Androgenicity and obesity are independently associated with insulin sensitivity in postmenopausal women

An increase in androgenicity may contribute to the development of insulin resistance in postmenopausal women. Increased androgenicity in women has been found to be associated with the development of type 2 diabetes. In addition, obesity and central obesity are associated with greater androgenicity. Insulin sensitivity, androgenicity, and body composition were characterized in 34 nondiabetic postmenopausal women age 72 +/- 1 years (mean +/- SEM) to test the hypothesis that androgenicity is a predictor of insulin sensitivity independent of measures of obesity. Androgenicity was measured using levels of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and free androgen index (FAI). Insulin sensitivity (S(I)) was determined from a frequently sampled intravenous glucose tolerance test. Body composition measures included body mass index (BMI) and dual energy x-ray absorptiometry measurements of total and central fat mass. S(I) was found to be associated with total fat mass (r = -.51, P =.002), central fat mass (r = -.62, P =.0001), BMI (r = -.55, P =.0008), SHBG levels (r =.65, P =.0001), and FAI (r = -.41, P =.01). SHBG levels were inversely correlated with central fat mass (r = -.59, P =.0002). Using multiple regression, SHBG and central fat mass were the only significant independent predictors of S(I), accounting for 50% of its variance (r =.71, P =.0001); total fat mass, BMI, total and free testosterone, DHEA-S, androstenedione, and FAI did not enter the model. We conclude that there is a significant association between insulin sensitivity and androgenicity in postmenopausal women that is independent of obesity. Interventions to decrease androgenicity may therefore be useful in improving insulin sensitivity in postmenopausal women.     

Correlates of plasma very-low-density lipoprotein concentration and composition in premenopausal women

Potential correlates of plasma very-low-density lipoprotein (VLDL) concentration and composition were studied in a sample of 75 premenopausal women. Fasting plasma free fatty acid (FFA) levels, as well as plasma glucose and insulin levels in the fasting state and during an oral glucose tolerance test, displayed significant positive correlations with plasma triglyceride (TG) and VLDL-TG levels (P less than .005). Plasma post-heparin lipoprotein lipase (LPL) activity, measured in a subsample of 31 women from the original sample, was negatively correlated with plasma TG, VLDL-cholesterol (CHOL), VLDL-TG, and VLDL-apolipoprotein (apo) B concentrations (.005 greater than P less than .05). Multivariate analyses showed that, after LPL was considered, the insulin area was the only other metabolic variable studied that was significantly correlated with VLDL-apo B concentration, whereas fasting FFA levels were significantly correlated with plasma TG and VLDL-TG levels. ANOVA revealed that plasma VLDL-CHOL, VLDL-TG, and VLDL-apo B levels were not associated with the glucose area, but were significantly associated with the insulin area (P less than .005). When the effect of insulin area was controlled for, the plasma FFA levels did not contribute significantly to the variance in VLDL-CHOL and VLDL-apo B, but showed an independent effect on VLDL-TG levels (P less than .05). Finally, stepwise multiple regression analyses indicated that once the variance explained by plasma LPL activity and by the insulin area was considered, no other metabolic variable could account for the variation in VLDL-CHOL and VLDL-apo B levels, whereas fasting FFA levels explained a further 5% of the VLDL-TG variance and one third of the variance observed in the VLDL-TG/apo B ratio.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of human ovarian insulin receptors in vivo

Insulin participates in regulating ovarian function in normal and in pathological states. This effect of insulin may be mediated by ovarian insulin receptors. We have previously characterized human ovarian insulin receptors and began to examine their regulation in vitro. The present study examines regulation of human ovarian insulin receptors in vivo. Stromal ovarian tissue was obtained from 21 women during an indicated surgical procedure. Ten women were premenopausal and 11 were postmenopausal. Specific 125I-insulin binding to stromal ovarian fragments ranged from 2.5% to 7.3%/mg protein. 125I-insulin binding to stromal fragments correlated positively with 125I-insulin binding to circulating leucocytes (r = .57; P less than .01). When postmenopausal and premenopausal women were analyzed separately, this relationship persisted in postmenopausal women (r = .70; P less than .05), but not premenopausal women. 125I-insulin binding to stromal ovarian fragments correlated negatively with age (r = -.63; P = .005). 125I-insulin binding to stromal ovarian fragments tended to correlate negatively with plasma insulin levels in postmenopausal women (r = -.67; P = .06), but not in premenopausal women. Plasma insulin levels correlated negatively with serum SHBG (r = -.62; P = .003). The percent free testosterone levels correlated positively with plasma insulin levels in premenopausal women (r = .95; P = .0001), but not in postmenopausal women.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adiponectin Is a Link Among Inflammation, Insulin Resistance, and High-Density Lipoprotein Cholesterol But Is Not Associated With Paraoxonase Activity in Premenopausal Women

