Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries

OBJECTIVE Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history. DESIGN A cross-sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls. PATIENTS AND METHODS We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11). RESULTS Results are expressed as mean ± SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 ± 0.7 vs LP 35.2 ± 1.2, P < 0.01; OC 34.7 ± l.8 vs OP 37.8 ± 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 ± 9 vs LP 179 ± 9, NS; OC 168 ± 12 vs OP 133 ± 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL₂-cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38–0.62), LP 0.31 (0.26–0.44), P < 0.05; OC 0.34 (0.21–0.47), OP 0.21 (0.12–0.32) mmol/l, P < 0.01). Total HDL-cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL-cholesterol and with HDL₂-cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL-cholesterol in women with polycystic ovaries. CONCLUSION Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.     

Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease

Aim The aim of this study was to investigate the relationships between bone mineral density (BMD) vs insulin resistance and metabolic risk factors in obese adolescents with nonalcoholic fatty liver disease (NAFLD). Patients and methods Eighty‐two obese adolescents [45 girls and 37 boys, mean age: 12·3 ± 1·7 years, mean body mass index‐standard deviation score (BMI‐SDS): 1·9 ± 0·2] and 30 control subjects (15 girls and 15 boys, mean age: 12·3 ± 1·45 years, mean BMI‐SDS: 0·5 ± 0·7) were enrolled the study. The obese subjects were divided into two groups based on the presence or absence of liver steatosis with high transaminases (NAFLD group and non‐NAFLD group). Insulin resistance was evaluated by homeostasis model assessment (HOMA‐IR) from fasting samples. BMD was determined by dual‐energy X‐ray absorptiometry. Results Fasting insulin levels in the NAFLD group were significantly higher than in the non‐NAFLD obese (32·3 ± 24·0 vs 11·02 ± 2·95 mU/l, P < 0·001) and control groups (8·4 ± 2·4 mU/l, P< 0·001). The NAFLD group had higher values of HOMA‐IR than the non‐NAFLD obese (7·3 ± 0·1 vs 2·3 ± 0·7, P < 0·001) and control groups (1·8 ± 0·5, P < 0·001). BMD‐SDS measurements were lower in the NAFLD group than in the non‐NAFLD (0·56 ± 0·3 vs 1·02 ± 0·9, P < 0·001) and control groups (0·56 ± 0·3 vs 1·37 ± 1·04, P < 0·001). BMD‐SDS was positively correlated with BMI‐SDS (r = 0·530, P = 0·004) and negatively correlated with HOMA‐IR (r = ?0·628, P = 0·017) in the NAFLD obese group. Conclusion This study reports the association between BMD‐SDS and insulin resistance in obese adolescents both with and without NAFLD, although the NAFLD group had a lower BMD‐SDS than the non‐NAFLD group. We suggest that NAFLD has a detrimental effect on bone health in adolescents, and it is correlated with increased insulin resistance.     

Adiponectin levels in adolescent girls with polycystic ovary syndrome (PCOS)

Objective To determine serum adiponectin concentrations in adolescent girls with and without polycystic ovary syndrome (PCOS) and to assess possible correlations of adiponectin levels with insulin and androgen levels. Design Prospective case–control study. Setting Endocrine clinics in the community. Patients Forty‐four adolescent girls were grouped as follows: 14 were overweight [body mass index (BMI) standard deviation score >1·645] with PCOS; 16 were lean (BMI SDS <1·036) with PCOS; and 14 were lean (BMI SDS <1·036) without PCOS. Intervention Blood samples were collected from all girls between 8 and 11 am , after an overnight fast. Main outcome measures Serum levels of adiponectin, leptin, insulin, Müllerian‐inhibiting substance, luteinizing hormone, follicle‐stimulating hormone, testosterone, 17‐alpha‐hydroxyprogesterone, androstendione, dehydroepiandrosterone sulphate (DHEAS) and 17β‐oestradiol. Results Adiponectin concentrations were significantly decreased in obese adolescents with PCOS (10·5 ± 5·5 μg/ml) compared with that in lean girls with or without PCOS (16·9 ± 8·64 and 18·0 ± 7·4 μg/ml respectively). Leptin levels were significantly elevated in obese adolescents with PCOS compared with the levels in normal weight adolescents with PCOS, and compared with that in normal weight controls. Insulin levels were markedly higher in obese adolescents with PCOS compared with that in normal weight adolescents (12·3 ± 12·2 vs. 4·5 ± 2·9, P < 0·05), and compared with that in normal weight PCOS adolescents (7·4 ± 4·9); however, this difference was not statistically significant. Insulin levels did not differ between normal weight adolescents with PCOS and normal controls. Adiponectin concentrations correlated inversely with BMI, leptin and insulin. Conclusions Hypoadiponectinaemia is evident only in obese adolescents with PCOS and therefore does not seem to be involved in the pathogenesis of PCOS in this age group.     

