Plasma homocysteine in polycystic ovary syndrome: does it correlate with insulin resistance and ethnicity?

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and premature coronary artery disease (CAD). Hyperhomocysteinaemia is a recognized risk factor for atherosclerosis, particularly among migrant South Asians, and has recently been shown to be correlated positively with the degree of insulin resistance/hyperinsulinaemia. OBJECTIVES: To compare total plasma homocysteine (Hcy) in PCOS with controls from ethnic groups at high and low risk of insulin resistance. METHODS: Case control study of three ethnic groups, Sri Lankans (SL), British Asians (BA) and white Europeans (C), with and without PCOS at specialist centres in Sri Lanka and Yorkshire, UK. Fasting total plasma Hcy concentration was analysed by fluorescence polarization immunoassay and examined for any correlation with age, body mass index (BMI), central obesity, fasting insulin and insulin sensitivity [calculated by the Quantitative Insulin Sensitivity Check Index (QUICKI) method], lipids and testosterone in each ethnic group. RESULTS: Eighty SL with PCOS and 45 controls, 47 BA with PCOS and 11 controls, and 40 C with PCOS and 22 controls were studied. Both Asian groups with PCOS were younger than affected Europeans (P = 0.008). Sri Lankans with PCOS had significantly lower BMI values than other affected groups: mean +/- SEM (SL) 26.3 +/- 0.95; (BA) 30.59 +/- 7.54; (C) 32.1 +/- 5.95 kg/m2 (P = 0.006). However, waist : hip ratios (WHR) of Sri Lankans with PCOS were similar to others: mean +/- SEM (SL) 0.97 +/- 0.01 (BA) 1.04 +/- 0.02 (C) 0.92 +/- 0.01, P = 0.33. Mean plasma Hcy was significantly higher in all PCOS groups than in their ethnically matched controls (Student's t-test): (SL) 10.2 +/- 1.9 vs 9.0 +/- 3.8, P = 0.01; (BA) 7.9 +/- 1.9 vs 6.8 +/- 2.5, P < 0.0001; (C) 8.3 +/- 2.3 vs 6.8 +/- 1.5, P = 0.0007 micromol/l. Sri Lankans with PCOS had significantly greater Hcy concentrations than British Asians and Europeans with PCOS [P = 0.001; single-factor analysis of variance (anova)] and also significantly greater fasting insulin concentrations [(SL) 242.9 +/- 38.9; (BA) 89.4 +/- 8.9; (C) 48.6 +/- 4.8 pmol/l (P = 0.0003)] and significantly lower QUICKI [(SL) 0.308 +/- 0.004; (BA) 0.335 +/- 0.005; (C) 0.375 +/- 0.002 (P = 0.0007)]. Fasting plasma Hcy correlated best with fasting insulin (r = 0.56, P = 0.0001) and QUICKI (r =-0.53, P < 0.0001) in Sri Lankans with PCOS. Hcy in PCOS subjects from all three ethnic groups correlated significantly with fasting insulin following adjustment for age, BMI and WHR (r = 0.45, P = 0.0001), but this was not evident in the controls (r =-0.32, P = 0.1). CONCLUSIONS: Elevation of fasting plasma homocysteine in PCOS varies with ethnicity and correlates significantly with fasting insulin. High homocysteine in young Sri Lankans with PCOS has major implications for their long-term risk for atherosclerosis.     

The relationship of ghrelin to biochemical and anthropometric markers of adult growth hormone deficiency