The aim of this study was to evaluate whether insulin sensitivity, inflammatory response, and plasma lipid profile are associated with circulating adiponectin levels in nondiabetic healthy women. The authors also assessed whether adiponectin has any effect on high-density lipoprotein cholesterol–linked paraoxonase 1 (PON-1) activity and on the susceptibility of low-density lipoproteins to oxidation. Plasma adiponectin was measured in 91 nondiabetic premenopausal women, and the patients were then divided into quartiles. Circulating adiponectin was found to be associated with body mass index ( r =.55, P <.001). After adjustment for body mass index, adiponectin showed an inverse correlation with the homeostasis model assessment of insulin resistance (HOMA-IR) ( r =−.41, P <.001) and a positive correlation with high-density lipoprotein cholesterol ( r =.43, P <.001). In linear regression analysis, HOMA-IR, tumor necrosis factor α, and high-density lipoprotein cholesterol levels were found to be independently associated with adiponectin. However, high-density lipoprotein cholesterol–linked PON-1 activity and the susceptibility of low-density lipoproteins to in vitro oxidation did not seem to be related to plasma adiponectin concentrations.     

Plasma cholesterol esterification and transfer, the menopause, and hormone replacement therapy in women.

With the onset of the menopause, plasma lipids and lipoprotein metabolism changes toward a more atherogenic profile that is improved by HRT. To determine whether cholesterol esterification rate (CER) and transfer of cholesteryl esters from high density lipoproteins to apolipoprotein B-containing lipoproteins are affected by menopause and HRT, plasma newly synthesized cholesteryl ester transfer (NCET) activity, CER and plasma lipids, lipoproteins, and apolipoprotein concentrations were measured in perimenopausal women (age range: 40-55 yr), including 49 premenopausal women and 32 postmenopausal women who were subsequently randomized to receive either placebo or 17-beta estradiol/norethisterone for 6 months. Plasma NCET (P = 0.03) and CER (P = 0.008) were significantly higher in postmenopausal women. Plasma low density lipoprotein cholesterol concentration, high density lipoprotein concentration, and body mass index were independent predictors of plasma NCET in premenopausal women, and plasma triglyceride and apolipoprotein B concentrations were corresponding predictors in postmenopausal women. When data were adjusted for plasma triglyceride, plasma NCET activity was no longer significantly different (P = 0.81) between premenopausal and postmenopausal women. Plasma NCET and CER did not change significantly in postmenopausal women during HRT. These data suggest that the determinants of plasma NCET activity after menopause and increased levels of triglyceride-rich lipoprotein acceptors of cholesteryl esters may lead to increased plasma NCET that is not reduced by HRT in postmenopausal women.     

Whole-body insulin sensitivity,low-density lipoprotein (LDL) particle size,and oxidized LDL in overweight,nondiabetic men

Insulin resistance is often accompanied by elevated plasma triglycerides (TG) and a preponderance of small, dense low-density lipoprotein (LDL) particles. However, it remains unclear whether or not insulin resistance is related to LDL particle size, independent of plasma TG. We sought to determine the strength of the relationships among these variables in a group of overweight, nondiabetic men (N = 34; body mass index [BMI], 25 to 35 kg/m(2); age, 50 to 75 years), as well as to examine the possible relation between insulin sensitivity and oxidized LDL (oxLDL). We also examined the strength of the relationships between these lipid variables and estimates of insulin sensitivity using calculated indices based on fasting insulin and glucose concentrations. Insulin sensitivity (Si) was significantly associated with total TG (r = -0.61, P <.001), very-low-density lipoprotein (VLDL)-TG (r = -0.60, P <.001), and LDL size (r =.414, P <.05). LDL size was also significantly associated with TG (r = -0.73, P <.001), VLDL-TG (r = -0.73, P <.001), high-density lipoprotein-cholesterol (HDL-C) (r = 0.65, P <.001), the quantitative insulin sensitivity check index (QUICKI) (rho = 0.46, P <.01), and the homeostatic model for the assessment of insulin resistance (HOMA-IR) (rho = -0.45, P <.01). Si was a significant predictor of LDL size, with age and BMI also independent contributors to the variance in LDL size (R(2) = 0.172). However, when TG and HDL-C were added to the model, Si was no longer a significant predictor of LDL size. The correlation between Si and oxLDL was weak, but stastically significant (rho = -0.40, P =.02). These data suggest that the relation between Si and LDL size is largely mediated by plasma TG, and that Si is only weakly related to oxLDL in overweight, nondiabetic men.     