A comparison between rimonabant and metformin in reducing biochemical hyperandrogenaemia and insulin resistance in patients with polycystic ovary syndrome (PCOS): a randomized open-label parallel study

Context Weight loss and metformin therapy are reported to be beneficial in improving the biochemical hyperandrogenaemia and insulin resistance of polycystic ovary syndrome (PCOS). Rimonabant has been found to reduce weight and improve the metabolic profile in patients with obesity, type 2 diabetes and metabolic syndrome. Objective To compare the effects of insulin sensitization with metformin to weight reduction by rimonabant on biochemical hyperandrogenaemia and insulin resistance in patients with PCOS. Design A randomized, open‐label parallel study. Setting Endocrinology outpatient clinic in a referral centre. Subjects Twenty patients with PCOS and biochemical hyperandrogenaemia with a body mass index (BMI) ≥ 30 kg/m² were recruited. Intervention Patients were randomized to 1·5 g daily of metformin or 20 mg daily of rimonabant. Main outcome measures The primary end‐point of the study was a change in total testosterone. Results After 12 weeks of rimonabant there was a significant reduction (mean ± SEM) in weight (104·6 ± 4·6 vs. 98·4 ± 4·7 kg, P < 0·01), waist circumference (116·0 ± 3·3 vs. 109·2 ± 3·7 cm, P < 0·01), hip circumference (128·5 ± 4·0 vs. 124·1 ± 4·2 cm, P < 0·03), waist–hip ratio (0·90 ± 0·02 vs. 0·88 ± 0·01, P < 0·01) free androgen index (FAI) (26·6 ± 6·1 vs. 16·6 ± 4·1, P < 0·01), testosterone [4·6 ± 0·4 vs. 3·1 ± 0·3 nmol/l (132·7 ± 11·5 vs. 89·4 ± 8·65 ng/dl), P < 0·01] and insulin resistance as measured by the homeostasis model assessment (HOMA) method (4·4 ± 0·5 vs. 3·4 ± 0·4, P = 0·05). There was no change in any of these parameters in the metformin‐treated group. Conclusion This study suggests that the weight loss through rimonabant therapy may be of use in patients with PCOS and appears superior to insulin sensitization by metformin in reducing the FAI and insulin resistance in obese PCOS patients treated over a 12‐week period.     

Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters

OBJECTIVE To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS). DESIGN AND PATIENTS Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2-hour 75-g oral glucose tolerance test (OGTT) in 85 women with PCOS (17–36 years, body mass index (BMI) 29.9 ± 0.9 kg/m², mean ± SD) and 18 control women (25–47 years, BMI 25 ± 1.7 kg/m²). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations. MEASUREMENTS Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay. RESULTS Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/hip ratio, on leptin concentrations. Comparison of control subjects to a BMI-matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 ± 1.3 vs 12.1 ± 2.3 μg/l, mean ± SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups. CONCLUSIONS Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.     

Tissue insulin sensitivity and body weight in polycystic ovary syndrome

OBJECTIVE: Polycystic ovarian syndrome (PCOS) and obesity both affect insulin sensitivity. This study was designed to investigate the biochemical indices of PCOS and tissue insulin sensitivity in groups of lean and obese women with clinically equivalent degrees of the syndrome, relative to control subjects. DESIGN: A prospective study of in vivo parameters and in vitro study of adipocytes to assess insulin sensitivity. PATIENTS: Six lean and 14 overweight patients fulfilling formal diagnostic criteria for PCOS were studied. The degree of hirsutism and amenorrhoea was similar in each group. Eight control subjects were also studied. MEASUREMENTS: Endocrine and metabolic parameters were measured in lean and overweight patients with PCOS and control subjects. In vitro studies of adipocyte insulin receptor binding and adipocyte insulin action were performed. RESULTS: The mean plasma LH level was elevated in both groups of PCOS but was significantly higher in the lean group (LH levels were 25.1 +/- 3.1 and 14.5 +/- 1.6 iu/l in lean PCOS and obese PCOS, respectively (P = 0.01)). There was a strong inverse correlation between BMI and LH levels (R = - 0.70, P = 0.001). Fasting insulin levels were elevated in both lean and obese groups (11.5 +/- 2.8 and 26.8 +/- 8.1 mU/l, respectively; P = 0.068). Mean serum testosterone and serum androstenedione levels were also elevated in PCOS compared to control subjects but there was no difference between the two groups of PCOS subjects. Insulin receptor binding in amenorrhoeic subjects with PCOS was low in both lean and obese patients with PCOS but was not significantly different between the two groups (0.79 +/- 0.17% and 0.66 +/- 0.07% per 10 cm2 cell membrane, respectively). Maximally insulin-stimulated rates of 3-O-methylglucose transport were low in both groups compared to previously studied normal subjects (0.96 +/- 0.21 and 0.64 +/- 0.07 pmol per 10 cm2 membrane in lean and obese PCOS subjects, respectively; P = NS). CONCLUSIONS: Lean subjects with a given phenotypic expression of PCOS have an equivalent degree of tissue insulin resistance compared to obese PCOS subjects. This implies that the insulin resistance may be a primary feature of PCOS. If this is so, a similar clinical degree of the syndrome may be brought about by genetically determined insulin resistance in lean subjects or by insulin resistance which is secondary to obesity.     

