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Summary Whether hormone replacement therapy (HRT) is beneficial for coronary heart disease (CHD) is controversial. We hypothesized that continuous combined transdermal HRT may have benefits on CHD risk markers without the potential adverse effects seen with certain other HRT regimens. Sixty apparently healthy postmenopausal women, aged 40‐65 years, entered a prospective, double-blind, randomized, placebo-controlled clinical trial; 55 women completed the 6-month study. Women received either transdermal oestradiol 17b 0AE05 mg and norethisterone acetate 0AE125 mg daily, or identical placebo. Circulating markers of vascular function and remodelling, forearm blood flow, lipids and lipoproteins, glucose and insulin, and haemostatic safety parameters were measured at baseline and after treatment. Compared with placebo after 6 months, HRT administration resulted in decreased E-selectin (P

In this study, we concurrently examined the effects of 8 and 40 weeks of growth hormone replacement (GHR) on lipids, lipoprotein composition, low-density lipoprotein (LDL) size, very-low-density lipoprotein (VLDL) apolipoprotein (apo)B kinetics and LDL apoB kinetics. Eight weeks of GHR did not alter lipid profiles. Forty weeks of GHR increased high-density lipoprotein-cholesterol (HDL-C) concentration (P =.01), nonsignificantly reduced LDL-C (P =.06), and reduced the HDL/LDL-C ratio (P =.04). Forty weeks of GHR increased HDL free cholesterol (P =.03), total cholesterol (P =.01), and cholesterol ester (P

OBJECTIVE: Levels of angiotensin I-converting enzyme (ACE) in blood are associated with variation in cardiovascular disease risk. Serum ACE activity in women may be reduced by combined oestrogen-progestogen hormone replacement therapy (HRT). However, the relative contribution of each hormonal component to this observation is uncertain. We investigated ACE activity in two groups of healthy postmenopausal women receiving HRT regimens. DESIGN: The first group received placebo or oestrogen-only HRT randomly (oral conjugated equine oestrogens or transdermal 17 beta-oestradiol). The second group was treated with oestrogen-only HRT (oral 17 beta-oestradiol) followed by sequential oestrogen-progestogen HRT (17 beta-oestradiol and dydrogesterone). MEASUREMENTS: Assay of blood for soluble ACE activity before and whilst receiving HRT. RESULTS: In the first group, oral conjugated equine oestrogens significantly reduced (P < 0.01) ACE activity by 18% on average relative to pretreatment whereas non-significant changes of -9% and +7% were seen with transdermal 17 beta-oestradiol or placebo treatment, respectively. In the second group oestrogen-only HRT significantly reduced (P < 0.001) ACE activity by 15% on average. The reduction during both the oestrogen-only and combined phases of sequential treatment was 12% and 19%, respectively, compared with pretreatment values (P < 0.01 and P < 0.001). ACE activity also differed significantly (P < 0.05) between the two phases of sequential treatment. CONCLUSIONS: Both oestrogen-only and oestrogen-progestogen HRT may reduce ACE activity in blood. Oestrogen and progestogen may exhibit additive effects on blood ACE activity.

Objectives: To investigate in depth the metabolic effects of oestradiol-17 β both alone and in combination with the progestagen dydrogesterone. Methods: Fifteen hysterectomised postmenopausal women were studied before treatment and after 24 weeks taking oestradiol-17 β alone (2 mg per day), then following a further 6 (oestrogen-alone phase) and 12 (oestrogen plus progestagen phase) weeks with inclusion of dydrogesterone (10 mg per day for days 17–28 of each 28 day cycle). Measurements at each visit included fasting serum lipid and lipoprotein concentrations, insulin sensitivity, secretion and elimination by modelling analysis of intravenous glucose tolerance test glucose, insulin and C-peptide concentrations, body fat distribution by dual-energy X-ray absorptiometry (DXA) and arterial function by carotid artery ultrasound. Results: Significant reductions were seen throughout in total and LDL cholesterol. The net reductions in total and LDL cholesterol by the end of the study were 5.8% (P