Menopause is associated with reduced protection from postprandial lipemia

Deficiency of endogenous estrogens has been associated with a higher incidence of coronary heart disease (CHD) in women. We investigated whether natural menopause is associated with reduced protection from postprandial lipemia, which represents a risk indicator of CHD. Twenty-three postmenopausal women (mean age, 50+/-1 [SD] years; body mass index, 24.6+/-2.8 kg/m(2)) and 21 premenopausal women matched for age and body mass index (age, 49+/-1 years; body mass index, 24. 1+/-2.6 kg/m(2)) underwent an oral vitamin A fat-loading test. Vitamin A is a marker of the metabolism of chylomicrons and chylomicron remnants. All women were normolipidemic, were in good health, were nonsmokers, and used no medication. Postprandial lipids and vitamin A were measured at hourly intervals up to 12 hours. In postmenopausal women, plasma total cholesterol and LDL cholesterol concentrations were significantly higher. Fasting plasma triglyceride (TG) concentrations were 1.14+/-0.57 mmol/L in postmenopausal women and 0.88+/-0.33 mmol/L in premenopausal women (P=NS). In the postprandial phase, postmenopausal women had higher plasma TG (13.0+/-6.1 versus 9.5+/-3.3 mmol x L(-1) x h(-1); P=0.024) and vitamin A (54.1+/-22.9 versus 35.9+/-9.6 mg x L(-1) x h(-1); P=0. 001) responses. To correct for the possible confounding effect of fasting TG, 13 postmenopausal women were carefully matched with 19 premenopausal women. Although fasting TG levels were identical (0. 72+/-0.20 versus 0.73+/-0.21 mmol/L), differences in postprandial vitamin A (45.3+/-14.5 versus 33.0+/-7.7 mg x L(-1) x h(-1); P=0.006) and incremental TG (ie, after subtraction of baseline TG) (3.2+/-1.8 versus 2.3+/-1.0 mmol x L(-1) x h(-1); P=0.023) persisted between postmenopausal and premenopausal women. Natural menopause is associated with aggravated postprandial lipemia in women matched for age and body mass index. Higher postprandial lipemia potentially explains the relation of TGs and CHD mortality risk in postmenopausal women.     

The postmenopausal ovary is not a major androgen-producing gland

It is currently believed that the postmenopausal ovary remains a gonadotropin-driven, androgen-producing gland. However, the adrenal contribution to circulating androgen levels may explain some conflicting results previously reported. In addition, the steroidogenic potential and gonadotropin responsiveness of the postmenopausal ovary have not been recently reassessed. Plasma T, bioavailable T, free T, androstenedione (Adione), and dehydroepiandrosterone sulfate levels were measured in postmenopausal or ovariectomized women with complete adrenal insufficiency, compared with women with intact adrenals. A stimulation human chorionic gonadotropin test (on d 0, 3, and 6) was performed in postmenopausal women with adrenal insufficiency. Dexamethasone was administered for 4 d in postmenopausal women with intact adrenals. Intraovarian T and androstenedione were also measured in homogenates of ovarian tissue from postmenopausal women. Immunocytochemistry was performed on postmenopausal ovaries and premenopausal controls to detect the presence of steroidogenic enzymes (P-450 aromatase, P-450 SCC, 3beta HSD, and P-450 C17) and gonadotropin receptors. Plasma androgen levels were below or close to the limit of the assay in all women with adrenal insufficiency. They were similar in postmenopausal and oophorectomized women with normal adrenals. No hormonal changes were observed after human chorionic gonadotropin injections in women with adrenal insufficiency. In contrast, a dramatic decrease of all steroids was observed after dexamethasone administration in postmenopausal women with intact adrenals. Intraovarian T and androstenedione levels were negligible in postmenopausal ovarian tissue. P-450 aromatase was absent from the 17 ovaries studied, and the enzymes for androgen biosynthesis were either absent (n = 13) or present in very low amounts (n = 4). In all the postmenopausal ovaries, FSH and LH receptors were completely absent. In the absence of adrenal steroids, postmenopausal women have no circulating androgens. This result is consistent with the immunocytochemical studies showing the almost constantly absent steroidogenic enzymes and LH receptors in the postmenopausal ovary. Thus, the climacteric ovary is not a critical source of androgens. The arrest of androgen secretion after menopause may impact significantly on women's health.     

