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 consequenses in uncomplicated Type 1 diabetes mellitus. [Diabetologia (2003[Diabetologia ( ) 46:1131[Diabetologia ( -1139

Modulation of the Renal Response to ACE Inhibition by ACE Insertion/Deletion Polymorphism During Hyperglycemia in Normotensive, Normoalbuminuric Type 1 Diabetic Patients

“…This is consistent with previous findings concerning kidney function and blood pressure in type 1 diabetic subjects selected on the basis of ACE genotype, studied during hyperglycemia (31), and during infusions of angiotensins 1 and 2 (32). During normoglycemia, ramipril had a dose-dependent effect on renal hemodynamics that did not differ with genotype.…”

“…There is evidence to suggest that the reninangiotensin system is highly active during hyperglycemia in the renal circulation of subjects with type 1 diabetes (34,35). We and others (14,31,32) have demonstrated that these renal hemodynamic changes are greater in subjects carrying the ACE D allele than in those with the II genotype. Intraglomerular capillary hydraulic pressure, the main determinant of renal failure (36), is largely conditioned by interaction between the vasodilatory effects of nitric oxide (NO) and the vasoconstrictive effects of angiotensin 2.…”

“…This phenomenon may account for the impact of the ACE D allele on renal circulation in type 1 diabetes (14,31,32). The well-known endothelial dysfunction observed in people with diabetes is primarily explained by a low capacity for NO-dependent vasodilatation (38), as a direct consequence of hyperglycemia (39).…”

ACE Gene Polymorphism and Losartan Treatment in Type 2 Diabetic Patients With Nephropathy

“…20,21 These findings strongly suggest that the enhanced progression of kidney function loss in DD and ID patients is the result of increased intrarenal activity of ACE. 5 In addition, the ACE/DD genotype has been shown to enhance the risk of developing diabetic glomerulopathy lesions in type 2 diabetic patients with microalbuminuria and macroalbuminuria. 22 In addition to nongenetic factors, drug responses are also known to be influenced by inherited factors (i.e., pharmacogenomics).…”

“…5 A meta-analysis of 14,727 type 1 and type 2 diabetic patients revealed an enhanced risk for development of diabetic nephropathy in the DD genotype compared with the II genotype. 6 Originally, Parving et al observed that the deletion allele of the ACE polymorphism reduces the long-term beneficial effect of ACE inhibition on the progression of overt diabetic nephropathy in patients with type 1 diabetes.…”