Plasma homocysteine levels are lowered by insulin and can be elevated in insulin-resistant states. However, it is uncertain whether homocysteine and insulin resistance or components of the metabolic (insulin resistance) syndrome are related in healthy individuals. Total homocysteine concentrations were measured by gas chromatography-mass spectrometry in samples from 100 male participants in the second follow-up cohort of the Heart Disease and Diabetes Risk Indicators in a Screened Cohort Study. Members of this cohort have each undergone an iv glucose tolerance test with measurement of insulin sensitivity by minimal model analysis. Age ranged from 31--62 yr (mean, 46.8), body mass index from 20.6--36.5 kg/m(2) (mean, 26.3), insulin sensitivity from 0.0--9.6 min/mU.L (mean, 2.32), and homocysteine concentrations from 7.5--30.6 micromol/L (mean, 12.2). In univariate correlation, homocysteine concentrations were unrelated to insulin sensitivity or to components of the metabolic syndrome, including fasting serum triglycerides, high density lipoprotein cholesterol, high density lipoprotein subfraction 2 cholesterol, blood pressure, uric acid, systolic blood pressure, or body mass index. These measures were, nevertheless, highly intercorrelated. These findings strengthen the possibility that in healthy humans, homocysteine metabolism is not substantially affected by insulin action.

Elevated plasma levels of triglyceride-rich lipoproteins, a decreased high-density lipoprotein (HDL) cholesterol concentration, hyperinsulinemia, and impaired fibrinolytic function frequently aggregate in patients with premature coronary heart disease (CHD). Experimental studies suggest that the cytokine tumor necrosis factor alpha (TNFalpha) produced by adipocytes plays a part in the regulation of triglyceride and glucose metabolism. The present study examined whether TNFalpha is implicated in these metabolic and fibrinolytic disturbances in young postinfarction patients. TNFalpha levels were determined in two groups of young (age45 years) male postinfarction patients (n = 92 and 60) and in matched, population-based control subjects (n = 63). Plasma TNFalpha was higher in patients than in controls (4.1 +/- 1.6 v2.5 +/- 0.4 pg/mL, P.0001). In hyperlipidemic patients, TNFalpha levels correlated significantly with the concentrations of very-low-density lipoprotein (VLDL) triglyceride and cholesterol and negatively with HDL cholesterol. Treatment with bezafibrate decreased VLDL triglycerides and increased HDL cholesterol, but did not affect TNFalpha levels. The TNFalpha concentration also correlated significantly with fasting glucose and proinsulin concentrations, as well as glucose and proinsulin levels after glucose ingestion. In contrast, no relations were found with the insulin level or degree of insulin resistance. The present results provide clinical evidence for a basic role of TNFalpha in hypertriglyceridemia, glucose intolerance, and the etiology of premature CHD.

Metabolic risk markers for coronary heart disease (CHD) were determined in apparently healthy females of differing racial origins residing in the United Kingdom. The females were of black (n = 122), Oriental (n = 114), South Asian (n = 128), and white (n = 271) origin, premenopausal, non-obese, and aged 16 to 45 years. In comparison to whites, South Asians had lower serum high-density lipoprotein (HDL) cholesterol and HDL 2 cholesterol and higher fasting and oral glucose tolerance test plasma insulin responses. Black females had higher fasting plasma and oral glucose tolerance test insulin and lower serum triglyceride and glucose compared with white females. Orientals differed from whites in having higher fasting and oral glucose tolerance test insulin concentrations. Resting systolic or diastolic blood pressures, total serum cholesterol, HDL 3 cholesterol, and low-density lipoprotein (LDL) cholesterol did not differ between groups. Whereas previous studies have demonstrated similar differences in representative samples from different ethnic communities, our results clearly demonstrate that differences also exist in young healthy females, individuals considered to have the least risk of CHD.

Background Glucose intolerance and hyperinsulinemia are common disturbances in nondiabetic men with premature coronary artery disease (CAD). To investigate the relation between insulin-like molecules and severity of coronary atherosclerosis, 62 consecutive nondiabetic men presenting with a first myocardial infarction before the age of 45 were studied along with 41 healthy, age-matched, male, population-based control subjects. Methods and Results Specific two-site immunoradiometric assays were used to distinguish intact proinsulin, (des 31,32)proinsulin, and “true” insulin in fasting plasma and during an oral glucose tolerance test (OGTT). Global coronary atherosclerosis and number and severity of distinct stenoses were determined in the patients in 15 proximal coronary arterial segments by use of separate semiquantitative classification systems. The patients had a two- to threefold increase in insulin and insulin propeptide concentrations in the fasting state as well as during the OGTT. Severity of coronary atherosclerosis correlated significantly ( P P r =.40) and the proinsulin area under the curve (AUC) ( r =.34), basal insulin ( r =.31), basal C peptide ( r =.30), and the glucose AUC ( r =.30). In multiple stepwise regression analysis including insulin-like molecules, major plasma lipoproteins, and lipoprotein subfractions, basal proinsulin (increase in R 2 =.09) and dense LDL triglycerides (increase in R 2 =.10) predicted 19% of the variation of the global coronary atherosclerosis score after adjustment for age, body mass index, fasting insulin concentration, and VLDL triglycerides. Conclusions This study shows that young, nondiabetic, male survivors of myocardial infarction are truly hyperinsulinemic during an OGTT and suggests a close association between proinsulin and coronary atherosclerosis.