Relationship of sex hormone-binding globulin to lipid, lipoprotein, glucose, and insulin concentrations in postmenopausal women.

Sex hormones play a major role in determining the risk of cardiovascular disease. While several studies have shown that reduced sex hormone-binding globulin (SHBG) is associated with increased insulin and triglyceride and decreased high-density lipoprotein cholesterol (HDLC) in premenopausal women, little data are available for postmenopausal women. We hypothesized that in postmenopausal women decreased SHBG would be associated with an atherogenic pattern of cardiovascular risk factors. We measured SHBG, lipids, lipoproteins, glucose, and insulin concentrations, and systolic and diastolic blood pressure in 101 postmenopausal women. SHBG was negatively associated with triglyceride (r = -.21) and insulin (r = -.47) concentrations and positively associated with HDLC concentrations (r = .47). After adjustment for overall adiposity (body mass index) and upper body adiposity (as measured by the ratio of waist to hip circumferences), SHBG was still associated with HDLC and insulin, but not with triglyceride. Sex hormones were not related to systolic and diastolic blood pressure. The results may help to explain an association of increased androgenicity, as measured by a lower SHBG concentration, with diabetes and risk of cardiovascular disease in older women.     

Linkage and association studies of the lipoprotein lipase gene with postheparin plasma lipase activities, body fat, and plasma lipid and lipoprotein concentrations: the HERITAGE Family Study

Lipoprotein lipase (LPL) is responsible for the hydrolysis of triglyceride (TG)-rich lipoproteins. The aims of the present study were (1) to test for potential linkages (sib-pair method) between postheparin plasma lipase (lipoprotein and hepatic lipase) activities, body fatness, plasma lipid concentrations, and LPL polymorphisms (Ser447Ter and a tetranucleotide repeat) and microsatellite markers flanking the LPL locus (D8S261 and D8S258); and (2) to investigate associations between the LPL Ser447Ter (S447X) polymorphism and these phenotypes. Data on 190 parents and 312 adult offspring from 99 Caucasian families participating in the HERITAGE Family Study were available for this study. Data were adjusted for the effects of age within sex, and lipases, lipid variables, and abdominal visceral fat were further adjusted for fat mass. A suggestive linkage was observed only between the S447X polymorphism and very-low-density (VLDL)-apolipoprotein B (apo B) (332 sib-pairs, P = .013). The S447X polymorphism was not associated with body fat phenotypes or postheparin plasma LPL (PH-LPL) activity (men, P = .19; women, P = .47). In contrast, the X447 allele carriers had lower plasma TG (men and women, P = .01), VLDL-TG (men and women, P = .01), and VLDL-apo B (men and women, P = .009). The relationships between the X447 allele and plasma TG, VLDL-TG, and VLDL-apo B in both genders were observed in obese (body mass index [BMI] > or = 30 kg/m2) but not in normal-weight (BMI < 25 kg/m2) subjects. Thus, the S447X polymorphism of the LPL gene is not associated with body fatness and postheparin plasma lipase activities. However, the obese carriers of the X447 allele have plasma TG, VLDL-TG, and plasma cholesterol/high-density lipoprotein cholesterol (HDL-C) levels equivalent to those of normal-weight sedentary adults.     

