ALDH2 rs671 Is Associated With Elevated FPG, Reduced Glucose Clearance and Hepatic Insulin Resistance in Japanese Men

Context: A recent meta-analysis of genome-wide association studies data from East Asians identified aldehyde dehydrogenase 2 (ALDH2) rs671 as a susceptibility variant for type 2 diabetes in males. Objective: To investigate the association between ALDH2 rs671 and metabolic characteristics. Methods: We studied 94 nonobese, nondiabetic, Japanese men. Using a 2-step hyperinsulinemic-euglycemic clamp, we evaluated insulin sensitivity in muscle and liver. Intrahepatic lipid and fat distribution were measured using 1 H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively. We divided participants into a risk-carrying group with ALDH2 rs671 GIG (n = 53) and a nonrisk-carrying group with ALDH2 rs671 G/A or A/A (n = 41). Results: The risk-carrying group had significantly higher levels of alcohol consumption (18.4 [interquartile range, IQR, 10.4-48.9]) vs 12.1 (IQR, 1.3-29.0) g/day; P= .003), elevated fasting plasma glucose (FPG) (97.5 +/- 7.9 vs 93.5 +/- 6.2 mg/dL; P= .010), lower hepatic insulin sensitivity (61.7 +/- 20.5% vs 73.1 +/- 15.9%; P= .003), and lower fasting glucose clearance (0.84 +/- 0.8 dL.m(-2) .min -1 vs 0.87 +/- 0.09 dL.m(-2).min(-1) ; P= .047) than the nonrisk-carrying group, while insulin resistance in muscle and body fat distribution were similar. The single linear correlation analysis revealed significant correlations between alcohol consumption and hepatic insulin sensitivity (r =-0.262, P= .011), fasting glucose clearance (r= -0.370, P< .001), or FPG (r= 0.489, P< .001). The multiple regression analysis revealed that both ALDH2 rs671 G/G genotype and alcohol consumption were significant independent correlates for hepatic insulin sensitivity, whereas only alcohol consumption was a significant independent correlate for fasting glucose clearance. Conclusion: Our data suggest that high-alcohol intake-dependent and independent hepatic insulin resistance and reduced fasting glucose clearance due to high alcohol intake could be a relatively upstream metabolic abnormality in ALDH2 rs671 G/G carriers.