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

Background The insertion (I) allele of the angiotensin-converting-enzyme (ACE) gene occurs at increased frequency in endurance athletes. This association suggests that low ACE activity is favourable for performance in conditions with limited substrate availability. Such conditions occur in endurance athletes during competition and in diabetic patients during insulin-induced hypoglycaemia. Patients rely on preserved functional capacity to recognise hypoglycaemic episodes and avoid progression by self-treatment. We studied whether ACE activity is related to the risk of severe hypoglycaemia in type 1 diabetes. Methods Consecutive adult outpatients with type 1 diabetes, untreated with ACE inhibitors or angiotensin-II-receptor antagonists (n=207) reported their experience of mild and severe hypoglycaemia during the previous 1 year and 2 years. The patients were further characterised by diabetes history, degree 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 hypoglycaemia in the preceding 2 years of 3.2 (95% CI 1.4-7.4) compared with those who had the II genotype. There was a significant relation between serum ACE 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 patients in the highest quartile than for those in the lowest quartile, Multiple regression analysis showed that the effect of the ACE genotype was explained by its influence on serum ACE activity and that the only other significant determinants of the risk of severe hypoglycaemia were the degree of hypoglycaemia 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 those with impaired defence against hypoglycaemia, These findings need to be confirmed in prospective studies.