Our purpose was to investigate the relationship between fetal pancreatic beta-cell function and fetal acidemia and macrosomia in pregnancies complicated by maternal diabetes mellitus.A cross-sectional study at the Harris Birthright Research Centre for Fetal Medicine, London, was performed. In 32 pregnancies complicated by maternal diabetes mellitus cordocentesis was performed at 36 to 39 weeks' gestation for the measurement of umbilical venous blood pH, PO2, PCO2, lactate, and glucose concentration; plasma insulin immunoreactivity; and insulin/glucose ratio. A reference range for plasma insulin and insulin/glucose ratio was constructed by studying fetal blood samples from 80 women who did not have diabetes mellitus.Mean umbilical venous blood pH was significantly lower and plasma insulin immunoreactivity and insulin/glucose ratio were significantly higher than the appropriate normal mean for gestation. There were significant associations between (1) maternal and fetal blood glucose concentrations (r = 0.95, p0.0001), (2) fetal blood glucose and plasma insulin immunoreactivity (r = 0.57, p0.01), (3) fetal plasma insulin immunoreactivity and blood pH (r = -0.39, p0.05), and (4) fetal insulin/glucose ratio and degree of macrosomia (r = 0.76, p0.0001).Fetal pancreatic beta-cell hyperplasia is implicated in the pathogenesis of both fetal acidemia and macrosomia.

Intravenous glucose tolerance tests (IVGTTs) with determination of plasma glucose, insulin, and C-peptide concentrations were performed in 136 men and 154 women. It was found that in 4% of men and 12% of women the plasma concentration of insulin exceeded that of C-peptide during the initial response to glucose. Subjects exhibiting this phenomenon had lower fasting and post-glucose C-peptide concentrations than those who did not; however, there were no statistically significant differences in glucose or insulin concentrations. The phenomenon was age-related, being absent from individuals aged 35 years and under, while in older age groups it appeared to be more prevalent in women than in men, suggesting an additional effect of menopause. However, in three follow-up IVGTTs performed in a subgroup of postmenopausal women over a period of 18 months, the phenomenon failed to recur in any of the individuals who first exhibited it, although it did occur in others. Our observations suggest the existence of an age-related but intermittent decrease in pancreatic insulin secretion, which does not lead to any significant change in plasma insulin concentrations, possibly as a result of reduced hepatic uptake of insulin. One consequence appears to be an excess of insulin over C-peptide during the early part of the IVGTT, which is probably related to the different distributional kinetics of the two peptides.

The effects of variation in body mass index (BMI; kg/m2) and body fat topography on insulin sensitivity, secretion, and clearance were determined in a group of 146 nonobese nondiabetic males. Volunteers underwent an i.v. glucose tolerance test, with determination of plasma glucose, insulin, and C-peptide levels. BMI was taken as a measure of overall adiposity, while skinfold thickness ratios were used to assess the centrality of fat distribution and the localization of central fat within the trunk. Measurements of insulin sensitivity, secretion, and clearance were obtained by mathematical modelling of the i.v. glucose tolerance test concentration profiles. Increasing BMI and centrality of fat distribution had no significant effect on glucose tolerance, but were independently associated with diminished insulin sensitivity and increased insulin secretion. The elevation in secretion occurred almost entirely during the second phase of pancreatic insulin release. These results show that the variations in insulin sensitivity and secretion that have often been reported in obesity are also present in a group within the normal range of BMI. However, the absence of any decrease in hepatic uptake, also reported in the obese, indicates that this might be an additional mechanism recruited to maintain glycemic control at higher levels of adiposity. Localization of central fat in the lower trunk was correlated with elevated first phase insulin secretion, but no concomitant change in insulin sensitivity. There may, therefore, be a direct effect of the distribution of central fat on insulin secretion.