The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries

OBJECTIVE Insulin insensitivity is a recognized feature of polycystic ovary syndrome (PCOS) but previous studies have suggested that circulating insulin concentrations are normal in hyperandrogenaemic women with regular cycles. The aim of this study was to examine the relationship between insulin sensitivity and menstrual pattern in women with PCO. DESIGN A cross-sectional study of insulin sensitivity in a cohort of PCO subjects with oligomenorrhoea compared to women with PCO and regular menstrual cycles and a group of normal control subjects. SUBJECTS Seventy-two women with polycystic ovaries on ultrasonography were studied. PCO subjects had clinical and/or biochemical evidence of hyperandrogenism; 53 had oligo/amenorrhoea (olig) and 19 had regular menses (reg). Results were compared with 31 control subjects. The groups were matched for age, weight and ethnic origin. METHODS Glucose and insulin responses to 75 g oral glucose were measured. Insulin sensitivity was assessed by the decline in plasma glucose following intravenous insulin (0.05 U/kg). RESULTS Glucose area (mean±SEM) after oral glucose was increased slightly in both PCO groups compared with controls (olig 37.6±1.4, reg 36.0±1.8, control 33.7±0.9 mmol/l h, both P < 0.01). Insulin area median (interquartile range) in response to glucose was significantly greater in the oligomenorrhoeic group (346 (239–734) mU/l h), compared with both PCO with regular cycles (246 (148–355), P<0.01) and controls (221 (147–277), P<001). Insulin sensitivity was reduced (P< 0.01) in the oligomenorrhoeic group (147 ±9.2 /imol/l min) compared to controls (185 ±7.4) but was normal in PCO with regular cycles (182 ±12.5). Insulin sensitivity did not correlate significantly with plasma testosterone or with SHBG levels, but plasma insulin concentrations correlated negatively with SHBG levels (fasting insulin vs SHBG, r= -0.47, P<0.01; insulin area vs SHBG, r= -0.47, P<0.01). CONCLUSIONS Insulin insensitivity in polycystic ovary syndrome occurs when there is oligo/amenorrhoea but not when the menstrual cycle is regular. This is consistent with PCO and insulin insensitivity being separate abnormalities which when combined are associated with anovulation.     

Cardiac flow velocity in women with the polycystic ovary syndrome

OBJECTIVE Women with the polycystic ovary syndrome (PCOS) often have several of the known risk factors for cardiovascular disease, including hyperinsulinaemia. We have therefore investigated variables of cardiac flow in young women with PCOS and related them to blood levels of reproductive hormones (LH, FSH, oestradiol and testosterone) and also of insulin. DESIGN A prospective study. PATIENTS Twenty-six young women with PCOS (mean age 22.8 ± 0.9 years; mean BMI 23.0 ± 0.8) and 11 healthy age matched women with regular ovulatory cycles (mean age 26.3 ± 1.7 years; mean BMI 22.9 ± 0.9). MEASUREMENTS Cardiac flow was measured by pulsed wave Doppler echocardiography in the follicular phase of the cycle in controls and oligomenorrhoeic women; there was no special timing for amenorrhoeic women. The indicators assessed were: ejection fraction (EF), pre-ejection time (PEP), ejection time (ET), peak systolic flow velocity (PFV), acceleration time (AT), flow velocity integral (FVI), mean acceleration (MA), diastolic time (DT), early diastolic filling time (EI), atrial filling time interval (AI), peak velocity of the early diastolic filling (PE) and peak velocity of the atrial filling (PA). Serum LH, FSH, oestradiol, testosterone, SHBG and insulin concentrations were analysed by standard RIA. RESULTS Significantly lower PFV (1.055 ± 0.025 vs 1.242 ± 0.054, P= 0.0006) and MA (17.06 ± 0.57 vs 23.00 ± 1.49, P= 0.0001) and longer AT (0.063 ± 0.001 vs 0.056 ± 0.004, P= 0.026) were found in women with PCOS as compared to age matched controls. Significant negative correlation between serum fasting insulin concentration and EF (r=-0.725, P= 0.002), PFV (r=?0.719, P= 0.0025), FVI (r=?0.654, P= 0.003) and MA (r=?0.757, P= 0.001) was observed In the 15 women with PCOS in whom insulin was measured. CONCLUSION An inverse relation between serum fasting insulin level and left ventricular systolic outflow parameters suggests that insulin is associated with the decreased systolic flow velocity observed in women with PCOS.     

