Activity of angiotensin-converting enzyme and risk of severe hypoglycaemiain type 1 diabetes mellitus

Background The insertion (I) allele of the angiotensin-converting-enzyme (A CE) gene occurs at increased frequency in endurance athletes. This associat ion suggests that low ACE activity is favourable for performance in conditi ons with limited substrate availability. Such conditions occur in endurance athletes during competition and in diabetic patients during insulin-induce d hypoglycaemia. Patients rely on preserved functional capacity to recognis e hypoglycaemic episodes and avoid progression by self-treatment. We studie d whether ACE activity is related to the risk of severe hypoglycaemia in ty pe 1 diabetes. Methods Consecutive adult outpatients with type 1 diabetes, untreated with ACE inhibitors or angiotensin-II-receptor antagonists (n=207) reported thei r experience of mild and severe hypoglycaemia during the previous 1 year an d 2 years. The patients were further characterised by diabetes history, deg ree of hypoglycaemia awareness, measurement of C-peptide, haemoglobin A(1c) , and serum ACE concentrations, and determination of ACE genotype. Findings Patients with the DD genotype had a relative risk of severe hypogl ycaemia in the preceding 2 years of 3.2 (95% CI 1.4-7.4) compared with thos e who had the II genotype. There was a significant relation between serum A CE activity and the rate of severe hypoglycaemia (relative risk per 10 U/L increment 1.4 [1.2-1.6]), corresponding to a 3.5 times higher risk for pati ents in the highest quartile than for those in the lowest quartile, Multipl e regression analysis showed that the effect of the ACE genotype was explai ned by its influence on serum ACE activity and that the only other signific ant determinants of the risk of severe hypoglycaemia were the degree of hyp oglycaemia awareness, beta -cell function, and duration of diabetes of more than 20 years. Interpretation ACE activity is a clinically significant marker of the risk of severe hypoglycaemia in patients with type 1 diabetes, especially in tho se with impaired defence against hypoglycaemia, These findings need to be c onfirmed in prospective studies.