Hemostatic risk factors and insulin sensitivity, regional body fat distribution, and the metabolic syndrome.

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/m(2)). 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 gamma-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.

Effects of low and high dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women.

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 < 0.01). Insulin elimination was increased at both the peripheral (16% to 43%, P < 0.05) and hepatic (18% to 31%, P < 0.05) levels. Insulin sensitivity was unaffected. Low density lipoprotein (LDL) cholesterol was reduced and high density lipoprotein (HDL) cholesterol increased with treatment. CONCLUSIONS: Postmenopausal hormone therapy with oestradiol plus dydrogesterone can favourably affect lipoprotein concentrations and can reverse menopause-associated changes in insulin secretion and elimination.

Randomized trial of effects of estradiol in combination with either norethisterone acetate or trimegestone on lipids and lipoproteins in postmenopausal women.

OBJECTIVE: This double-blind, randomized, multicenter study was designed to compare the blood lipid profiles in postmenopausal women after treatment with either a combined formulation containing estradiol (2 mg) and trimegestone (TMG 0.25 or 0.5 mg) or a standard hormone therapy (HT) containing estradiol and norethisterone acetate. METHOD: The serum concentrations of several lipids and lipoproteins were measured in this study, which was conducted over 13 cycles, each of 28 days. A total of 487 subjects were included, 349 of whom completed the study. RESULTS: The circulating concentrations of high density lipoprotein (HDL) cholesterol, HDL2 cholesterol and apolipoprotein (apo) AI increased from baseline in both estradiol/trimegestone groups, whilst levels of HDL3 cholesterol were unchanged. In contrast, in the estradiol/norethisterone acetate group, HDL cholesterol, HDL3 cholesterol and apo AI concentrations were reduced from baseline, while HDL2 cholesterol remained unchanged. Total cholesterol, low density lipoprotein (LDL) cholesterol, lipoprotein(a) and apo-B concentrations were reduced in all treatment groups. The concentration of triglycerides was elevated after treatment with the estradiol/trimegestone combinations but was unchanged after treatment with the estradiol/norethisterone acetate combination. The differences in the lipid pattern between the groups may be explained by the different pharmacological properties of the two progestogens: norethisterone exerts an androgenic effect and opposes the estrogen-induced increase in HDL cholesterol, whilst trimegestone has no androgenic effect and does not oppose the estrogenic effect. CONCLUSION: Overall, the results of this study suggest that the use of trimegestone in combination with estradiol may be preferable to norethisterone acetate because of the more favorable HDL and apo AI profile.

Effect of postmenopausal oestradiol and dydrogesterone therapy on lipoproteins and insulin sensitivity, secretion and elimination in hysterectomised women.

OBJECTIVES: To investigate in depth the metabolic effects of oestradiol-17 beta 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 beta 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<0.05) and 18.4% (P<0.001), respectively. HDL and HDL subfraction cholesterol concentrations rose during treatment with oestradiol alone, the rise being primarily in the HDL(2) subfraction (+21.6%, P<0.001). Fasting serum triglycerides rose 30% on oestradiol treatment. These increases were unaffected by the addition of dydrogesterone. Insulin sensitivity, secretion and elimination, body fat distribution and arterial function were not significantly affected at any stage of the therapy. CONCLUSIONS: The small study sample and high variability in measures of glucose and insulin metabolism may have contributed to the absence of the expected significant improvement in these parameters. Orally administered oestradiol had beneficial effects on total, LDL and HDL cholesterol which were unaffected by the addition of dydrogesterone.

Plasma total homocysteine concentrations are unrelated to insulin sensitivity and components of the metabolic syndrome in healthy men.

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.

Non-invasive assessment of vascular function; paradoxical vascular response to intravenous glucose in coronary heart disease.

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 7 min and remained above baseline up to 180 min 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 7 min and -25.8% at 180 min. 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+/-72.4 min ml(-1). 100 ml(-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.

Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk.

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/m2] 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<0.001), S:T (r=0.34, P=0.003), S:B (r=0.37, P<0.001), systolic and diastolic blood pressures (both 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<0.001). A negative correlation was observed between leptin and insulin sensitivity (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<0.001) emerged as independent predictors of plasma leptin concentrations (R2=0.56, P<0.001). After adjustment for BMI, only IVGTT insulin emerged as a significant predictor of plasma leptin concentrations (SC=0.56, P<0.001, R2=0.45, P<0.001). Factor analysis of plasma leptin concentrations and the variables that are considered relevant to the insulin resistance syndrome revealed a clustering of plasma leptin concentrations with a factor dominated by insulin resistance and high IVGTT insulin, separate from a high IVGTT glucose/central obesity factor and a high triglyceride/low high density lipoprotein cholesterol factor. Together, these factors accounted for 55.9% of the total variance in the dataset. In conclusion, interindividual variations in plasma leptin concentrations are strongly related to the principal components of the insulin resistance syndrome. Further studies are needed to determine whether the insulin-leptin axis plays a coordinating role in this syndrome and whether plasma leptin concentrations could provide an additional measure of cardiovascular risk.

Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease.

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 (age <45 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.

Third trimester fetal growth and measures of carbohydrate and lipid metabolism in umbilical venous blood at term.

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 birth-weight and subsequent adult disease.

High-density lipoprotein: relations to metabolic parameters and severity of coronary artery disease.

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).

Lipid and carbohydrate metabolic risk markers for coronary heart disease and blood pressure in healthy non-obese premenopausal women of different racial origins in the United Kingdom.