Effect of menopausal status on lipolysis: comparison of plasma glycerol levels in middle-aged, premenopausal and early, postmenopausal women

To determine whether menopausal status affects systemic lipolysis, we measured plasma glycerol concentrations following an overnight fast and during euglycemic hyperinsulinemic conditions (40 mU x m(-2) x min(-1)) in 43 middle-aged, premenopausal women (mean +/- SE; 47 +/- 0.4 years) and 26 early, postmenopausal (51 +/- 0.8 years) women. In addition, body composition was measured by dual-energy x-ray absorptiometry and abdominal fat distribution by computed tomography (CT). Postmenopausal women had greater amounts of whole body (fat mass, 22.8 +/- 1.4 v 17.4 +/- 1.2 kg; percent fat, 34.7 +/- 1.2 v 29.1 +/- 1.4; both P <.01) and intra-abdominal fat (89.0 +/- 6.5 v 55.9 +/- 4.4 cm2; P <.01) compared with premenopausal women. Despite greater adiposity, plasma glycerol concentrations were similar between pre- and postmenopausal women following an overnight fast (142.7 +/- 9.7 v 136.1 +/- 6.4 micromol/L) and at 30 minutes (112.7 +/- 5.5 v 108.4 +/- 4.5 micromol/L ) and 120 minutes (92.7 +/- 4.5 v 97.5 +/- 5.9 micromol/L ) into the euglycemic hyperinsulinemic clamp. Plasma glycerol levels remained similar after statistical adjustment for fat mass, percent fat, and intra-abdominal fat. Moreover, no differences in plasma glycerol were observed in pre- and postmenopausal women matched (+/- 5%) for fat mass (n = 22/group) or intra-abdominal fat (n = 15/group). In premenopausal women, plasma glycerol levels at 30 and 120 minutes of hyperinsulinemia were positively related to adiposity measures (range, r =.314 to r =.493; P <.05 to P <.01), although no relationships were found in postmenopausal women. Our results suggest no effect of menopausal status on plasma glycerol levels under postabsorptive or hyperinsulinemic conditions.     

Contribution of glucose tolerance and plasma insulin levels to the relationships between body fat distribution and plasma lipoprotein levels in women.

Numerous interrelated metabolic and morphological variables such as plasma insulin levels, glucose tolerance and abdominal obesity are associated with changes in plasma lipoprotein levels. The present study was undertaken to differentiate, using a multivariate approach, the respective contributions of plasma glucose and insulin levels, obesity and regional adipose tissue distribution to the variance in plasma lipoproteins. The study group was composed of 69 healthy premenopausal women (age 35.4 +/- 5.0 years (mean +/- s.d.); percent body fat 40.7 +/- 10.1). Indices of carbohydrate metabolism showed significant univariate correlations with triglyceride (TG) and/or cholesterol (CHOL) content of plasma VLDL, LDL and HDL (P less than 0.05). Multivariate analyses indicated that the explained variance in plasma VLDL-TG (R2 x 100 = 44 percent, P less than 0.05) and LDL-apoprotein (apo) B levels (R2 x 100 = 33.1 percent, P less than 0.08) was entirely accounted for by indices of carbohydrate metabolism and body fat distribution, whereas total body fatness added no significant contribution to these models. Multivariate analyses also revealed that the best possible regression model to predict the variation in plasma HDL2-CHOL levels only included computed tomography-derived deep abdominal adipose tissue area (P less than 0.0001). All other variables were unable to further improve the explained variance in plasma HDL2-CHOL levels. In partial correlation analyses, indices of carbohydrate metabolism and the waist-to-hip circumference ratio (WHR) remained significantly correlated with plasma VLDL-TG and LDL-apo B levels after adjustment of VLDL-TG and LDL-apo B for either insulin and glucose levels, or for the WHR (P less than 0.08). After correcting for deep abdominal fat accumulation, no significant correlation was observed between indices of carbohydrate metabolism and plasma HDL2-CHOL levels whereas deep abdominal fat showed significant correlations with HDL2-CHOL levels (P less than 0.05) after correction for indices of carbohydrate metabolism. These results suggest that both disturbances in glucose-insulin homeostasis and abdominal obesity are significantly associated with changes in plasma VLDL-TG and LDL-apo B levels and that these associations are partly independent from each other. These results also indicate that mechanisms other than disturbances in glucose homeostasis and hyperinsulinemia are responsible for the association between the level of deep abdominal fat and plasma HDL2-CHOL levels.     

