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


CONCLUSIONS
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.
Luik
P T
PT
Department of Internal Medicine, Division of Nephrology, University Hospital Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB, Groningen, The Netherlands.
Hoogenberg
K
K
Kerstens
M N
MN
Beusekamp
B J
BJ
De Jong
P E
PE
Dullaart
R P F
RP
Navis
G J
GJ
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000803:Angiotensin I / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics*; D004039:Diet, Sodium-Restricted; D005260:Female; D005838:Genotype; D015309:Glucose Clamp Technique; D006439:Hemodynamics / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012079:Renal Circulation / Q000235:genetics / Q000502:physiology*; D014563:Urodynamics / Q000187:drug effects / Q000502:physiology*
D001786:Blood Glucose; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A