Aims Randomized trials have not demonstrated coronary heart disease benefit from hormone replacement therapy (HRT). We hypothesized that low-dose HRT may avoid harm. Methods and results We studied the effects of HRT on lipids and coagulation in women with acute coronary syndromes. A total of 100 post-menopausal women .55 years were enrolled between 2 and 28 days after an acute coronary syndrome and randomized to oral oestradiol-17b 1 mg plus norethisterone acetate 0.5 mg daily, or matching placebo, and followed for up to 12 months. Levels of lipids, lipoproteins, and haemostasis markers were measured at baseline, 3, and 6 months. There were no significant differences in lipid levels between the two groups, probably due to concomitant statin use. Antithrombin and factor VII levels were significantly lower in the HRT group, whereas fibrinogen was significantly decreased in the placebo group. No evidence of increased coagulation activation was observed, nor of adverse cardiovascular outcomes [odds ratio (OR) 0.63 (95% confidence intervals 0.31–1.31)]. Conclusion Low-dose HRT may give cardiovascular benefit. These findings require confirmation in a full clinical trial with evaluation of cardiovascular outcomes as the primary objective.

The aim of this study was to determine the significance of insulin resistance as an independent risk factor for impaired prognosis in patients with chronic heart failure (CHF).In CHF, impaired insulin sensitivity (S(I)) indicates abnormal energy metabolism and is related to decreased exercise capacity and muscle fatigue. The relationship between insulin resistance (i.e., low S(I)) and survival in patients with CHF has not been established.We prospectively studied 105 male patients with CHF due to ischemic (63%) or non-ischemic (37%) etiology. All patients were in clinically stable condition (age 62 +/- 1 year, New York Heart Association [NYHA] functional class 2.6 +/- 0.1, left ventricular ejection fraction [LVEF] 28 +/- 2%, peak oxygen uptake [Vo(2)] 18.2 +/- 0.7 ml/kg/min). Insulin sensitivity was assessed from glucose and insulin dynamic profiles during an intravenous glucose tolerance test using the minimal model technique.During a mean follow-up period of 44 +/- 4 months, 53 patients (50%) died. Patients with S(I) below the median value (median: 1.82 min(-1) x microU x ml(-1).10(4); n = 52) had worse survival (at two years 61% [range 47% to 74%]) than patients with S(I) above the median value (n = 53; at two years 83% [range 73% to 93%]; risk ratio [RR] 0.38, 95% confidence interval [CI] 0.21 to 0.67; p = 0.001). Both patient groups were similar in terms of age, NYHA functional class, and body composition parameters (dual-energy X-ray absorptiometric scan; p0.2), but patients with a lower S(I) had a lower LVEF (24 +/- 2% vs. 33 +/- 3%) and peak Vo(2) (16.8 +/- 1.0 ml/kg/min vs. 19.7 +/- 1.0 ml/kg/min; both p0.05). On univariate Cox analysis, higher S(I) predicted better survival (RR 0.56, 95% CI 0.35 to 0.89; p = 0.015). On stepwise multivariate analysis, S(I) predicted mortality independently of other variables.In patients with CHF, lower S(I) relates to higher mortality, independent of body composition and established prognosticators. Impaired S(I) may have implications in the pathophysiology of CHF disease progression. Therapeutically targeting impaired insulin sensitivity may potentially be beneficial in patients with CHF.

Disturbances in the thrombotic and fibrinolytic systems are a feature of insulin resistance, obesity, and the metabolic syndrome. However, there are few studies in which these relationships have been explored in mainly asymptomatic individuals using sophisticated measures of insulin sensitivity and regional adiposity. Variables of the hemostatic system were measured in 106 men (aged 32–68 yr; body mass index, 20–34 kg/m2). Insulin sensitivity was measured by minimal model analysis and regional adiposity by dual energy x-ray absorptiometry. Clustering of intercorrelated variables was assessed by the statistical technique of factor analysis. Plasma levels of procoagulant factors VII and X, anticoagulant proteins C and S, and plasminogen activator inhibitor-1 correlated positively with total and percent central body fat (r = 0.25–0.38; P < 0.05) and negatively with insulin sensitivity (except protein S; r = −0.24 to −0.35; P < 0.05). On factor analysis, procoagulant factors VII and X, proteins C and S, and plasminogen activator inhibitor-1 were components of the cluster of variables that explained the greatest proportion of the variance in the data (39.2%). Other variables included in this cluster were those typical of the metabolic syndrome and also serum γ-glutamyl transferase activity. These results suggest that factors VII and X and proteins C and S are features of the intercorrelated disturbances of the metabolic syndrome. Associations with adiposity and liver enzyme activity suggest the involvement of hepatic fat deposition.