Plasma cholesteryl ester fatty acid composition, insulin sensitivity, the menopause and hormone replacement therapy

This study was designed to determine the effect of menopause and hormone replacement therapy (HRT) on plasma cholesteryl ester fatty acid (CEFA) composition and insulin sensitivity and the relationships between these variables in perimenopausal women (aged 40-55 years) including 49 who were premenopausal and 32 who were postmenopausal. Plasma cholesteryl ester proportions of dihomo-gamma-linolenic acid (20:3 n-6) were correlated significantly with insulin sensitivity index (r=-0.319, P=0.005), fasting serum insulin levels (r=0.230, P=0.038), body mass index (r=0.242, P=0.03) and per cent body fat (r=0.329, P=0.003) in perimenopausal women (n=81). Similar associations were observed in premenopausal women. Regression analysis suggested the relationships between 20:3 n-6 proportions and indices of insulin action may be partly mediated by levels of adiposity. In postmenopausal women, 6 months of HRT significantly (P=0.008) increased the ratio of arachidonic acid (20:4 n-6) to linoleic acid (18:2 n-6), which is an indicator of activity in the pathway of 20:4 n-6 synthesis, compared with placebo. These findings suggest that the type of fat in the diet indicated by plasma CEFA composition is linked to adiposity and insulin action. They also suggest that in postmenopausal women, HRT may increase the synthesis of 20:4 n-6, which is the precursor for eicosanoids with important cardiovascular functions.     

Transdermal 17 beta-estradiol combined with oral progestogen increases plasma levels of insulin-like growth factor-I in postmenopausal women.

In order to evaluate the effect of postmenopausal estrogen replacement therapy on the plasma levels of the insulin-like growth factor-I (IGF-I) 12 postmenopausal women aged 44 to 59 years were studied. The control group consisted of 15 healthy premenopausal women aged 20-44 years. In the postmenopausal women the plasma levels of IGF-I, gonadotrophins and sex hormones were determined before and after 3 and 6 months cyclic replacement therapy with transdermal 17 beta-estradiol (E2 100 micrograms patches applied twice weekly) combined with oral chlormadinone acetate (2 mg daily for 7 days in each cycle). Basal levels of estradiol (E2), IGF-I, dehydroepiandrosterone sulphate (DHEA-S), testosterone and androstenedione were lower, but gonadotropin levels were higher in postmenopausal than in premenopausal women. In all the women studied age was inversely correlated with IGF-I levels (r = -0.793, p less than 0.001) and with DHEA-S concentrations (r = -0.435, p less than 0.02). In postmenopausal women transdermal estradiol administration restored the circulating E2 levels to the early follicular range and increased the IGF-I levels (from 76.4 +/- 9.2 micrograms/l to 141.8 +/- 20.8 micrograms/l; p less than 0.01). Transdermal estradiol decreased gonadotrophin levels without changes in concentration of DHEA-S, testosterone, androstenedione and SHBG. In postmenopausal women before and during replacement therapy a positive correlation was found between estradiol and IGF-I concentrations (r = -0.439, p less than 0.01). These results suggest that cyclic replacement therapy with transdermal 17 beta-estradiol in combination with chlormadinone acetate given orally increase the plasma levels of IGF-I in postmenopausal women.     

Steroid hormone interconversions in human adipose tissue in vivo.

The objective of this study was to demonstrate directly, by measurement of arteriovenous concentration differences, the interconversion of steroid hormones in human subcutaneous adipose tissue in vivo. Simultaneous arterial (or arterialized) and adipose tissue-venous plasma samples were collected from eight men and seven women, for measurement of estradiol, estrone, testosterone, and androstenedione concentrations by radioimmunoassay. Despite the heterogeneity of the groups (premenopausal and postmenopausal women, one subject with insulin-dependent diabetes mellitus), some very consistent findings emerged. Both estrogens were added to plasma during passage through adipose tissue in almost all subjects (P less than .01 for each hormone). In all the men but one, testosterone was removed from plasma, and the arteriovenous difference was correlated with the arterial concentration (r = .70, P = .05). In all the women but one (in whom there was no change), the testosterone concentration increased during passage through adipose tissue. The handling of androstenedione was less consistent. This study demonstrates the feasibility of direct measurement of the peripheral production or utilization of steroid hormones, and confirms the belief that adipose tissue is an important site for such interconversions.     