The effect of recombinant IGF-I on anterior pituitary function in healthy volunteers

OBJECTIVE Insulin-like growth factor-I is the mediator of many of the actions of GH and is a potent metabolic regulator. Recombinant IGF-I (rhIGF-I) is of potential value in the treatment of syndromes associated with either GH or insulin resistance. This study was designed to assess the effects of subcutaneous (s.c.) rhIGF-I on anterior pituitary function. DESIGN Double-blind, placebo controlled, randomized cross-over study. The interval between investigations was 2 weeks. SUBJECTS Twelve normal volunteers received on one occasion a single S.C. dose of 40 μg/kg rhIGF-I and on the other, placebo. MEASUREMENTS Circulating levels were measured, over 24 hours, of GH, LH, FSH, PRL, TSH, cortisol, ACTH, glucose, IGF-I, IGF-II, Insulin, C-peptide; IGF binding proteins by Western ligand blotting; total IGF bioactivity using FRTL-5 thyroid cells; and glucose by the glucose oxidase method. RESULTS Recombinant IGF-I Increased AUC for plasma IGF-I, measured by radioimmunoassay (rhIGF-I mean 7065 ± SEM 33 vs 3895 ± 204 μg/l, P < 0·0001) and IGF bioactivity (22·5 ± 3·4 vs 14·2 ± 1·8 U/ml, P < 0·001) but plasma IGF-II fell (9308 ± 403 vs 11052 ± 451 μg/l, P < 0·0001). There was no biochemical or clinical evidence of hypoglycaemia and no difference in mean glucose levels. No difference existed in AUC for GH, LH, FSH, ACTH and cortisol between rhIGF-I and placebo; additionally, pulse number and amplitude for GH and LH were unaffected. TSH fell following rhIGF-I (33·0 ± 3·36 vs 42·5 ± 5·98 mU h/l, P= 0·01). Both mean plasma C-peptlde (0·73 ± 0 06 vs 0·91 ± 0±05 nmol/l, P= 0·03), and insulin (10·81 ± 1·02 vs 15·36 ± 1·18 mU/l, P= 0·03) were lower following rhIGF-I. There was no change In IGFBPs. CONCLUSION A single injection of 40 μg/kg of subcutaneous rhIGF-I does not cause hypoglycaemia. IGF bioactivity was increased without inhibition of GH secretion. The only change observed in anterior pituitary function was a fall in plasma TSH.     

Plasma visfatin concentrations increase in both hyper and hypothyroid subjects after normalization of thyroid function and are not related to insulin resistance, anthropometric or inflammatory parameters

Objective The objective of this study was to evaluate plasma visfatin levels in thyroid dysfunction and its relationship with inflammatory, anthropometric and insulin resistance parameters. Design and patients Twenty‐four hyperthyroid and 27 hypothyroid patients were studied before and after treatment. Forty‐five euthyroid subjects were used as control group. Measurements Fasting plasma visfatin, IL‐6, C reactive protein, adiponectin, thyroid hormones, waist‐to‐hip ratio, BMI, percentage of body fat and homeostasis model insulin resistance index (HOMA‐IR) were measured. Results Hyperthyroid patients showed increased insulin resistance, IL‐6 and visfatin levels compared with controls (3·21 ± 3·0 vs. 1·67 ± 0·75, P = 0·022; 3·35 ± 0·41 vs. 2·10 ± 0·25 pg/ml, P = 0·016; and 37·4 ± 5·81 vs. 23·79 ± 4·2 ng/ml, P = 0·061 respectively). After normalization of thyroid function, IL‐6 levels and HOMA‐IR decreased (2·35 ± 0·37 vs. 2·10 ± 0·25 pg/ml, P = 0·045 and 3·21 ± 0·60 vs. 2·28 ± 0·38, P = 0·032 respectively), while body weight, adiposity and visfatin levels increased (26·1 ± 1·2 vs. 26·7 ± 1·2 kg/m², P = 0·049; 30·9 ± 1·6 vs. 32·2 ± 1·6%, P = 0·007; and 37·4 ± 5·81 vs. 63·13 ± 8·72 ng/ml, P = 0·047 respectively). C reactive protein and adiponectin levels were similar to those of the control group. Hypothyroid patients showed high visfatin levels (40·59 ± 3·07 vs. 29·34 ± 4·9 ng/ml, P = 0·049) that increased after treatment (81·4 ± 9·2 ng/ml, P = 0·001) without changes in anthropometric or insulin resistance parameters. C reactive protein, IL‐6 and adiponectin levels were similar to those of the control group. No correlations between visfatin and any analysed parameter were found in either hyper‐ or hypothyroidism. Conclusion Visfatin exhibits a marked increase after normalization of thyroid function in both hyper and hypothyroid patients. We suggest that visfatin may play a role in the hormone stabilization process independent of anthropometric, inflammatory or insulin resistance variables.     