INTRODUCTION: Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R) and potently stimulates GH release in humans. Ghrelin is found in the hypothalamus, but most circulating ghrelin is derived from the stomach. Ghrelin stimulates food intake but circulating levels are low in obesity. We hypothesized that GH deficiency (GHD) might be associated with increased circulating ghrelin concentrations as a result of low GH levels. We therefore measured circulating ghrelin concentrations, leptin and body composition in subjects with GHD and healthy controls. METHODS: Subjects with GHD (n = 18) were compared to healthy control subjects (n = 18), matched for body mass index (BMI). They underwent assessment of body composition [waist circumference, BMI and percentage body fat (using bioimpedance)]. Plasma ghrelin, leptin, insulin, GH and IGF-1 were measured in the fasting state. Plasma ghrelin was measured using a specific radioimmunassay, and the other hormones using commercially available assays. RESULTS: The groups were well-matched for BMI (GHD vs. control; 32.9 +/- 10.8 vs. 31.3 +/- 11.7, P = ns) and waist circumference (GHD vs. control; 102.9 +/- 20.0 vs. 99.8 +/- 25.2, P = ns), but percentage body fat (GHD vs. control; 37.0 +/- 9.1 vs. 29.4 +/- 13.0, P = 0.06) tended to be higher in the GHD group. As expected, IGF-1 was lower in GHD (GHD vs. control; 12.5 +/- 6.8 vs. 19.2 +/- 5.8 nmol/l, P = 0.003). Ghrelin [GHD vs. controls; geometric mean (95% CI); 828.8 (95% CI 639.9-1074.2) vs. 487.9 (95% CI 297.2-800.2) pmol/l] and leptin [GHD vs. controls; 13.2 (95% CI 6.6-26.5) vs. 7.9 (95% CI 3.7-16.9) ng/ml] were similar in the two groups. Plasma ghrelin correlated inversely with waist circumference and waist hip ratio in GHD subjects (r = -0.6, P = 0.02) but not with IGF-1 or GH concentrations. There was no significant correlation in the control subjects. CONCLUSION: Circulating ghrelin concentrations are influenced by body fat distribution, but not by levels of either GH or IGF-1. However, given that obesity is associated with reduced ghrelin concentrations and that GHD is commonly associated with increased body fat, it is possible that these two opposing influences on circulating ghrelin levels result in normal concentrations in subjects with GHD.     

Total ghrelin levels during acute insulin infusion in patients with polycystic ovary syndrome

Controversial data were reported concerning fasting ghrelin (decreased, normal or elevated) in polycystic ovary syndrome (PCOS). The aim of our study was to clarify ghrelin levels in non-obese, overweight, and obese PCOS patients; to investigate the effect of acute insulin infusion on ghrelin in PCOS as a chronic insulin-resistant state, with and without the impact of obesity, and to examine ghrelin-androgen interaction. In that order, we evaluated 1) ghrelin levels among 8 nonobese patients with PCOS [body mass index (BMI): 20.52+/-1.31 kg/m2], 8 overweight and obese patients with PCOS (BMI: 34.36+/-6.53 kg/m2) and their respective controls, 2) ghrelin suppression during euglycemic hyperinsulinemic clamp, and 3) ghrelin-androgen interrelationship. After overnight fast, 2-h euglycemic hyperinsulinemic clamp, was performed in all investigated women. Fasting ghrelin was significantly lower in non-obese PCOS than in controls (64.74+/-25.69 vs 108.36+/-52.60; p<0.05) as well as in overweight and obese PCOS in comparison with controls (38.71+/-14.18 vs 98.77+/-40.49; p<0.05). Insulin infusion significantly suppressed ghrelin in all subgroups of investigated women. Analysis of variance for repeatable measures confirmed that there was no significant difference in pattern of response between PCOS and controls. In conclusion, women with PCOS had lower fasting ghrelin and decreased insulin sensitivity independently of their BMI, compared to the controls. In addition, there were no differences between fasting ghrelin levels among non-obese, overweight, and obese women with PCOS. During euglycemic hyperinsulinemic clamp, ghrelin decreased in all studied groups to a similar extent, implying that, compared to chronic hyperinsulinemia, acute hyperinsulinemia reduces ghrelin levels independently of the degree of insulin resistance.     

Serum ghrelin levels are inversely correlated with body mass index,age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.     

The use of anti-mullerian hormone in predicting menstrual response after weight loss in overweight women with polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with reproductive and metabolic abnormalities, specifically menstrual dysfunction and anovulation in conjunction with elevated pre-antral follicle number and arrested follicular maturation. Although anti-müllerian hormone (AMH), an inhibitor of follicle recruitment and maturation, is increased in women with PCOS, the usefulness of circulating AMH levels as a clinical predictor of menstrual response to weight loss in PCOS is not known. METHODS: Overweight women with PCOS (n = 26, age 32.9 +/- 5.8 yr, weight 98.9 +/- 20.8 kg, body mass index 36.1 +/- 7.0 kg/m(2), mean +/- sd) followed an 8-wk weight loss and 6-month weight maintenance program. RESULTS: Net reductions in weight (4.6 +/- 4.8 kg), waist circumference (6.0 +/- 5.3 cm), testosterone (0.3 +/- 0.6 nmol/liter), fasting insulin (3.7 +/- 7.6 mU/liter), and the homeostasis model assessment of insulin sensitivity (0.7 +/- 1.3) occurred for all subjects over the entire study duration. Of 26 subjects, 15 (57.7%) responded to the intervention with improvements in menstrual cyclicity (responders). Compared to nonresponders, responders had lower AMH levels at baseline (23.6 +/- 12.0 vs. 37.9 +/- 17.8 pmol/liter; P = 0.021). Only responders had reductions in fasting insulin (6.1 +/- 5.9 mU/liter; P = 0.001) and homeostasis model assessment (1.3 +/- 5.9; P = 0.002) with acute weight loss (wk 0-8). Baseline AMH was most strongly predicted by baseline ghrelin, free testosterone, and insulin (r(2) = 0.528; P = 0.002). CONCLUSIONS: Overweight women with PCOS who respond to weight loss with menstrual improvements have significantly reduced preweight loss AMH and demonstrate improvements in surrogate measures of insulin resistance with weight loss. Pretreatment AMH is a potential clinical predictor of menstrual improvements with weight loss in PCOS.     

Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference?

OBJECTIVE: Polycystic ovary syndrome (PCOS) is more prevalent in South Asian women residing in the UK than in Caucasians. Insulin resistance (IR) is central to the pathogenesis of PCOS, while type 2 diabetes is commoner in South Asians. We aimed to determine a possible ethnic difference in the clinical and biochemical characteristics of South Asian vs. Caucasian women with PCOS. PATIENTS AND DESIGN: A case-control cross-sectional observational study of consecutive women with anovular PCOS (47 South Asians, 40 Caucasians) and their age-matched controls (11 South Asians and 22 Caucasians). MEASUREMENTS: Index subjects: a questionnaire-based interview on clinical symptoms and family history; anthropometric measurements, clinical observations of the presence and degree of acne, hirsutism and acanthosis nigricans; transvaginal pelvic ultrasound; biochemical analyses of fasting blood sugar, fasting plasma insulin, fasting lipids, testosterone, and SHBG concentrations. Control group: age- and weight-matched unrelated women from the same ethnic backgrounds without PCOS seeking treatment for male infertility were studied by similar methods to those used with the index subjects. RESULTS: South Asians with PCOS presented at a younger age (age 26 +/- 4 vs. 30.1 +/- 5 years, P = 0.005). Body mass index (BMI) and waist : hip ratios were similar in the two affected cohorts. More South Asians had oligomenorrhoea commencing at a younger age. Hirsutism (Ferriman Gallwey score 18 vs. 7.5, P = 0.0001), acne, acanthosis nigricans and secondary infertility were significantly more prevalent in South Asians. The fasting glucose was similar (4.52 +/- 0.08 vs. 4.62 +/- 0.09 mmol/l, P = 0.25), the fasting insulin higher (89.4 +/- 8.9 vs. 48.6 +/- 4.8 pmol/l, P = 0.0001) and insulin sensitivity (IS) lower (0.335 +/- 0.005 vs. 0.357 +/- 0.002, P = 0.0001) among South Asians. Serum SHBG was significantly less in South Asians (35 +/- 3.3 vs. 55 +/- 9.4 nmol/l, P = 0.02), while serum testosterone was similar (2.69 +/- 0.11 vs. 2.64 +/- 0.13 nmol/l, P = 0.37). CONCLUSIONS: We conclude that South Asians with anovular PCOS seek treatment at a younger age, have more severe symptoms, and have higher fasting insulin concentrations and lower insulin sensitivity than Caucasians.     

Ghrelin and adiponectin in patients with Cushing's disease before and after successful transsphenoidal surgery