Summary objective Menopause diminishes insulin secretion and elimination, increases risk of diabetes and adversely affects lipoprotein metabolism. This study was undertaken to establish whether oral oestradiol plus dydrogesterone postmenopausal hormone therapy can modify these changes. design Randomized prospective trial of postmenopausal women taking low dose therapy (1 mg/day oestradiol-17 beta with 5 or 10 mg/day dydrogesterone for days 17–28 of each cycle, n = 15) or high dose therapy (2 mg/day oestradiol-17 beta with 10 or 20 mg/day orally administered dydrogesterone, n = 9). measurements Patients underwent measurement of glucose, insulin and C-peptide in the fasting state and during an intravenous glucose tolerance test (IVGTT) at baseline and after 12 and 24 cycles of treatment. Modelling analysis was used to derive measures of insulin secretion, elimination and sensitivity. Fasting serum lipids, lipoproteins and apolipoproteins were also measured. results In both groups there were significant reductions in fasting glucose, insulin and C-peptide. Pancreatic insulin secretion during the IVGTT was increased by treatment (ranging from 45% to 92%, P

Background In healthy individuals, insulin administration causes an increase in forearm blood flow which is dependent on the effects of insulin on the vascular endothelium. Glucose, administered as an intravenous bolus, produces a transient hyperinsulinaemic response. We hypothesized that the insulin response to an intravenous glucose challenge during the intravenous glucose tolerance test might lead to increases in forearm blood flow in healthy individuals, and that such a response might be altered in patients with coronary heart disease. Methods and Results Healthy individuals (n=10, aged 41·6±3·0 years, mean±SEM) and patients with angiographically proven coronary heart disease (n=13, aged 65·5±2·4 years) underwent an intravenous glucose tolerance test with simultaneous measurement of right forearm blood flow at 28 time points, using mercury-in-silastic venous occlusion plethysmography. In controls, forearm blood flow increased to a mean of 31·7% above baseline values at 7min and remained above baseline up to 180min after intravenous glucose. In contrast, patients with coronary heart disease exhibited an opposite response, with forearm blood flow decreasing to a mean of −16·2% below baseline values at 7min and −25·8% at 180min. Marked group differences emerged in net changes from baseline in forearm blood flow throughout the intravenous glucose tolerance test, expressed as incremental areas under the forearm blood flow profiles (controls: +351·3±121·7; coronary heart disease patients: −244·3±72·4minml−1.100ml−1, P =0·001). Conclusions We have demonstrated for the first time that in healthy individuals forearm blood flow increases after an intravenous bolus of glucose, and that paradoxically, this response is reduced below baseline forearm blood flow in patients with coronary heart disease. Further studies are needed to determine whether plethysmographic measurement of forearm blood flow after an intravenous bolus of glucose could provide a clinically useful non-invasive test for the diagnosis of occult coronary heart disease.

Abstract —In humans, production of the adipocyte-derived peptide leptin has been linked to adiposity, insulin, and insulin sensitivity. We therefore considered that alterations in plasma leptin concentrations could constitute an additional component of a metabolic syndrome of cardiovascular risk. To explore this hypothesis, we employed factor analysis, a multivariate statistical technique that allows reduction of large numbers of highly intercorrelated variables to composite, biologically meaningful factors. Seventy-four men [age, 48.4±1.3 years (mean±SEM); body mass index (BMI), 25.6±0.3 kg/m 2 ] who were free of coronary heart disease and diabetes underwent anthropometric measurements (subscapular-to-triceps [S:T] and subscapular-to-biceps [S:B] skinfold thickness ratios, measurement of fasting plasma leptin, and an intravenous glucose tolerance test (IVGTT) for assessment of insulin sensitivity. Plasma leptin concentrations were correlated with BMI ( r =0.57, P r =0.34, P =0.003), S:B ( r =0.37, P r =0.24, P =0.044), fasting triglycerides ( r =0.31, P =0.007), serum uric acid ( r =0.35, P =0.003), fasting glucose ( r =0.32, P =0.003) and insulin ( r =0.33, P =0.004), and IVGTT insulin ( r =0.63, P r =−0.32, P =0.006). No significant correlations emerged between plasma leptin concentrations and age, high density lipoprotein cholesterol, or IVGTT glucose. In multivariate regression analyses, BMI (standardized coefficient [SC] =0.40, P =0.001), fasting insulin (SC=0.23, P =0.036), and IVGTT insulin (SC=0.51, P R 2 =0.56, P P R 2 =0.45, P