The impact of intensified exercise training on insulin resistance and fitness in overweight and obese women with and without polycystic ovary syndrome

Objective To evaluate mechanisms of insulin resistance (IR) in overweight and obese women with and without polycystic ovary syndrome (PCOS) and explore relationships between IR, fitness and body mass index (BMI) at baseline and following exercise intervention. Design Prospective controlled intensified exercise intervention study. Patients A total of 20 overweight (BMI > 25 kg/m²) and obese (>30 kg/m²), reproductive‐aged PCOS women and 13 non‐PCOS overweight, healthy controls of comparable BMI and age were studied at baseline. Measures were repeated in 13 PCOS and eight control women following three 1‐h exercise sessions per week over 12 weeks. Measurements Insulin resistance was measured by glucose infusion rate on euglycaemic hyperinsulinaemic clamp, and fitness was assessed by VO_2max. Results At baseline, PCOS women were 46% more insulin resistant than controls (175·6 vs 257·2 mg/m²/min, P < 0·05) with IR independently associated with VO_2max and BMI in the PCOS group only (P < 0·01). Postexercise IR improved across both groups (P < 0·01). In PCOS women, IR improved by 16% (P < 0·05) but was not restored to the same level as controls (P < 0·05). Improvement in IR and in VO_2max was related to the PCOS group (r² = 0·85, P < 0·05), yet change in IR and in fitness was not related. No associations were found in controls. Conclusions While intensified exercise improves IR in PCOS women, a higher IR persisted following exercise in PCOS women, and a clear relationship between improved IR and improved fitness was not found. Therefore, other mechanisms of, and therapies for, IR must be explored in PCOS as IR remains higher than observed in non‐PCOS controls.     

Sex differences in essential hypertension

Abstract. A group of 41-year-old hypertensive men (n = 35, blood pressure (BP) 149.9 ± 2.1/ 98.9 ± 1.1 mmHg, mean ± SEM) who had never received treatment for their condition were compared with hypertensive women of the same age (n = 18, BP 155.9 ± 4.3/ 98.1 ± 1.6 mmHg) with comparable body mass index (BMI. 25.9 ± 0.5 vs. 24.9 ± 4.5 kg m^?2) who, also, had never received treatment. The lipid profile was more atherogenic in the men, with lower HDL cholesterol (1.21 ± 0.04 vs. 1.38 ± 0.06 mmol l^?1 P = 0.04), higher total cholesterol (6.04 ± 0.14 vs. 5.54 ± 0.18 mmol l^?1. P = 0.04) and triglycerides (1.80 ± 0.16 vs. 0.96 ± 0.10 mmol l^?1, P < 0.001). The hypertensive men had higher haemoglobin (P < 0.001) and haematocrit. Plasma catecholamines were inversely related to BMI in the women only (r = ?0.52, P < 0.05 for both noradrenaline and adrenaline). Women with BMI above 25 kg m^?2 had significantly lower arterial plasma adrenaline and noradrenaline than those with BMI below 25 kg m^?2 (28 ± 5 vs. 78 ± 16 pg ml^?1, P < 0.01 and 101 ± 17 vs. 206 ± 33 pg ml^?1, P < 0.01 respectively). A negative curvelinear relationship appeared between arterial adrenaline and insulin (r = 0.49, P= 0.05). These results suggest a male propensity for athero-thrombogenic risk factors in otherwise comparable hypertensive subjects. A close relationship between metabolic risk factors within the normal range seems to exist even in hypertensive women. The decreased sympathetic activity at rest in the obese hypertensive women indicates different pathophysiological mechanism for hypertension in lean and obese. Decreased sympathetic activity and thus reduced energy expenditure, promotes a risk for weight gain, and could explain the inverse relationship between insulin and adrenaline.     