BACKGROUND: Ghrelin, an endogenous ligand of the GH secretagogue receptor that exerts orexigenic activity, is negatively correlated with body mass index (BMI) and insulin resistance. Conversely, low levels of adiponectin (ApN), a circulating adipocytokine with antidiabetic, antiatherogenic and anti-inflammatory properties, have been found in several insulin-resistant conditions. Although Cushing's syndrome causes several metabolic and hormonal changes leading to insulin resistance and central obesity, few data concerning the impact of glucocorticoid excess on ghrelin and ApN levels are so far available. DESIGN: We evaluated ghrelin and ApN levels in 14 women (age +/- SE 39.5 +/- 3.9 years, BMI +/- SE 25.8 +/- 1.4 kg/m2) with Cushing's disease (CD) at baseline and after successful transsphenoidal surgery (TSS) and in 14 age- and BMI-matched healthy women. RESULTS: Despite similar levels of fasting glucose, insulin, homeostatic model assessment-estimated insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) values, patients with CD had ghrelin levels lower than controls (117.8 +/- 21.5 vs. 269.6 +/- 51.4 pmol/l, P < 0.01), and ghrelin levels did not correlate with ACTH, cortisol, androgen and GH levels. Patients and controls showed similar ApN levels (11.1 +/- 1.6 vs. 11.5 +/- 2.0 mg/l), which correlated negatively with insulin, HOMA-IR and BMI and positively with QUICKI and high density lipoprotein (HDL)-cholesterol only in controls. At 10.2 +/- 0.7 months after successful TSS, patients showed a significant increase in ghrelin levels compared to pretreatment values (342.5 +/- 25.6 vs. 117.8 +/- 21.5 pmol/l, P < 0.005) along with significant modifications in BMI, insulin, HOMA-IR and HDL-cholesterol and no change in ApN levels. In two patients tested on days 2-4 after TSS, no modification in ghrelin and ApN levels was observed, despite a dramatic reduction in cortisol levels. CONCLUSION: Cortisol excess did not directly affect ghrelin and ApN levels in patients with CD. The observation that ghrelin levels were low during the active phase of CD and increased after recovery suggests that glucocorticoids may influence ghrelin levels indirectly by modulating adiposity and metabolic signals over the long term.     

Ghrelin and measures of satiety are altered in polycystic ovary syndrome but not differentially affected by diet composition

Polycystic ovary syndrome (PCOS) is a common endocrine condition in women of reproductive age associated with obesity. It may involve dysregulation of ghrelin, a hormone implicated in appetite regulation. The effect of diet composition on ghrelin is unclear. Overweight women with and without PCOS were randomized to a high-protein (40% carbohydrate, 30% protein; 10 PCOS, six non-PCOS) or standard protein diet (55% carbohydrate, 15% protein; 10 PCOS, six non-PCOS) for 12 wk of energy restriction and 4 wk of weight maintenance. Diet composition had no effect on fasting or postprandial ghrelin or measures of satiety. Non-PCOS subjects had a 70% higher fasting baseline ghrelin (P = 0.011), greater increase in fasting ghrelin (57.5 vs. 34.0%, P = 0.033), and greater maximal decrease in postprandial ghrelin after weight loss (-144.1 +/- 58.4 vs. -28.9 +/- 14.2 pg/ml, P = 0.02) than subjects with PCOS. Subjects with PCOS were less satiated (P = 0.001) and more hungry (P = 0.007) after a test meal at wk 0 and 16 than subjects without PCOS. Appetite regulation, as measured by subjective short-term hunger and satiety and ghrelin homeostasis, may be impaired in PCOS.     

Lipids and lipoprotein subfractions in women with PCOS: relationship to metabolic and endocrine parameters

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit an abnormal lipoprotein profile, characterized by raised concentrations of plasma triglyceride, marginally elevated low density lipoprotein (LDL)-cholesterol, and reduced high density lipoprotein (HDL)-cholesterol. However, a normal LDL-cholesterol level may be misleading since LDL exists as subpopulations of particles differing in size and atherogenic potential. Smaller LDL particles are more atherogenic and high concentrations often occur in association with elevated circulating triglyceride concentrations (but frequently normal total LDL-cholesterol), increased hepatic lipase activity (HL) and insulin resistance. Information on LDL subclasses and HL activity in women with PCOS is sparse. The aim of this study was to determine the concentrations of small, dense LDL (LDL-III) in women with PCOS relative to body mass index (BMI)-matched controls. We also examined the association of lipoprotein subfraction concentrations with endogenous sex hormone concentrations, since existing literature suggested that androgens up-regulate and oestrogens down-regulate HL activity, a key determinant of LDL subfraction distribution. DESIGN: Cross sectional study. PATIENTS: Fifty-two women with oligomenorrhoea and polycystic ovaries determined by ultrasound and BMI matched women with normal menstrual rhythm (NMR) and normal ovarian appearances (n = 14) were recruited from gynaecology clinics. Anthropometric data and fasting blood samples were obtained for metabolic, hormonal and LDL subfraction estimation and a heparin provocation test was used to estimate HL activity. RESULTS: Subjects with PCOS demonstrated higher waist:hip ratio (WHR), testosterone, triglyceride, VLDL-cholesterol concentrations, and HL activity (P < 0.05), whereas SHBG concentrations were significantly lower than controls. PCOS women had higher concentrations (38.0 vs. 25.0 mg/l; P = 0.026) and proportions (12.8 vs. 8.2%; P = 0.006) of small, dense LDL (LDL III), relative to controls. Within the PCOS group, plasma triglyceride and HL activity were the strongest univariate predictors of LDL III mass. They remained as independent predictors in multivariate analysis, and together accounted for 37% of its variability (P = 0.0002). Independent predictors of plasma triglyceride and HL in turn, were measures of fat distribution (waist circumference or WHR) and fasting insulin concentration. Serum testosterone concentration was not associated either in univariate or multivariate analysis with any of the measured lipid, lipoprotein or subfraction parameters, nor with HL activity in the women with PCOS. CONCLUSION: We conclude that women with polycystic ovary syndrome have increased hepatic lipase activity and mass and percentage of small, dense low density lipoprotein relative to body mass index-matched controls with normal menstrual rhythm and normal ovaries. Further, these metabolic perturbances appear related more closely to adiposity/insulin metabolism than to circulating androgen levels.     

