The insertion allele of the ACE gene I/D polymorphism. A candidate gene for insulin resistance?

BACKGROUND: The insertion/deletion (ID) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with increased coronary heart disease (CHD), although the mechanism of this association is not apparent. We tested the hypothesis that the deletion allele of the ACE gene is associated with insulin resistance. METHODS AND RESULTS: We related ACE genotype to components of the insulin-resistance syndrome in 103 non-insulin-dependent diabetic (NIDDM) and 533 nondiabetic white subjects. NIDDM subjects with the DD genotype had significantly lower levels of specific insulin (DD 38.6, ID 57.1, and II 87.4 pmol.L-1 by ANOVA, P = .011). Non-insulin-treated subjects with the DD genotype had increased insulin sensitivity by HOMA % (DD 56.4%, II 29.4%, P = .027) and lower levels of des 31,32 proinsulin (DD 3.3, II 7.6 pmol.L-1, P = .012) compared with II subjects. There were no differences in prevalence of CHD or levels of blood pressure, serum lipids, or plasminogen activator inhibitor-1 (PAI-1) activity between the three ACE genotypes. In nondiabetic subjects there were no differences in insulin sensitivity, levels of insulin-like molecules, blood pressure, PAI-1, serum lipids, or CHD prevalence between the three ACE genotypes. CONCLUSIONS: We conclude that increased cardiovascular risk of the DD genotype is not mediated through insulin resistance or abnormalities in fibrinolysis. Conversely, we report an increased sensitivity in NIDDM subjects with the ACE DD genotype.

Association of proinsulin-like molecules with lipids and fibrinogen in non-diabetic subjects--evidence against a modulating role for insulin.

Elevated concentrations of proinsulin-like molecules, other than insulin, may be associated with abnormalities of cardiovascular risk factors, promoting atherogenesis and thrombosis. Using specific assays we examined the relationship of levels of insulin, intact proinsulin and des-31,32 proinsulin to blood pressure, lipids, fibrinogen, factor VII and albumin excretion rate in 270 europids with normal glucose tolerance. After correcting for age and body mass index, fasting and 2-h insulin concentrations were significantly associated with those of total and LDL-cholesterol (r = 0.18-0.22), HDL-cholesterol (both r = -0.20) and triglycerides (r = 0.21 and 0.18), but not with blood pressure. Concentrations of intact and des-31,32 proinsulin showed significant associations with those of total and LDL-cholesterol (r = 0.20-0.23), HDL-cholesterol (r = -0.31 and -0.32) and triglycerides (r = 0.22 and 0.26). Fasting insulin and intact proinsulin concentrations were significantly associated with fibrinogen (r = -0.15 and 0.18). Concentrations of proinsulin-like molecules comprised less than 10% of all insulin-like molecules, and so were calculated not to influence previously described relationships between insulin concentrations and cardiovascular risk factors measured using non-specific assays. In multiple regression analyses des-31,32 proinsulin concentration was more strongly associated with those of HDL-cholesterol (negatively), LDL-cholesterol and triglycerides than fasting insulin concentrations, while intact proinsulin replaced insulin concentrations in their relationships with fibrinogen. Our results show correlations between dyslipidaemia and proinsulin-like molecules at concentrations at which biological, insulin-like, activity appears unlikely. We also show relationships between LDL-cholesterol and fibrinogen and the proinsulin-like molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Associations of urinary albumin excretion rate with vascular disease in europid nondiabetic subjects.

Microalbuminuria and its association with vascular disease has previously been reported in nondiabetic individuals. The aims of this study were to determine whether there is a cross-sectional relationship between urinary albumin excretion rate and cardiovascular disease in nondiabetic subjects and to investigate hereditary predisposition to microalbuminuria by studying offspring of the main study population. Europid patients, aged 40-70 years, were randomly selected from a large inner-city general practice; there was a 62.6% attendance rate, and a study population of 959 remained after exclusions. Blood pressure, ankle systolic pressure, height, and weight were measured. Albumin excretion rate was calculated from overnight and morning urine collections. Venous blood was taken for lipids, fibrinogen, and factor VII; and resting electrocardiograms were carried out. Offspring (aged 15-40 years) of those found to be microalbuminuric were invited to attend for the same tests, and controls were selected by age and sex matching the parents. There was no association between parents' albumin excretion rate with that of their offspring, and there were no significant differences in albumin excretion rate between offspring subjects and their controls. There were no statistically significant associations of prevalent coronary heart disease (CHD) with albumin excretion rate or microalbuminuria in either sex [CHD in women: odds ratio (OR) 1.85; 95% confidence interval (CI) 0.19,9.0] [CHD in men: OR 2.13; 95% CI (0.64, 6.59)]. In women, there were significant associations between albumin excretion rate and peripheral vascular disease (positive) and fibrinogen (negative). Because established risk factors may not be as strongly associated with CHD in cross-sectional studies, we intend to follow this group prospectively.

Microalbuminuria: associations with height and sex in non-diabetic subjects.

OBJECTIVES: To study the association(s) between microalbuminuria and cardiovascular risk factors in non-diabetic subjects. DESIGN: Patients aged 40-75 years were randomly selected from a general practice list and invited to participate. SETTING: Health centre in inner city London. SUBJECTS: Of those invited, 1046 out of 1671 (62.6%) attended. Subjects were excluded for the following reasons: not being white (44); urinary albumin excretion rate > 200 micrograms/min (3); having a urinary infection (5); taking penicillamine or angiotensin converting enzyme inhibitors (7); older than 75 (2); having diabetes (25); missing data on glucose concentration (1). MAIN OUTCOME MEASURES: Glucose tolerance test results, albumin excretion rate from overnight and timed morning collections of urine; blood pressure; height. RESULTS: Mean albumin excretion rate was significantly lower in women than men (mean ratio 0.8, 95% confidence interval (0.69 to 0.91)). Mean albumin excretion rate was significantly associated with age, blood pressure, and blood glucose concentration (fasting, 1 hour, and 2 hour) in men and inversely with height. Men who had microalbuminuria in both samples were significantly shorter (by 5 cm (1.3 to 9.3 cm)) than those who had no microalbuminuria in either sample when age was taken into account. In the case of women only systolic pressure was significantly associated with albumin excretion rate. CONCLUSIONS: Microalbuminuria and short stature in men are associated. Cardiovascular risk has been associated with both of these factors and with lower birth weight. The inverse association of microalbuminuria with height is compatible with the suggestion that factors operating in utero or early childhood are implicated in cardiovascular disease. The higher prevalence of microalbuminuria in men compared with women may indicate that sex differences in cardiovascular risk are reflected in differences in albumin excretion rate.