Reappraisal of the role of insulin in hypertriglyceridemia

We have previously proposed a sequential hypothesis to help explain the genesis of endogenous hypertriglyceridemia in man. This scheme states that insulin resistance → hyperinsulinemia → increased very low density lipoprotein (VLDL)-triglyceride (TG) production rate → increased plasma TG levels. In this study we have measured each of these metabolic variables in 34 nonobese subjects all consuming the same isocaloric diet. We have found highly significant positive correlations between insulin resistance and insulin response (r = 0.74, p < 0.0001), between insulin response and VLDL-TG production rate (r = 0.72, p < 0.0001), and between VLDL-TG production rate and plasma TG level (r = 0.88, p < 0.0001). Furthermore, these relationships were found to be independent of any possible effect of obesity. Thus, highly positive correlations were found for each step of the scheme, and we believe the over-all hypothesis is greatly strengthened. Additionally, the cross correlation between plasma TG levels and insulin response was also highly significant (r = 0.73, p < 0.0001). On the other hand, glucose response did not correlate with any measure of TG metabolism. On the basis of these results we conclude that insulin plays an important role in the genesis of endogenous hypertriglyceridemia through its influence on VLDL-TG production.     

Gender differences in relation to leptin concentration and insulin sensitivity in nondiabetic Chinese subjects.

OBJECTIVE: To investigate the relationship between fasting plasma leptin concentrations and insulin resistance in Chinese men and women. DESIGN: Cross-sectional study design. SUBJECTS: Ninety-six nondiabetic Chinese (51 men and 45 women) with body mass index (BMI) between 18.4-35.8 kg/m2 were studied. MEASUREMENTS: Plasma glucose and insulin concentrations were measured every 30 min for 2 h after a 75 g oral glucose load. The degree of insulin resistance was assessed using a modified insulin suppression test. Plasma leptin values were determined by radioimmunoassay. RESULTS: Fasting plasma glucose, glucose areas, fasting insulin, insulin areas, most of the lipoprotein concentrations and steady state plasma glucose (SSPG) concentrations were relatively similar between men and women. Despite the fact that men had higher BMI values (26.1 +/- 0.5 vs 24.7 +/- 0.5 kg/m2, P < 0.05), fasting plasma leptin concentrations were significantly lower in men than in women (4.9 +/- 0.5 vs 9.0 +/- 0.8 ng/ml, P < 0.001). Fasting leptin values were positively related to SSPG concentrations by simple correlation analysis in both sexes. However, this relationship persisted in men (r = 0.513, P < 0.01) but not in women (r = 0.119, P = NS) after adjustment for BMI. Multiple regression analysis showed that SSPG concentrations, BMI, glucose and insulin responses together accounted for 62.5% and 52.2% of the variation in plasma leptin concentrations in Chinese men and women respectively. CONCLUSION: Fasting plasma leptin concentrations were lower in Chinese men than in Chinese women despite the higher BMI observed in men. After adjustment for BMI, plasma leptin values correlated with the degree of insulin resistance in men but not in women.     

Age-related differences in features associated with polycystic ovary syndrome in normogonadotrophic oligo-amenorrhoeic infertile women of reproductive years.

OBJECTIVE: To assess the effect of age on clinical, endocrine and sonographic features associated with polycystic ovary syndrome (PCOS) in normogonadotrophic anovulatory infertile women of reproductive years. DESIGN: Cross-sectional study. METHODS: Four hundred and seventy-two oligo-amenorrhoeic infertile patients, presenting with normal FSH and oestradiol concentrations, aged 17-42 years underwent a standardised initial evaluation including: cycle history, body mass index, waist-to-hip ratio and transvaginal ultrasound scanning of ovaries. Fasting blood samples were obtained for extensive endocrine evaluation. Cycle duration, serum levels of gonadotrophins, androgens, oestradiol, insulin, glucose, inhibin B as well as mean number of follicles, ovarian volume and ovarian stroma echogenicity were assessed. RESULTS: Older women had significantly lower LH and androgen and inhibin B serum levels. Similarly, older women presented with a reduced number of ovarian follicles. Age was inversely correlated with cycle duration (r=-0.112, P=0.02), LH (r=-0.154, P=0.001), testosterone (r=-0.194, P=0.001), androstenedione (r=-0.170, P=0.001), dehydroepiandrosterone (r=-0.157, P=0.001), insulin (r=-0.126, P=0.02), inhibin B (r=-0.118, P=0.03) serum levels and mean follicle number (r=-0.100, P=0.03). A positive correlation was observed between age and glucose to insulin ratio (r=0.138, P=0.009). CONCLUSIONS: Advanced age in normogonadotrophic anovulatory infertile women is associated with lower LH and androgen levels and with a decreased number of ovarian follicles. Although during reproductive years observed differences are relatively small, these age-related changes may affect the observed incidence of PCOS.     