Effect of long-term orlistat treatment on serum levels of advanced glycation end-products in women with polycystic ovary syndrome

BACKGROUND Women with polycystic ovary syndrome (PCOS) exhibit elevated serum advanced glycation end-products (AGE) compared with healthy subjects. Short-term administration of orlistat has been shown to reduce the postmeal increase in serum AGE levels in women with PCOS and in controls. OBJECTIVE: To evaluate the long-term effect of orlistat and a low-calorie diet on serum AGE levels, and on the hormonal and metabolic profile of obese PCOS and normal women. DESIGN: A clinical trial of 6 months of orlistat administration with an energy-restricted diet [basic metabolic rate (BMR) 600 kcal/day] in all subjects. SUBJECTS: Twenty-nine women with PCOS [aged 27.52 +/- 5.77 years; body mass index (BMI) 35.43 +/- 5.31 kg/m(2)] and 18 controls (aged 32.06 +/- 5.64 years; BMI 36.39 +/- 6.47 kg/m(2)). MEASUREMENTS: Serum AGE levels (U/ml), hormonal and metabolic profile. RESULTS: PCOS and controls did not differ in BMI (P = 0.58), waist-to-hip ratio (WHR) (P = 0.44), fasting insulin concentration (P = 0.45) and glucose-to-insulin ratio (GIR) (P = 0.34). PCOS women exhibited statistically higher AGE (P < 0.001) and testosterone levels (P < 0.001) compared with controls. After 6 months of orlistat treatment, AGE levels showed a statistically significant decrease in both groups (PCOS: baseline 9.08 +/- 1.84, post-orlistat 8.56 +/- 1.95, P = 0.001; controls: baseline 5.02 +/- 0.62, post-orlistat 4.91 +/- 0.69, P = 0.03), independently of the BMI reduction in the PCOS group. A significant reduction was observed in BMI (PCOS: P < 0.001; controls: P < 0.001), WHR (PCOS: P = 0.002; controls: P = 0.04), fasting insulin (PCOS: P < 0.001; controls: P = 0.008), and testosterone concentrations in PCOS (P < 0.001). SHBG concentration (PCOS: P = 0.004; controls: P = 0.008) and GIR (PCOS: P < 0.001; controls: P = 0.03) were significantly increased. A significant improvement was also observed in insulin resistance indices post-treatment in both groups. CONCLUSIONS: Our data suggest that orlistat has a beneficial effect in reducing elevated AGE levels and improving the hormonal and metabolic profile in women with PCOS after 6 months of treatment, independently of BMI changes.     

The ketosis-resistance in fibro-calculous-pancreatic-diabetes. 1. Clinical observations and endocrine-metabolic measurements during oral glucose tolerance test.