The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women

OBJECTIVE To investigate the basal levels of gonadotrophins and sex steroids, with special reference to the effects of obesity and body fat distribution, In premenopausal women, both those with polycystic ovary syndrome (PCOS) and those with normal ovaries and regular menstrual cycles. DESIGN Cross-sectional study. The separate effects of obesity (and body fat distribution and fasting Insulin levels) and PCOS on endocrine variables were evaluated by means of analysis of covariance. PATIENTS Sixty-seven women with anovulatory menstrual cycles and polycystic ovaries according to ultrasonography and 59 women with normal ovaries and regular cycles, both groups covering a wide range of body mass index (BMI, PCOS, 17·6-37·4, mean 25·7 kg/m²; controls, 18·8-40·9, mean 25·1 kg/m²). MEASUREMENTS Serum levels of gonadotrophins, sex steroid hormones, prolactin and GH obtained in the early follicular phase in the controls, fasting insulin levels, anthropometric measures (BMI, skinfolds, waist hip ratio). RESULTS Mean serum concentrations of LH, andro-stenedione, testosterone, the free androgen index (FAI; all P < 0·0001) and DHEAS (P < 0·01) were higher, and serum FSH (P < 0·01) and serum SHBG levels lower (P < 0·0001), in the PCOS group than in the controls. Women with PCOS had a more pronounced upper body fat distribution and higher fasting insulin levels than the controls. Independent of PCOS, BMI was positlvely associated with serum levels of FSH (P < 0·001) and negatively with levels of LH (P < 0·05), LH/FSH ratio (P < 0·0001), SHBG (P < 0·0001) and androstenedione (P < 0·01), whereas for levels of testosterone, FAI and DHEAS the impact of obesity differed significantly between the groups. Thus, in the PCOS group, testosterone levels (P < 0·05) and the FAI (P < 0·001) were positively associated with BMI, whereas they were constant throughout the entire range of BMI in the controls. DHEAS levels were positively associated with BMI in the PCOS group (P < 0·05) and negatively in the controls (P < 0·01). Measures of upper body fat were related to testosterone and FAI levels, independent of BMI. CONCLUSIONS Lower FSH levels were found in women with PCOS than during the early follicular phase of normally ovulating women, suggesting a role in anovulation in PCOS. Obesity itself exerted effects on endocrine variables, with the net result of a reduced LHIFSH ratio and lower serum levels of androstenedione and SHBG in both groups; obesity was associated with increased levels of DHEAS, testosterone and FAI exclusively in the women with PCOS. The results underline the endocrine impact of obesity and body fat distribution and the necessity of applying reference values of BMI matched subjects when establishing the endocrine profile of women with PCOS.     

Fatty acid binding protein expression in different adipose tissue depots from lean and obese individuals

Aims/hypothesis: This study investigated the expression of adipose tissue fatty acid binding proteins (FABPs) in subcutaneous and visceral human adipose tissue depots from lean and obese individuals. Methods: Adipocyte lipid binding protein (ALBP) and keratinocyte lipid binding protein (KLBP) expression was quantified by western blot in subcutaneous and omental adipose tissue from 20 obese and 9 lean individuals. RNA expression was quantified by Northern blot in the obese subjects. Results: In the obese subjects, ALBP protein and RNA expression was higher in subcutaneous compared with omental adipose tissue (increases of 31 ± 14 % and 40 ± 13 % respectively, both p < 0.05), whereas in the lean group, KLBP protein levels were 32 ± 9 % lower in subcutaneous fat (p < 0.03). However, the ALBP/KLBP ratio was greater in subcutaneous compared to omental adipose tissue from both lean and obese subjects: increases of 187 ± 71 % (p = 0.01) and 52 ± 23 % (p = 0.17) respectively for the protein ratio, and 21 ± 6 % for RNA (p = 0.01, obese individuals). In lean subjects, insulin concentrations correlated positively with the ALBP/KLBP protein ratio in both depots (both p≤ 0.03). Conclusion/interpretation: There are regional differences in adipose tissue FABP expression, which could be influenced by obesity. However, the ALBP/KLBP ratio is greater in subcutaneous than visceral adipose tissue in lean as well as in obese subjects. Investigation of adipose tissue FABPs could further our understanding of the role of fatty acids in the insulin resistance syndrome. [Diabetologia (2001) 44: 1268–1273] Received: 1 February 2001 and in revised form: 25 June 2001     

In anorexia nervosa, even a small increase in abdominal fat is responsible for the appearance of insulin resistance

