Influence of the ACE Gene Insertion/Deletion Polymorphism on Insulin Sensitivity and Impaired Glucose Tolerance in Healthy Subjects

OBJECTIVE:--Recent studies suggested that the blockade of the renin-angiotensin system (RAS) may be associated with metabolic benefits. However, data about the potential influence of the ACE insertion/deletion (I/D) genotype on insulin resistance have been contradictory with studies of limited sample sizes. The purpose of this study was to investigate the relationship between the ACE gene I/D polymorphism and both insulin sensitivity and glucose intolerance in a large cohort of healthy subjects. RESEARCH DESIGN AND METHODS--A total of 1,286 participants in the Relationship Between Insulin Sensitivity and Cardiovascular Disease Risk Study had a 75-g oral glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess whole-body insulin sensitivity. RESULTS:--Age, BMI, waist, fat-free mass (ffm), and physical activity did not differ by ACE genotype. Fasting glucose and insulin were similar among genotypes, but 2-h glucose levels were higher in DD than in ID and II subjects (DD: 5.9 ± 1.7; ID: 5.7 ± 1.5; II: 5.6 ± 1.5 mmol/l) (P = 0.004). Participants with the DD genotype were more likely to have impaired glucose tolerance than those with the ID and II genotypes (13.1 vs. 8.7%; P = 0.02). Insulin sensitivity was lower in participants with the DD genotype than in those with the II genotype (136 ± 63 vs. 147 ± 65 μmol · min⁻¹· kg ffm⁻¹ · mmol⁻¹ · l⁻¹; P = 0.02). The presence of the D allele was associated with a trend, albeit not significant, for reduced insulin secretion during the oral glucose tolerance test (P = 0.07). CONCLUSIONS:--The ACE I/D polymorphism is associated with whole-body insulin sensitivity and with impaired glucose tolerance in our healthy population. These findings confirm potential interactions between the RAS and glucose metabolism.