We measured circulating levels of C-peptide, pancreatic glucagon, cortisol, growth hormone and metabolites (glucose, non-esterified fatty acids, glycerol and 3-hydroxybutyrate) in fibro-calculous-pancreatic diabetic (FCPD, n = 28), insulin-dependent diabetic (IDDM, n = 28) and non-diabetic control (n = 27) subjects during an oral glucose tolerance test. There was no difference in the two diabetic groups in age (FCPD 24 +/- 2, IDDM 21 +/- 2 years, mean +/- SEM), BMI (FCPD 16.0 +/- 0.6, IDDM 15.7 +/- 0.4 kg/m2), triceps skinfold thickness (FCPD 8 +/- 1, IDDM 7 +/- 1 mm), glycaemic status (fasting plasma glucose, FCPD 12.5 +/- 1.5, IDDM 14.5 +/- 1.2 mmol/l), fasting plasma C-peptide (FCPD 0.13 +/- 0.03, IDDM 0.08 +/- 0.01 nmol/l), peak plasma C-peptide during OGTT (FCPD 0.36 +/- 0.10, IDDM 0.08 +/- 0.03 nmol/l) and fasting plasma glucagon (FCPD 35 +/- 4, IDDM 37 +/- 4 ng/l). FCPD patients, however, showed lower circulating concentrations of non-esterified fatty acids (0.73 +/- 0.11 mmol/l), glycerol (0.11 +/- 0.02 mmol/l) and 3-hydroxybutyrate (0.15 +/- 0.03 mmol/l) compared to IDDM patients (1.13 +/- 0.14, 0.25 +/- 0.05 and 0.29 +/- 0.08 mmol/l, respectively). This could be due to enhanced sensitivity of adipose tissue lipolysis to the suppressive action of circulating insulin and possibly also to insensitivity of hepatic ketogenesis to glucagon. Our results also demonstrate preservation of alpha-cell function in FCPD patients when beta-cell function is severely diminished, suggesting a more selective beta-cell dysfunction or destruction than hitherto believed.     

Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa.

OBJECTIVE: Ghrelin is a new gastric hormone that has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor subtype 1a (GHS-R1a). Ghrelin administration however not only stimulates GH secretion but also induces adiposity in rodents by increasing food intake and decreasing fat utilization. We hypothesized that impaired ghrelin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role for ghrelin in regulating energy homeostasis, we analyzed circulating ghrelin levels in patients with anorexia nervosa and examined possible correlations with clinical parameters before and after weight gain. METHODS: Plasma ghrelin levels were measured in overnight fasting plasma samples from 36 female patients with anorexia nervosa (age: 25.0+/-1.2 years, BMI: 15.2+/-0.2 kg/m(2)) before and after weight gain following psychotherapeutic treatment intervention in a psychosomatic institution. Plasma ghrelin levels were also measured in fasting plasma samples from 24 age-matched female controls (31+/-1.4 years, BMI: 22.9+/-0.45 kg/m(2)). For quantification of ghrelin levels a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA) was used. RESULTS: Fasting plasma ghrelin levels in anorectic patients were significantly higher (1057+/-95 pg/ml) than in normal age-matched female controls (514+/-63 pg/ml n=24, P=0.02). Therapeutic intervention in a psychosomatic institution caused an BMI increase of 14% (P<0.001) leading to a significant decrease in circulating ghrelin levels of 25%, (P=0.001). A significant negative correlation between Deltaghrelin and DeltaBMI was observed (correlation coefficient: -0.47, P=0.005, n=36). CONCLUSION: We show for the first time that fasting plasma levels of the novel appetite-modulating hormone ghrelin are elevated in anorexia nervosa and return to normal levels after partial weight recovery. These observations suggest the possible existence of ghrelin resistance in cachectic states such as caused by eating disorders. Future studies are necessary to investigate putative mechanisms of ghrelin resistance such as a possible impairment of intracellular ghrelin receptor signaling in pathophysiological states presenting with cachexia.     

Prandial regulation of ghrelin secretion in humans: does glucagon contribute to the preprandial increase in circulating ghrelin?

OBJECTIVE: Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects. SUBJECTS AND MEASUREMENTS: Nine healthy volunteers, mean age 47 years (range 33-58) and body mass index (BMI) 24 kg/m2 (range 20.9-27.6) were recruited and received either 1 mg glucagon (n = 9) or 1 ml saline (n = 6) subcutaneously on separate days between 0800 and 0830 h after an overnight fast. Venous blood was then sampled at 15-min intervals during the first hour, followed by 30-min intervals up to 4 h for glucose, insulin, GH, cortisol, somatostatin and ghrelin. RESULTS: Mean +/- SE basal ghrelin was 213.1 +/- 34.3 pmol/l and decreased significantly by 15 min after glucagon administration to 179.3 +/- 28 pmol/l (P = 0.01), then remaining suppressed relative to the basal value until 240 min after glucagon. Plasma insulin increased from a basal value of 46.7 +/- 7.7 pmol/l to a peak of 327.1 +/- 54.9 pmol/l (P < 0.0001). There was an inverse statistical relationship between the increase in insulin over the first 120 min and the decrease in ghrelin (P = 0.005), while somatostatin, GH and glucose were not significant contributors to the decrease in ghrelin (P > 0.05). Mean +/- SE basal GH was 7.3 +/- 2.9 microg/l and increased by 150 min after glucagon to a peak of 20.5 +/- 6.8 microg/l (P = 0.006). Changes in neither ghrelin nor glucose were related to the increase in GH (P = 0.7). Saline administration did not produce any significant change in ghrelin, insulin or somatostatin although the expected diurnal reduction in cortisol (P < 0.05) was observed. CONCLUSIONS: Our study found no evidence that glucagon stimulates ghrelin secretion in humans and supports the hypothesis that insulin is a negative regulator of ghrelin secretion in the postprandial state. We did not find a negative relationship between endogenous somatostatin and ghrelin despite earlier reports that exogenously administered somatostatin analogues suppress plasma ghrelin. Finally, glucagon-induced GH secretion is not mediated by an increase in plasma ghrelin.     

