective analyses were conducted in 773 subjects (353 non-drinkers and 420 heavy drinkers). In the baseline cross-sectional study, one SNP (rs758989) in GCK and four SNPs (rs7245757, rs1035942, rs1035940, and rs2042901) in INSR were selected as candidate SNPs that interact with alcohol to affect prediabetes and diabetes. We identified that these GCK and INSR polymorphisms are affected by chronic heavy alcohol consumption and have an effect on the incidence of diabetes. The incidence of diabetes was increased in chronic heavy alcohol drinkers carrying the C allele of GCK compared with never-drinkers with the C allele (HR, 2.15; 95% CI 1.30-3.57), and was increased in chronic heavy alcohol drinkers who were not carrying the INSR haplotype (-/-) compared with never-drinkers carrying the AACT haplotype (HR, 1.98; 95% CI 1.24-3.18). Moreover, we observed that the aggravating effects on the late insulin secretion (I/G₁₂₀ and I/G _{AUC 60-120}) in individuals who were chronic heavy drinkers with C allele of GCK. In the INSR haplotype, chronic heavy drinkers not carrying AACT were associated with lower disposition index. These results potentially suggest that chronic heavy alcohol consumption induce β-cell dysfunction partially mediated by decreased GCK expression or decline of insulin sensitivity via inhibition of INSR, thereby contributing to the development of diabetes.

Figure 1

Kaplan-Meier curves for the incidence of diabetes according to the combined model of genetic variants ((A) GCK or (B) INSR) and chronic heavy alcohol consumption.

Figure 2

Effect of the interaction between chronic heavy alcohol consumption and genetic variants of (A) GCK or (B) INSR on diabetes incidence. P-values were calculated by Cox proportional hazard analysis with adjustment for age, physical activity, family history of diabetes, smoking status, and BMI.

Figure 3

Glucose concentrations during the oral glucose tolerance test according to the combined model of genetic variants (GCK and INSR) and chronic heavy alcohol consumption. P values for glucose levels at 0 min, 1 h, and 2 h post-OGTT were calculated by general linear models with adjustment for age, physical activity, smoking status, BMI, and follow-up period. Significant differences of means among genotype-alcohol consumption groups by Duncan test (a: highest mean; c: lowest mean; a > b > c).