AIM—To compare measures of carbohydrate and lipid metabolism in umbilical venous blood after birth at term in pregnancies with normal and retarded fetal growth during the third trimester. METHODS—Three groups of pregnancies reaching term, in which fetal growth had been prospectively monitored by repeated ultrasound measurements during the third trimester, were studied. Sequential fetal abdominal circumference measurements remained above the 10th centile in 42 (normal size, normal growth group), below the 10th centile but did not depart further than 1.5 SD (small, normal growth group), or below the 10th centile and subsequently fell away by more than 1.5 SD before delivery (small, growth retarded group). Birthweight, neonatal morphometric measures (ponderal index, mid arm:head circumference ratio, subscapular and triceps skinfold thickness), umbilical venous blood concentrations of glucose, insulin, pro-insulin, des 31,32 proinsulin, total cholesterol, free cholesterol, cholesterol ester, triglycerides, lipoprotein (a), apolipoprotein A-1 and apolipoprotein B were measured. RESULTS—The median birthweight of the three groups was significantly different (3570, 2569, and 2277 g, respectively). Median values of ponderal index and mid arm:head circumference ratio were significantly lower in the small, growth retarded group and did not differ between the small and normal size groups with normal growth. Both groups with small fetuses had significantly lower mean glucose and cholesterol ester concentrations, and higher mean free cholesterol:cholesterol ester ratios, compared with the normal size, normal growth group. The group showing fetal growth retardation had mean total cholesterol and mean cholesterol ester concentrations that were significantly lower than those of both the other two groups. Mean des 31,32 proinsulin concentrations were low in both groups of small fetuses, but only significantly so in the group without fetal growth retardation. Mean insulin, proinsulin, free cholesterol, triglycerides, lipoprotein(a), apolipoprotein A-1, apolipoprotein B concentrations and the ratio of A-1:B were similar in all three groups. CONCLUSION—The similarity in the umbilical venous blood carbohydrate and lipid profile at term between pregnancies with documented third trimester fetal growth retardation and those with "genetically" small babies argues against a major role for intrauterine nutritional deprivation as a cause for the association between birthweight and subsequent adult disease. Keywords: carbohydrate and lipid metabolism; fetal growth retardation; umbilical venous blood; ultrasonography.

The regulation of plasma high-density lipoprotein (HDL) cholesterol level by the joint influence of plasma lipoprotein lipids, lipoprotein lipase (LPL), hepatic lipase (HL), cholesteryl ester transfer protein (CETP), oral glucose tolerance, and postload plasma insulin and proinsulin levels was investigated in young postinfarction patients and healthy population-based control subjects. In addition, the association between HDL cholesterol and the number and severity of coronary stenoses previously reported in this cohort of young postinfarction patients was further investigated by analyzing the determinants and angiographic relations of HDL subclasses measured by gradient gel electrophoresis. The following parameters showed significant univariate relations with HDL cholesterol level in the patient group: very-low-density lipoprotein (VLDL) cholesterol and triglyceride, low-density lipoprotein (LDL) triglyceride, and postload plasma insulin concentrations, preheparin plasma LPL mass, and postheparin plasma HL activity. In the control group, significant correlations with HDL cholesterol concentration in addition to those noted among the patients were found for body mass index (BMI), LDL cholesterol level, postload plasma intact proinsulin concentration, and LPL activity in postheparin plasma. In contrast to the patients, no significant relations were noted for postload plasma insulin level and preheparin plasma LPL mass. Multiple stepwise regression analysis showed that 42% of the variability of HDL cholesterol in the patients could be accounted for by VLDL cholesterol concentration (29%), LDL triglyceride level (7%), and postheparin plasma HL activity (8%), whereas the corresponding figure in controls was 35% (VLDL cholesterol concentration [9%] and postheparin plasma HL activity [26%]. The strength of the relationships of HDL cholesterol and HDL subclasses to the coronary stenosis score was similar and statistically significant (r = .25 to .36). When the metabolic parameters that correlated with HDL cholesterol and HDL subclass concentrations in univariate analysis were used as covariates, all relations to the coronary stenosis score disappeared. This clearly indicates that the influence of triglyceride-rich lipoproteins and lipolytic enzymes needs to be considered when assessing the association between HDL cholesterol and coronary artery disease (CAD).