Circulating ghrelin levels in patients with polycystic ovary syndrome

The syndrome of polycystic ovaries (PCOS) is associated with adiposity and metabolic changes predisposing to insulin resistance and diabetes mellitus. Because the recently discovered GH secretagogue, ghrelin, is intimately involved in the control of appetite and weight regulation, we studied ghrelin levels in a group of 26 otherwise healthy women with PCOS. They were compared with 61 healthy female control subjects and 5 gastrectomized women. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) and continuous infusion of glucose with model assessment (CIGMA) in all patients. In PCOS women, serum ghrelin levels were significantly lower than in healthy lean or obese controls (P < 0.001). In insulin-sensitive PCOS women, ghrelin concentrations compared well with the healthy controls, whereas in insulin-resistant PCOS ghrelin levels were significantly lower and indistinguishable from the low levels found in the gastrectomized women. There was a close correlation of ghrelin to insulin sensitivity (HOMA, r(2) = 0.330, P < 0.002; CIGMA, r(2) = 0.568, P < 0.0001). Treatment of 10 insulin-resistant PCOS women with metformin significantly increased circulating fasting ghrelin concentrations (P < 0.02). Ghrelin levels did not correlate to any of the parameters of hyperandrogenemia, to the LH/FSH ratio, to body mass index, or to fasting insulin and glucose concentrations. In summary, ghrelin levels are decreased in PCOS women and are highly correlated to the degree of insulin resistance. This suggests that ghrelin could be linked to insulin resistance in PCOS women. However, whether low ghrelin in PCOS is a cause or the consequence of insulin resistance awaits further investigations.     

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.     

Peculiarities of functional state of endothelium in women with polycystic ovaries

To reveal factors of elevated risk of development of cardiovascular diseases we examined 59 women with polycystic ovarian syndrome (PCOS). Control group comprised 12 healthy body mass and age matched women. Functional state of endothelium was assessed by endothelium dependent brachial artery dilation (EDV), intima-media thickness (ITM), and endothelin-1 level (ET-1). Carbohydrate metabolism, lipid and hormonal composition of blood were also investigated. Significant differences between groups were revealed in EDV (9.3 +/- 2.95%, 13.8 +/- 2.79%, p=0.001) and ET-1 (1.85 +/- 1.4 fmol/l; 0.4 +/- 0.54 fmol/l). Left/right common carotid artery IMT did not differ significantly between groups (0.52 +/- 1.12/0.55 +/- 0.16 mm; 0.52 +/- 0.05/0.53 +/- 0.05 mm, p > 0.05). 27% of patients with PCOS had metabolic syndrome. Correlation analysis allowed to reveal direct relationship of EDV, IMT, ET-1 with level of fasting immunoreactive insulin (HOMA index). Results of this investigation allow to suggest presence of factors of elevated risk of development of cardiovascular diseases in patients with PCOS.     

Circulating oxidized LDL is associated with parameters of the metabolic syndrome in postmenopausal women

Oxidized low-density lipoproteins (ox-LDL) play a significant role in the development of atherosclerosis. OBJECTIVE: To investigate the relation between circulating ox-LDL and components of the metabolic syndrome (MS) in a sample of 124 postmenopausal women with varying glucose tolerance status. METHODS: This cross-sectional study included postmenopausal women not using hormone therapy. Ox-LDL concentrations were measured in plasma by a monoclonal antibody (mAb-4E6) based competition ELISA. LDL peak particle diameter (LDL-PPD) was measured by non-denaturating polyacrylamide gradient gel electrophoresis (PAGGE). Presence of the MS was determined according to the definition of the NCEP-ATPIII. RESULTS: Circulating ox-LDL concentrations were significantly associated with some factors of the MS such as triglyceride (r=0.48; p<0.0001), high-density lipoprotein cholesterol (r=-0.34; p=0.0001) and fasting plasma glucose concentrations (r=0.21; p=0.02). Ox-LDL concentrations were also associated with LDL cholesterol (r=0.54; p<0.0001), total cholesterol (r=0.48; p<0.0001), LDL apolipoprotein B (r=0.62; p<0.0001) and LDL-PPD (r=-0.18; p<0.05). Moreover, women with the MS had significantly higher ox-LDL concentrations (79.5+/-28.3 U/l) compared to women without the MS (64.2+/-19.9 U/l) (p<0.05). CONCLUSION: Ox-LDL concentrations are associated with individual components of the MS and are significantly higher in postmenopausal women with MS compared to healthy postmenopausal women.     