Circulating E-selectin,vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in men with coronary artery disease assessed by angiography and disturbances of carbohydrate metabolism

It is hypothesized that adhesion molecules could be an early predictor of coronary artery disease. Therefore we investigated the relationship between the concentrations of soluble forms of adhesion molecules and disturbances of glucose metabolism in 78 men referred for coronary angiography but with no previous history of diabetes. The group consisted of 78 men (mean age, 47.6 +/- 7.0 years; mean body mass index [BMI], 28.4 +/- 3.24 with the symptoms of angina pectoris and positive exercise test. All subjects were given a standard oral glucose tolerance test (OGTT) with glucose and insulin estimations. Fasting plasma concentrations of the soluble (s) forms of E-selectin, intercellular adhesion cell molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and HbA(1c) were also measured. According to the OGTT, 10.2% of the patients (n = 8) fulfilled the criteria for type 2 diabetes mellitus and 44.9% (n = 35) for impaired glucose tolerance (IGT). The highest concentrations of sE-selectin were observed in patients with type 2 diabetes mellitus and were significantly higher in comparison to the group with normal glucose tolerance and IGT. The concentration of sVCAM-1 increased with the progression of disturbances of glucose metabolism and remained the highest in type 2 diabetic patients. sICAM-1 concentration was not significantly different. sE-selectin concentration correlated significantly with fasting glucose (r = 0.23, P =.041), postload glucose (r = 0.39, P =.001), and postload insulin (r = 0.28, P =.023). sVCAM-1 was significantly related to the postload glucose concentration (r = 0.30, P =.009). A significant correlation between sICAM-1 concentration and postload insulin was also observed (r = 0.27, P =.025). This would suggest that hyperglycemia increases sE-selectin and sVCAM-1 in plasma, which reflects excessive formation of atherosclerotic plaques in patients with disturbances of glucose metabolism.     

Impact of abdominal visceral fat,growth hormone,fitness, and insulin on lipids and lipoproteins in older adults

We examined the relationship between abdominal visceral fat (AVF) and plasma concentrations of lipids and lipoproteins in 19 females (F) (not on estrogen) and 31 males (M) over the age of 60 (age = 66.8 years). In addition, the effects of growth hormone (GH) release, fitness (Vo(2) peak), insulin, and glucose concentrations (both fasting and in response to an oral glucose tolerance test) on lipids were examined. Subjects were categorized by low (L) and high (H) AVF (L < 130 cm(2), H > 130 cm(2)), fat mass (FM) (above or below median value), and AVF corrected for fat mass. Factorial analysis of variance (ANOVA) showed that when subjects were divided by AVF and FM, similar results were observed with H > L (P <.05) for very-low-density lipoprotein-cholesterol (VLDL-C), triglycerides (TG), VLDL-TG, apolipoprotein (apo)-B, apo-B VLDL, cholesterol (Chol)/high-density lipoprotein (HDL), LDL/HDL, apoB/A1 and L > H for HDL, HDL(2), HDL(3), apo A1, and LDL/apo-B LDL. Gender differences were also observed with F > M for Chol, LDL, HDL, and HDL(2). When AVF was corrected for FM, these gender differences were still present. After correcting for FM, differences remained between H and L AVF groups for VLDL, TG, VLDL-TG, apo-B, apo-B LDL, apo-B VLDL, apoB/A1 (P <.05). Twenty-four hour integrated GH concentration (IGHC) was inversely related to VLDL, TG, VLDL TG, LDL TG, apoB, apoB VLDL, apoB LDL, Chol/HDL, LDL/HDL, and apoB/A1 in F, but not M (P <.05). Vo(2) peak was directly related to Chol, LDL, HDL(3), and apoB LDL with stronger relationships observed in F. Fasting insulin was related to lipids and lipoproteins in both men and women. These data suggest that, in older adults, elevated levels of AVF, FM, and AVF corrected for FM are associated with unfavorable lipid-lipoprotein profiles and extend similar findings reported in younger males and females with elevated AVF. These data also support previous findings indicating that AVF is a primary determinant of GH release.