Is the influence of variation in the ACE gene on the prospective risk of Type 2 diabetes in middle-aged men modified by obesity?

There is strong evidence for the presence of a functional renin–angiotensin system in diabetogenic tissues, and ACE (angiotensin-converting enzyme) inhibitors may improve glucose metabolism in those individuals at high risk of developing T2DM (Type 2 diabetes). In the present study, we tested the hypothesis that subjects with genetically lower plasma and tissue ACE activity, because of their ACE [I/D (insertion/deletion)] genotype, would have a lower risk of T2DM in 2642 healthy middle-aged Caucasian men (mean age, 56 years) followed-up for 15 years. Obesity was the strongest predictor of T2DM, with an HR (95% CI) [hazard ratio (95% confidence interval)] of 3.74 (2.66-5.26) (P<0.0001). Overall there was no association between ACE genotype (II homozygotes, n=623; and D allele carriers, n=2019) and risk of T2DM, and although in lean men there was no genotype difference in risk in D allele carriers compared with II homozygotes [adjusted HR=0.75 (95% CI, 0.46–1.22)], in obese (body mass index >30 kg/m²) men the risk of T2DM was higher [adjusted HR=4.26 (95% CI, 1.30–13.93)] with a genotype–obesity interaction of P=0.01. A similar pattern of risk was seen by re-analysis of a previously published case-control study, where D allele carriers had a non-significant 1.30 (0.97–1.74)-fold higher risk of developing T2DM than II homozygotes when non-obese, but a 1.79 (1.17–2.72) (P=0.007)-fold higher risk when obese. Further prospective studies are needed to confirm these findings. The ACE D allele may worsen glucose metabolism, which could raise the prospective T2DM risk in obese men, but not in lean men. In obesity, adipose tissue undergoes inflammatory infiltration and the subsequent higher levels of pro-inflammatory angiotensin II may explain this association.