A characteristic lipoprotein phenotype, including hypertriglyceridemia, a low high-density lipoprotein (HDL) cholesterol concentration, and a predominance of small, dense low-density lipoprotein (LDL) particles, is linked to insulin resistance and hyperinsulinemia. Individuals with these characteristics are supposed to be at increased risk of developing coronary heart disease (CHD). To address this issue further, relations between basal and postload glucose, insulin and insulin propeptide concentrations, and subfractions of apolipoprotein (apo) B—containing lipoproteins were examined in 62 consecutive Swedish nondiabetic men who had experienced a first myocardial infarction before the age of 45. A total of 41 age-matched, population-based healthy men were investigated as controls. Highly specific immunoradiometric assays were used for measuring intact proinsulin and des 31,32proinsulin levels. In all, 39% of the patients were found to be glucose-intolerant, and basal and postload hyper(pro)insulinemia were characteristic features irrespective of glucose tolerance category. Hypertriglyceridemic (HTG) lipoprotein phenotypes with a low HDL cholesterol concentration dominated among the patients, and hyperinsulinemia was linked to hypertriglyceridemia and putatively atherogenic lipoprotein traits, such as increased particle numbers of small very—low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) and triglyceride enrichment of LDL. The corollary of these findings is that insulin resistance is a characteristic feature of young postinfarction patients and is accompanied by a complex atherogenic lipoprotein phenotype, new components of which are an abundance of small cholesteryl ester—rich VLDL and an elevated LDL triglyceride concentration.

The mechanisms by which hormone replacement therapy (HRT) reduces the risk of coronary heart disease (CHD) are incompletely understood, but may include direct arterial effects. We examined the effect of oestrogen/progestagen HRT on serum angiotensin-converting-enzyme (ACE) activity in postmenopausal women. After 6 months, ACE activity was reduced by 20% (p < 0.001) on average in 28 treated women but remained unchanged in 16 controls. Serum ACE activity is modifiable by gonadal steroids and changes in serum ACE may represent a novel mechanism by which HRT reduces CHD risk in women.

Polymorphism of the angiotensin-I-converting enzyme (ACE) gene is associated with variations in serum ACE activity and the incidence of cardiovascular disease. Whether a similar association exists with cardiological syndrome X (chest pain, positive ECG exercise test, and normal angiography) is unclear. As ACE activity affects vascular tone, it could be involved in the pathogenesis of this syndrome. We measured serum ACE activity in 18 postmenopausal women with syndrome X and in 18 healthy controls matched for age, adiposity, and menopausal status. The relationship of ACE activity to coronary heart disease risk factors was also examined within these groups. Serum ACE activity did not differ significantly between women with syndrome X and controls. Neither blood pressure, serum total cholesterol, triglyceride, nor high density lipoprotein subfraction 2 cholesterol was associated with ACE activity in either patient group. However, serum high density lipoprotein cholesterol, high density lipoprotein subfraction 3 cholesterol, and apolipoprotein-A-I and -A-II were inversely associated with ACE activity in women with syndrome X, but not in controls. Insulin sensitivity, fasting plasma glucose, insulin, and C-peptide as well as their postglucose challenge concentration profiles were not significantly associated with ACE activity in either group. We conclude that serum ACE activity and, consequently, ACE polymorphism are not associated with syndrome X and are largely independent of metabolic risk factors in these women.

Routine insulin assays measure not only biologically active insulin but also the relatively inactive propeptides, proinsulin and desdipeptide proinsulin. Such measurements may be misleading if insulin propeptide levels are increased, as has been reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). Inferences regarding insulin resistance, based on hyperinsulinemia, could thus be invalidated where routine insulin assays have been used. We have measured plasma insulin levels using a routine assay, together with measurements of the major circulating insulin propeptides, intact proinsulin and des 31,32proinsulin, in various clinical situations associated with apparently increased insulin levels and insulin resistance. Major increases of insulin propeptide levels relative to insulin levels were not seen in obese subjects or in patients taking oral contraceptives or danazol, or in obese subjects compared with non-obese controls. Although the insulinemic responses observed with routine radioimmunoassay in these situations associated with insulin resistance are not confounded by major changes in the proportion of circulating insulin propeptides, further studies will be necessary to validate investigations in other insulin-resistant states.

