The influence of the ACE ( I/D) polymorphism on systemic and renal vascular responses to angiotensins in normotensive, normoalbuminuric Type 1 diabetes mellitus

Abstract

Aim/hypothesis: The renin-angiotensin-aldosterone system is important in diabetic nephropathy, with the angiotensin-converting-enzyme DD-genotype being a renal risk factor. The D-allele is associated with higher ACE concentrations, but functional consequences in diabetes mellitus are not known. To analyse these consequences, we assessed renal and systemic responsiveness to angiotensin I infusion, with the response to angiotensin II as reference.

Methods: Uncomplicated Type 1 (insulin-dependent) diabetic patients with contrasting genotypes (11 II and 11 DD) were studied, during low (50 mmol/24 h) and liberal (200 mmol/24 h) sodium diet, during a euglycaemic clamp. Angiotensin I was infused at 4 and 8 ng.kg(-1).min(-1), 1 h each, followed by infusions of angiotensin II after a 2-h wash-out period.

Results: During low sodium, DD-homozygotes showed higher blood pressure sensitivity to angiotensin I ( DD 21+/-5% vs II 15+/-5%, p<0.01). With liberal sodium, no differences in blood pressure were detected, whereas angiotensin I induced a higher response of ERPF ( DD 40+/-5% vs II 35+/-4%, p<0.05) and RVR ( DD 105+/-20% and II 89+/-16% p<0.05) in DD-homozygotes. Differences were not explained by altered angiotensin II sensitivity. Multiple-linear regression analysis showed that angiotensin I induced responses of blood pressure and renal haemodynamics are higher in subjects carrying the DD-genotype. The magnitude of the responses was modulated by sodium intake and long-term glycaemic control.

Conclusion/interpretation: This study showed that responses of blood pressure and renal haemodynamics to angiotensin I are increased in diabetic subjects carrying the DD-genotype. Genotype-associated differences in ACE concentrations could, under certain circumstances, have functional consequences in uncomplicated Type 1 diabetes mellitus.