Context The aim of treatment in patients affected by anorexia nervosa (AN) is weight recovery. However, during weight gain, anorectic patients’ body composition is changed, with an increase in abdominal fat, particularly in the visceral compartment. Objective We hypothesized that changes in body composition, particularly in abdominal fat, are responsible for the variability in insulin sensitivity (IS) in different stages of AN. Design and Measurements We compared 20 anorectic patients in the acute stage, 19 in the weight‐recovery stage and 21 controls. All subjects underwent an oral glucose tolerance test, hyperinsulinaemic euglycaemic clamp and dual energy X‐ray absorptiometry to measure body composition. Results The percentage of trunk fat was higher in weight recovery than in the acute phase (47·7 ± 8·4%vs 34·6 ± 7·6%; P ≤ 0·01) and in the control group (33·4 ± 7·6; P < 0·01 vs weight recovery). Although the recovery group gained weight, their body mass index (BMI) was not statistically different from that of the acute group (14·4 ± 1·1 vs 13·6 ± 1·8 kg/m²). Insulin sensitivity was lower in the weight‐recovery group than the acute group (4·7 ± 1·5 vs 7·8 ± 1·6 mg/kg/min; P < 0·01) and controls (7·7 ± 1·4 mg/kg/min; P < 0·01). A linear negative correlation was found between IS and the percentage of abdominal fat in the weight‐recovery and acute groups (r = ?0·51; P = 0·04 and r = ?0·53; P = 0·04 respectively), while IS did not correlate with BMI. Conclusion Although weight‐recovery represents the main aim of treatment in AN, refeeding is associated with an increase in abdominal fat which might be responsible of the onset of insulin resistance. As BMI and weight‐recovery were associated with impaired IS, they cannot be considered the only aim of treatment of AN.     

Metformin maintains the weight loss and metabolic benefits following rimonabant treatment in obese women with polycystic ovary syndrome (PCOS)

Objective Rimonabant has been shown to reduce weight, free androgen index (FAI) and insulin resistance in obese patients with polycystic ovary syndrome (PCOS) compared to metformin. Studies have shown that significant weight regain occurs following the cessation of rimonabant therapy. This study was undertaken to determine if subsequent metformin treatment after rimonabant would maintain the improvement in weight, insulin resistance and hyperandrogenaemia in PCOS. Design An extension study for 3 months with the addition of metformin to the randomised open labelled parallel study of metformin and rimonabant in 20 patients with PCOS with a body mass index ≥ 30 kg/m². Patients who were on 3 months of rimonabant were changed over to metformin for 3 months, whereas those on 3 months of metformin were continued on metformin for another 3 months. Measurements The primary end‐point was a change in weight; secondary end‐points were a change in FAI and insulin resistance. Results The mean weight loss of 6·2 kg associated with 3 months of rimonabant treatment was maintained by 3 months of metformin treatment (mean change +0·2 kg, P = 0·96). Therefore, the percentage reduction in weight remained significantly higher in the rimonabant/metformin group compared to metformin only subjects at 6 months compared to baseline (–6·0 ± 0·1%vs. –2·8 ± 0·1%, P = 0·04). The percentage change in testosterone and FAI from baseline to 6 months was also greater in the rimonabant/metformin group. [Testosterone (–45·0 ± 5·0%vs. –16 ± 2·0%, P = 0·02); FAI (–53·0 ± 5·0%vs. –17·0 ± 12·2%, P = 0·02)]. HOMA‐IR continued to fall significantly in the rimonabant/metformin group between 0, 3 and 6 months (4·4 ± 0·5 vs. 3·4 ± 0·4 vs. 2·7 ± 0·3, respectively, P < 0·01) but not at all in the metformin only group (3·4 ± 0·7 vs. 3·4 ± 0·8 vs. 3·7 ± 0·8, respectively, P = 0·80). Total cholesterol and LDL reduced significantly in both groups, but improvements in triglycerides and HDL were limited to the rimonabant/metformin group. Conclusions In these obese patients with PCOS, metformin maintained the weight loss and enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone.     

Gastric inhibitory polypeptide (GIP) hypersecretion in obesity depends on meal size and is not related to hyperinsulinemia

Summary The response of immunoreactive gastric inhibitory polypeptide (IR-GIP), immunoreactive insulin (IRI) and immunoreactive C-peptide (IR-C-peptide) to the ingestion of mixed liquid test meals containing 1031 kcal (550 ml) and 422 kcal was studied in 17 obese and 17 normal weight control subjects. When the 422 kcal load was ingested in a volume of 550 ml, the plasma IR-GIP response was significantly greater than in a volume of 225 ml at 15 and 30 min in lean and obese subjects, but the total integrated IR-GIP response was not significantly different between the obese and lean group. Also intraduodenal infusion of 150 ml (280 kcal) of the test meal elicited identical plasma IR-GIP concentrations in lean and obese subjects. An exaggerated IR-GIP response in obese subjects was seen only following the 1031 kcal load (integrated IR-GIP response: 23.6±1.9 in lean subjectsvs 50.3±3.8 nmol/1/180 min in obese subjects; p<0.01). The IRI response was always significantly greater in obese than in lean subjects and not related to the GIP response. Fasting plasma IR-C-peptide levels were significantly elevated in obese subjects (lean: 0.52±0.04; obese: 1.42±0.12 nmol/l; p<0.005), but the postprandial integrated IR-C-peptide responses in the obese and lean group were identical, indicating decreased hepatic insulin extraction in obesity. It is concluded that an exaggerated IR-GIP response in obesity occurs only after ingestion of a high calorie meal probably as consequence of an increased gastric emptying rate and that the hyperinsulinemic response of obese subjects is not attributable to GIP hypersecretion.     