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=144), South Asian (n=128), and white (n=271) origin, premenopausal, non-obese, and aged 16-45 years. In comparison to whites, South Asians had lower serum high-density lipoprotein (HDL) cholesterol and HDL2 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, HDL3 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.

Association of insulin and insulin propeptides with an atherogenic lipoprotein phenotype.

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.

Insulin, intact and split proinsulin, and coronary artery disease in young men.

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 < .05 to P < .01) with basal proinsulin (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 R2 = .09) and dense LDL triglycerides (increase in R2 = .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.

Hormone replacement therapy and serum angiotensin-converting-enzyme activity in postmenopausal women.

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.

Relationships of insulin and intact and split proinsulin to haemostatic function in young men with and without coronary artery disease.

Glucose 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 < 0.05-0.001) characterized the patients. PAI-1 activity was more closely associated with insulin, intact proinsulin and des 31.32 proinsulin in patients than in controls, whereas the plasma levels of fibrinogen, activated factor VII (VIIa) and VIIag were stronger correlated with insulin and insulin propeptides in subjects without coronary artery disease. Very low density lipoprotein (VLDL) triglyceride was a strong determinant of VIIag and PAI-1 activity levels in both cases and controls, whereas VLDL triglyceride in controls and LDL cholesterol in patients related significantly to the plasma fibrinogen concentration. Thus, our data suggests that plasma insulin and insulin propeptides might be involved in the regulation of plasma fibrinogen concentration, factor VII level and plasma PAI-1 activity. However, apolipoprotein B-containing lipoproteins appear to influence the relationships between insulin, insulin propeptides and haemostatic factors in individuals with premature coronary artery disease.

Serum angiotensin-I-converting enzyme activity in women with cardiological syndrome X: relation to blood pressure and lipid and carbohydrate metabolic risk markers for coronary heart disease.

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.

Aldosterone concentration in normal, growth-retarded, anemic, and hydropic fetuses.

OBJECTIVE: To establish a gestational age reference range for fetal plasma aldosterone concentration and to determine whether anemia, growth retardation, or hydrops are associated with abnormal levels. METHODS: Aldosterone concentration was measured in umbilical venous blood obtained by funipuncture from pregnancies complicated by red blood cell isoimmunization (n = 17), fetal growth retardation (n = 8), and nonimmune hydrops fetalis (n = 17). Values were compared to reference ranges constructed from the study of samples obtained by funipuncture or at elective cesarean delivery from 40 essentially normal fetuses and maternal blood from 33 uncomplicated pregnancies. RESULTS: In the control group, the fetal plasma aldosterone concentration increased linearly with gestation, reaching adult levels at term. In nonimmune hydrops and red blood cell isoimmunization, the aldosterone concentration was increased. In the growth-retarded fetuses, the levels were not significantly different from normals. CONCLUSION: The gestational age-related increase in fetal plasma aldosterone concentration presumably reflects maturation of adrenal function. In certain abnormal pregnancies, fetal aldosterone concentrations increase.

Atrial natriuretic factor concentration in normal, growth-retarded, anemic, and hydropic fetuses.

OBJECTIVE: Our purpose was to establish a reference range with gestation for plasma concentrations of atrial natriuretic factor in fetal blood and to examine whether the concentration is altered in fetal anemia, acidemia, or hydrops. STUDY DESIGN: Atrial natriuretic factor was measured in umbilical venous blood taken by cordocentesis from pregnancies complicated by red blood cell isoimmunization (n = 17), intrauterine growth retardation (n = 12), and hydrops fetalis (n = 20) and from controls (n = 66). Additionally, maternal blood atrial natriuretic factor concentration was measured in 40 uncomplicated pregnancies. RESULTS: In the control group detectable levels were found from 16 weeks onward, and the fetal plasma atrial natriuretic factor concentration did not change with gestation. In anemic, acidemic, and hydropic fetuses the concentration was higher than in controls. CONCLUSION: Fetuses are capable of producing atrial natriuretic factor under physiologic conditions, and the concentration is increased appropriately in pathologic states.

Insulin propeptides in conditions associated with insulin resistance in humans and their relevance to insulin measurements.

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.

HRT mechanisms of action: carbohydrates.

Elevated insulin concentrations are frequently found in both men and women with coronary heart disease (CHD), and are likely to be due to insulin resistance. Hyperinsulinaemia may increase CHD risk by directly promoting atherogenesis, and insulin propeptides may also be important in this respect. However, increased insulin concentrations may adversely affect several other CHD risk factors, and it has been postulated that insulin resistance is a pivotal metabolic disturbance in a constellation of CHD risk factors. There is an association between hyperinsulinaemia and hypertension, although it is not known if this association is direct. Increased insulin concentrations are also associated with high triglycerides, low HDL or HDL2 concentrations, and increased small dense LDL. Obesity is also associated with insulin resistance, and it is the central or android body fat distribution which correlates with these metabolic disturbances. All these associated factors constitute a distinct syndrome--the insulin resistance syndrome--which is a frequent finding in patients with CHD, including microvascular angina. It is possible that the adverse associations of insulin resistance and dyslipidaemia are mediated through increased nonesterified fatty acid flux. Increased insulin levels are also associated with increases in the anti-fibrinolytic factor, plasminogen activator inhibitor-I (PAI-I). Whilst increased insulin levels are typically associated with insulin resistance, reduced hepatic insulin uptake may also be important. We now have techniques which can quantitate insulin secretion, hepatic uptake and release, elimination, and resistance. The menopause has appreciable effect on insulin and glucose metabolism. Estrogen and progesterone augment pancreatic insulin secretion, but the former reduces insulin resistance whilst the latter increases it.(ABSTRACT TRUNCATED AT 250 WORDS)