Our objective was to compare the effects of low-estrogen-dose oral contraceptives containing desogestrel or gestodene progestins on metabolic risk markers for coronary heart disease.A cross-sectional comparison of 70 women who used a formulation that contained 30 micrograms ethinyl estradiol and 150 micrograms desogestrel, 43 women who used a formulation that contained 30 micrograms ethinyl estradiol and 75 micrograms gestodene, and 54 women who did not use steroidal contraceptives was performed.Oral contraceptive users had higher concentrations of high-density lipoproteins than did women in the control group (+10% to +20%, p0.001) primarily because of increases in high-density lipoprotein subfraction 3. High-density lipoprotein subfraction 2 concentrations were higher in users of the desogestrel formulation. Low-density lipoprotein cholesterol concentrations were normal in oral contraceptive users, but triglyceride concentrations were high (+80% to +100%, p0.001). Fasting glucose, insulin, and C-peptide concentrations were similar in the three groups, but their responses to a glucose load were higher in oral contraceptive users than in controls (p0.01 to p0.001). The late plasma insulin response to glucose was higher in the women who used the gestodene formulation than in those who used the desogestrel formulation.The metabolic profiles induced by these oral contraceptives were remarkably similar and may reflect the activity of the estrogen component.A comparative study of low-dose oral contraceptives (OCs) containing either desogestrel or gestodene failed to detect any major differences in metabolic risk markers for coronary heart disease. Included in the investigation were 70 women who used an OC composed of 30 mcg of ethinyl estradiol and 150 mcg of desogestrel, 43 women who took an OC containing 30 mcg of ethinyl estradiol and 75 mcg of gestodene, and 54 controls who did not use hormonal contraception. The study subjects, 18-35 years of age, were recruited from family planning clinics and general practices in England. Concentrations of serum total cholesterol, high-density lipoproteins (HDL), and apolipoproteins were higher in both groups of OC users than in controls, primarily because of increases in the protective HDL subfraction 3. Low-density lipoprotein cholesterol concentrations were unaffected, but serum triglyceride concentrations were elevated in OC users. Fasting plasma glucose, insulin, and C-peptide concentrations were similar in all three groups. The only significant differences between the two OCs were in HDL subfraction 2 concentrations (higher with desogestrel) and the late oral glucose tolerance test plasma insulin response (higher with gestodene). Further research and development, perhaps involving modification of the estrogen component, are needed to avoid the increased triglyceride concentrations and insulin responses associated with these low-dose formulations.

1. Eighty-six apparently healthy postmenopausal women not receiving hormone replacement therapy were given an intravenous glucose tolerance test. Plasma glucose, insulin and C-peptide concentrations were determined in fasting and post-glucose challenge samples. 2. Using a multivariate regression model, with predictor variables of chronological age, menopausal age and body mass index, neither chronological age nor menopausal age correlated with fasting or post-challenge plasma glucose or C-peptide concentrations. In contrast, menopausal age was positively associated with fasting plasma insulin concentration (P = 0.038, model r2 = 0.107), insulin area (P = 0.01, model r2 = 0.236) and incremental insulin area (P = 0.024, model r2 = 0.243). This relationship could not be explained by differences in lifestyle variables of alcohol consumption, physical activity, previous duration of oral contraceptive usage, history of cigarette smoking or body mass index. 3. Our findings suggest that loss of ovarian function is associated with hyperinsulinaemia, possibly via alterations in the clearance of circulating insulin from the plasma. The hyperinsulinaemia observed may contribute to the increased risk of cardiovascular disease seen in postmenopausal women.

Fasting serum lipids, lipoproteins and apolipoproteins, and fasting plasma glucose, insulin and C-peptide were measured in 107 non-users and 83 users of an oral contraceptive containing the progestin desogestrel, combined with 20 micrograms ethinyl estradiol. Plasma glucose, insulin and C-peptide concentrations during an oral glucose tolerance test (OGTT) were measured in a subgroup of 69 non-users and 39 users. Compared with non-users, users had higher concentrations of total, high density lipoprotein (HDL), HDL subfraction 3 and very low density lipoprotein (VLDL) cholesterol, total triglycerides, VLDL triglycerides, apolipoproteins AI and AII and fasting plasma insulin. There were no differences in HDL subfraction 2, low density lipoprotein cholesterol and apolipoprotein B. OGTT glucose was 60% higher in the users and OGTT insulin response 19% higher. The OGTT C-peptide response did not differ. The effects of 20 micrograms ethinyl estradiol combined with 150 micrograms desogestrel on lipid, lipoprotein, glucose and insulin metabolism are similar to those described previously with a 30 micrograms ethinyl estradiol combination containing the same dose of desogestrel. The relatively favourable metabolic profile associated with the higher estrogen dose desogestrel combination is maintained at the lower dose.

SummaryGlucose intolerance, hyperinsulinaemia, dyslipoproteinaemia and multiple disturbances of haemostatic function are characteristics of young men with premature coronary artery disease. The relations between glucose, insulin and insulin propeptides, in the fasting state, and after an oral glucose load, and haemostatic function were examined in 62 consecutive non-diabetic men with myocardial infarction before the age of 45 and in 41 age-matched healthy men. “True” hyperinsulinaemia, raised plasma concentrations of insulin propeptides, dyslipoproteinaemia, elevated plasma levels of fibrinogen, factor VII antigen (VIIag) and plasminogen activator inhibitor-1 (PAI-1) activity, and lower antithrombin activity (p