Angiotensin converting enzyme gene polymorphism and renal hemodynamic function in early diabetes

Abstract

An insertion/deletion (I/D) of the human angiotensin converting enzyme (ACE) gene is a major determinant of circulating ACE levels. Recent studies suggest that the ACE I/D polymorphism may influence the risk of developing nephropathy in patients with insulin dependent diabetes mellitus (IDDM), although the mechanism responsible for the effect is unknown. Since an early increase in glomerular filtration rate (GFR) may also be a risk factor for the development of diabetic nephropathy, we sought to determine if the ACE I/D polymorphism influenced renal hemodynamic function in patients with IDDM. Genomic DNA was obtained from 39 normotensive male and female patients with uncomplicated IDDM (mean duration 3.4 years; range 1 to 6 years), and from 20 non diabetic control subjects. The ACE I/D polymorphism was determined using the polymerase chain reaction. Subjects were divided into three groups based on their ACE genotype. Values for GFR, renal plasma flow (ERPF), filtration fraction, and renal vascular resistance were determined in both groups using classic inulin and paraaminohippurate clearance techniques. Blood glucose was maintained between 4 to 6 mmol/liter in the patients with IDDM using a modified euglycemic clamp technique. Mean values for GFR were significantly greater in patients homozygous for the I allele (143 +/- 7 ml/min/1.73 m2) compared to patients homozygous for the D allele (121 +/- 3 ml/min/1.73 m2, P < 0.01), while the mean GFR values for the heterozygous patients were intermediate. ERPF was also significantly greater in patients homozygous for the I allele (850 +/- 103 ml/min/1.73 m2) compared to patients homozygous for the D allele (672 +/- 31 ml/min/1.73 m2, P < 0.04), while there were no differences in the values for mean arterial pressure, glycosylated hemoglobin, or albumin excretion rates amongst the groups. There was no dominant effect of the ACE gene I/D polymorphism in the control group. These results suggest that: (1) the ACE gene I/D polymorphism influences glomerular filtration and renal plasma flow rates in patients with early uncomplicated IDDM; and (2) differences in renal hemodynamic function do not appear to explain the protection against the development of diabetic nephropathy offered by the I allele.