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.

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.

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.

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.

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)

A comparative metabolic study of two low-estrogen-dose oral contraceptives containing desogestrel or gestodene progestins.

OBJECTIVES: 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. STUDY DESIGN: 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. RESULTS: Oral contraceptive users had higher concentrations of high-density lipoproteins than did women in the control group (+10% to +20%, p < 0.001) 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%, p < 0.001). 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 (p < 0.01 to p < 0.001). 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. CONCLUSIONS: The metabolic profiles induced by these oral contraceptives were remarkably similar and may reflect the activity of the estrogen component.

PIP: 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.

Effects of a low-estrogen, desogestrel-containing oral contraceptive on lipid and carbohydrate metabolism.

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.

The effects of the menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women.

We have carried out intravenous glucose tolerance tests with measurement of plasma glucose, insulin and C-peptide concentrations on 66 premenopausal and 92 postmenopausal non-obese caucasian women. After adjustment for the effects of a number of possible confounding variables, including age and body mass index, there was little difference between pre and postmenopausal women in glucose and insulin concentrations either fasting or in response to intravenous glucose. Mathematical modelling analysis of the resultant plasma concentration profiles was used to obtain measures of insulin sensitivity, secretion and elimination, and non-insulin dependent glucose disposal. We found reciprocal differences in mean insulin sensitivity (increased by 50%) and non-insulin dependent glucose disposal (decreased by 30%). Plasma C-peptide response and pancreatic insulin secretion were markedly lower in the postmenopausal group (-35% and -51% respectively). However, the rate constant for insulin elimination was also lower in these women. As a result, intravenous glucose tolerance test plasma insulin concentrations were not significantly different between the two groups. We conclude that, despite the occurrence of little or no variation in plasma glucose and insulin concentrations, the menopause is associated with significant changes in insulin metabolism.

Fetal pancreatic beta-cell function in pregnancies complicated by maternal diabetes mellitus: relationship to fetal acidemia and macrosomia.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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, p < 0.0001), (2) fetal blood glucose and plasma insulin immunoreactivity (r = 0.57, p < 0.01), (3) fetal plasma insulin immunoreactivity and blood pH (r = -0.39, p < 0.05), and (4) fetal insulin/glucose ratio and degree of macrosomia (r = 0.76, p < 0.0001). CONCLUSION: Fetal pancreatic beta-cell hyperplasia is implicated in the pathogenesis of both fetal acidemia and macrosomia.

An apparently anomalous relationship between insulin and C-peptide concentrations in their initial response to intravenous glucose.

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.

Ageing and the response of plasma insulin, glucose and C-peptide concentrations to intravenous glucose in postmenopausal women.

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.

Effect of body mass index and fat distribution on insulin sensitivity, secretion, and clearance in nonobese healthy men.

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.

Evaluation of four mathematical models of glucose and insulin dynamics with analysis of effects of age and obesity.

Despite there being a number of mathematical models of glucose and insulin dynamics, there have been no evaluations of their operation in large groups of subjects. We have carried out intravenous glucose tolerance tests on a group of 182 healthy males, with determination of plasma glucose, insulin, and C-peptide concentrations. Parameters of glucose and insulin dynamics were determined using the minimal model of glucose disappearance, a minimal model of peripheral insulin delivery, and two different models of pancreatic insulin secretion (models I and II). Successful identifications were obtained in 96, 95, 76, and 100% of cases, respectively. The models were evaluated in terms of their ability to recover effects of obesity and aging on carbohydrate metabolism. The glucose disappearance model successfully detected the insulin resistance of both obesity and aging, whereas the peripheral insulin delivery model indicated an increased responsiveness of insulin delivery to glucose in obesity but detected no significant change associated with age. No parameter of pancreatic secretion model I exhibited a significant association with either age or obesity. Insulin secretion model II indicated that the hyperinsulinemia accompanying obesity resulted from both increased pancreatic secretion and decreased hepatic insulin uptake.