Effects of modified sham feeding on ghrelin levels in healthy human subjects

The mechanisms involved in the preprandial rise and postprandial fall of circulating ghrelin levels are as yet unknown. Many hormonal and metabolic responses to nutrient intake begin during the cephalic or preabsorptive phase and are mostly mediated by the autonomous nervous system. The aim of the present study was to investigate the effects of the cephalic phase on ghrelin response to feeding in human subjects. The modified sham feeding (MSF), a well established technique in which nutrients are smelled, chewed, and tasted, but not swallowed, was used. Sixteen healthy volunteers (seven men and nine women; mean age +/- sd: 31 +/- 8 yr; body mass index, 22 +/- 3 kg/m(2)) were studied after overnight fasting. Seven of them received a standardized mixed meal, and nine underwent MSF. Blood samples for ghrelin, insulin, and glucose were taken at time -30, 0, 15, 30, 45, 60, 120 min during both tests. Pancreatic polypeptide determinations were evaluated at all times as markers of vagal activity only during MSF. Ghrelin levels significantly increased from time -30 to 0 min before the two tests, then significantly decreased: after the real feeding from 933 +/- 479 pg/ml (277 +/- 142 pmol/liter) to 455 +/- 185 pg/ml (135 +/- 55 pmol/liter; P < 0.05), and after the sham feeding from 917 +/- 313 pg/ml (272 +/- 93 pmol/liter) to 519 +/- 261 pg/ml (154 +/- 77 pmol/liter; P < 0.05). There were no significant differences between the patterns of the responses as evaluated by ANOVA (P = 0.863). As expected after MSF, plasma pancreatic polypeptide concentrations promptly increased from 58 +/- 29 pg/ml (14 +/- 7 pmol/liter) to 113 +/- 38 pg/ml (27 +/- 9 pmol/liter) at 15 min (P < 0.01). Both insulin and glucose levels increased during the actual mixed meal, whereas they were not significantly modified by MSF. In conclusion, circulating ghrelin concentrations are decreased by sham feeding as they are by real feeding in humans. These findings underline the importance of the cephalic response to nutrient intake, i.e. the role of vagal activity, in the control of ghrelin secretion.     

The correlation of plasma omentin-1 with insulin resistance in non-obese polycystic ovary syndrome

ObjectivesAberrant circulating adipokines are considered to be related to the pathological mechanism of polycystic ovary syndrome (PCOS). This study aims to evaluate the relationship between plasma omentin-1 levels, metabolic and hormonal parameters in the setting of non-obese Chinese women with PCOS.Material and methodsThis was a case-controlled, cross-sectional study of 153 non-obese (BMI < 25 kg/m²) PCOS and 114 age-matched healthy non-obese control individuals. Levels of plasma omentin-1, fasting blood glucose, insulin and sexual hormones and ovary volume were analyzed in all subjects.ResultsPlasma omentin-1 levels of non-obese PCOS individuals were significantly lower than in healthy non-obese controls. Body Mass Index (BMI), homeostasis model of assessment for insulin resistance index (HOMA-IR), levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), LH/FSH ratio and ovary volume (OV) were significantly higher in subjects with PCOS than controls. In the HOMA-IR stratified subgroups, PCOS individuals with insulin resistance had lower omentin-1 than those without insulin resistance after BMI adjustment. Omentin-1 was negatively correlated with BMI, HOMA-IR and fasting insulin. Multiple linear regressions revealed that BMI contributed to omentin-1 levels. Ovary volume was negatively correlated to HOMA-IR but had no correlation with omentin-1.ConclusionsPlasma omentin-1 concentrations were decreased in the non-obese PCOS group. Insulin resistance could further decrease plasma omentin-1 in non-obese individuals with PCOS independent of BMI status.