Association between Circulating Tumor Necrosis Factor-Alpha, Interleukin-6, and Insulin Resistance in Normal-Weight Women with Polycystic Ovary Syndrome

Background: Insulin resistance is a common finding in both obese and lean women with polycystic ovary syndrome (PCOS). Factors contributing to insulin resistance are still controversial. The purpose of the study was to compare the tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) concentrations in normal weight women with PCOS and a weightmatched healthy control group, and also to evaluate the role of these cytokines in the pathogenesis of insulin resistance. Methods: Thirty-two women with PCOS and 25 age- and weight-matched healthy controls participated in this study. Patients were evaluated clinically and by pelvic ultrasound. Fasting insulin, glucose, lipid profile, follicle-stimulating hormone (FSH), leutinizing hormone (LH), prolactin, testosterone, sex hormone binding globulin (SHBG), 17-hydroxyprogesterone, IL-6, TNF-alpha concentrations, and insulin sensitiviy indices homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) were measured. Results: TNF-alpha and IL-6 concentrations were significantly higher in women with PCOS than in the control group. Significant correlations were found between TNF-alpha serum concentrations and Body Mass Index (BMI), waist circumference, triglyceride concentrations, fasting insulin, and insulin resisitance indices (p < 0.001). IL-6 concentrations were correlated with fasting glucose and insulin resistance (p < 0.05). Conclusions: The study demonstrated that TNF-alpha and IL-6 concentrations were elevated in normal weight women with PCOS. The findings may contribute to evidence of insulin resistance in lean women with PCOS.     

Retinol-binding protein in nonobese women with polycystic ovary syndrome

Objective Although polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance, cardiovascular disease and various metabolic diseases, the mechanisms linking PCOS to metabolic changes are not fully understood. Retinol‐binding protein (RBP) was recently reported as an adipocytokine that may link insulin resistance and lipid metabolism. The aim of this study was to investigate the potential role of RBP in women with PCOS. Research design and methods Fifty women with PCOS and 40 healthy women, all of whom were age‐ and weight‐matched, were studied. Blood was obtained to determine RBP levels as well as metabolic and hormonal parameters, and the homeostasis model assessment of insulin resistance (HOMA‐IR) was calculated for each subject. Results The RBP levels were higher (P < 0·01) in women with PCOS after adjusting for age, body mass index (BMI), mean blood pressure, triglyceride (TG), high density lipoprotein (HDL)‐cholesterol, low density lipoprotein (LDL)‐cholesterol, fasting glucose, fasting insulin, estimated glomerular filtration rate (GFR), LH/FSH, total testosterone and SHBG levels. PCOS status was the strongest predictor of elevated RBP levels. In both the PCOS and control groups, RBP levels were significantly correlated with HOMA‐IR (P = 0·03 in the PCOS group; P = 0·01 in controls). In addition, RBP levels were significantly correlated with total cholesterol, LDL‐cholesterol and TG levels in PCOS (P < 0·01, P < 0·01 and P = 0·01, respectively). Conclusions Higher RBP levels in the PCOS group, when compared to the non‐PCOS group, were observed, and this difference may play a role in the pathophysiology found in women with PCOS. Further studies are needed to clarify the role of RBP in these women.     

Lean mass and insulin resistance in women with polycystic ovary syndrome

Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Muscle is the major tissue utilizing glucose while excess adipose tissue relates to insulin resistance. Thus, body composition is likely to be an important regulator of insulin sensitivity. Thirty-nine PCOS patients (age: 29.9 ± 1.0 years; BMI: 33.8 ± 1.2 kg/m²) participated in a cross sectional study. Body composition was measured by dual energy x-ray absorptiometry (DEXA). Insulin resistance and secretion were assessed using oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FS-IVGTT). In contrast with the conventional expectations, lean mass correlated directly (P < .05) with the insulin resistance measure HOMA (r = 0.440); and inversely with the insulin sensitivity index QUICKI (r = ?0.522) independent of fat mass. In 11 pairs of subjects matched for fat mass (35.6 ± 2.2 and 35.6 ± 2.4 kg) but with discordant lean mass (52.8 ± 1.8 vs 44.4 ± 1.6 kg), those with higher lean mass had a higher glucose response during OGTT (AUC_Glucose; P = .034). In contrast, 17 pairs matched for lean mass (48.7 ± 1.7 and 48.9 ± 1.6 kg) but discordant for fat mass (43.3 ± 2.6 vs 30.3 ± 8.9 kg) showed no differences in insulin resistance parameters. These novel findings indicate that lean mass relates directly to insulin resistance in PCOS.