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 lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables

OBJECTIVE Although often associated with insulin resistance and glucose intolerance, various lipoprotein abnormalities have been found in polycystic ovary syndrome (PCOS) but not Invariably so when the degree of obesity is taken into account. We have therefore Investigated the serum lipid profile in a group of women with polycystic ovary syndrome with and without obesity. DESIGN Cross-sectional study of serum lipoprotein lipids and plasma free fatty acids in relation to anthropometric, metabolic and hormonal variables in women with PCOS and weight-matched controls. PATIENTS Twenty-four obese (Pob, mean BMI ± SD 30·6±3·3kg/m²) and 25 non-obese (Pnob, 22·2 ±2·3kg/m²) women with PCOS. Twenty obese (Cob, 30·2 ± 3·5 kg/m²) and 20 non-obese (Cnob, 21·4 ± 1·5 kg/m²) controls. MEASUREMENTS Fasting concentrations of plasma free fatty acids, serum cholesterol and triglycerides in high density lipoproteins (HDL), low density lipoproteins (LDL) and very low density lipoproteins (VLDL) In relation to insulin sensitivity index (M/I; assessed with the euglycaemic insulin clamp), glucose tolerance (k-value; intravenous glucose tolerance test), basal serum hormone concentrations, and body fat distribution (skinfolds and waist hip ratio). RESULTS Plasma concentrations of free fatty acids were markedly higher in Pob than in the other groups (all P < 0 001). The lipoprotein lipids did not differ between Pob and Cob, or between the non-obese groups, whereas both obese groups had higher serum concentrations of triglycerides, totally and in VLDL, and lower HDL-cholesterol than their non-obese counterparts. Pob also had higher serum levels of total and LDL-cholesterol than Pnob. Pob had a more pronounced subcutaneous truncal-abdominal adiposity, higher fasting insulin levels and lower M/I than the other groups, and a lower k-value than Cob. Cob had higher levels of fasting insulin than Cnob. Free fatty acid levels correlated with the k-value (inversely) in both women with PCOS and controls, and with M/I (inversely), age and testosterone levels in PCOS. Step-wise regression analysis for the total population, comparing endocrine, anthropometric and metabolic explanatory variables, showed that the serum levels of HDL-cholesterol and triglycerides were mainly correlated with body fat distribution (both) and fasting insulin levels (triglycerides), and levels of total and LDL-cholesterol with BMI and age. CONCLUSIONS Plasma free fatty acid correlations were markedly increased In obese women with PCOS, closely associated with the lower insulin sensitivity and lower glucose tolerance in these women. In spite of these profound metabolic aberrations, the lipoprotein lipid profile was not significantly more abnormal in obese women with PCOS than in their weight-matched controls.     

Plasma insulin, cholecystokinin, galanin, neuropeptide Y and leptin levels in obese women with and without type 2 diabetes mellitus

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.     

Growth-hormone response to combined stimulation with GHRH plus GH-releasing peptide-6 in obese patients with polycystic ovary syndrome before and after short-term fasting

Controversial data were reported on GH response to different provocative stimuli in obese patients with polycystic ovary syndrome (PCOS). The objective of our study was to assess the effect of short-term fasting on GH response to combined stimulus with GHRH+GH-releasing peptide-6 (GHRP-6) in obese patients with PCOS and possible relation with leptin and insulin changes during fasting. Twelve obese PCOS women and nine obese control women participated in 3-day fasting. GH response, IGF-I, insulin and leptin were measured after GHRH+ GHRP-6, before and after short-term fasting. Obese PCOS patients had significantly greater GH peak after GHRH+GHRP-6 before fasting. Enhanced response to GH stimulation was found after fasting without substantial differences between obese PCOS and obese controls. Insulin and leptin significantly decreased, while insulin sensitivity significantly improved in both groups during fasting. In conclusion, obese PCOS patients have peculiar type of GH response to GHRH+GHRP-6 before fasting, possibly due to enhanced sensitivity of somatotrophs. Observed changes in insulin and leptin may participate in modulation of enhanced GH response after short-term fasting to GHRH+GHRP-6 in PCOS and obese controls.     

GH release after GHRH plus arginine administration in obese and overweight women with polycystic ovary syndrome

Few and unclear data are available in the literature about the relationship between impairment of GH/IGF-I axis and polycystic ovary syndrome (PCOS). This study was aimed to evaluate the basal GH and IGF- levels, and GH release after challenge test in obese and overweight women with PCOS. Thirty patients with PCOS and other 30 healthy women matched for age, body mass index (BMI) and waist-hip ratio (WHR) were studied. Serum follicle-stimulating hormone (FSH), LH, PRL, E2, P, 17OH-progesterone (17OH-P), total T, delta4, DHEA-S, SHBG, GH and IGF-I levels were evaluated in each subject. A GHRH plus arginine challenge test was performed in all subjects. After provocative test, in PCOS and control women the GH levels were significantly (p<0.05) higher in comparison to basal values from 30 min to 120 min. At the same times, a significant (p<0.05) difference was observed between women with PCOS in comparison to healthy women. The mean peak value of GH resulted significantly (p<0.05) lower in PCOS women in comparison to healthy women. The total GH response (area under curve, AUC) to GHRH plus arginine test resulted significantly (p<0.05) lower in PCOS than in healthy women. These findings were statistically significant (p<0.05) also considering the distinction in obese and overweight women. The AUC for GH secretion was significantly lower (p<0.05) in obese in comparison to overweight subjects in the control group, whereas no significant difference was detected between obese and overweight women in the PCOS group. In conclusion, in PCOS women there is a BMI-independent alteration of the GH levels. Further investigations will be necessary to establish the real cause of these data.     

An association between hypothalamic-pituitary dysfunction and peripheral endocrine function in extreme obesity

OBJECTIVE: The aim was to investigate a possible relationship between measures of insulin secretion and glucose disposal and hypothalamic-pituitary function in extreme obesity. DESIGN: A cross-sectional analysis of obese subjects attending the Obesity Clinic at the Royal London Hospital and normal weight volunteers was undertaken. Investigations were performed on separate occasions and in random order. PATIENTS: The subjects were 34 extremely obese women, menstruating and with normal glucose tolerance (mean Body Mass Index, BMI = 42) and 15 normal weight female controls (mean BMI = 22). MEASUREMENTS: The following were measured: fasting insulin, relative insulin resistance calculated using fasting insulin and plasma glucose by the homeostatic model of assessment, insulin release during a 75-g oral glucose tolerance test (insulin area under the curve), steady-state plasma glucose level achieved during a simultaneous intravenous infusion of dextrose, insulin and somatostatin, and the prolactin and growth hormone (GH) responses to insulin-induced hypoglycaemia. RESULTS: In the obese group an impaired prolactin response to hypoglycaemia (mean area under the curve obese 54 U/l min, controls 155 U/l min; P = 0.0001) was inversely correlated to fasting insulin, r2 = 0.142, P = 0.03; relative insulin resistance, r2 = 0.134, P = 0.03 and steady-state plasma glucose level, r2 = 0.345, P = 0.0004 whereas the impaired GH response (mean GH area under the curve obese 1.9 U/l min, controls 65.7 U/l min; P = 0.0001) was inversely correlated to steady-state plasma glucose level, r2 = 0.196, P = 0.01. Backward procedure for stepwise regression analysis confirmed the steady-state plasma glucose level to be the most important variable associated with the prolactin and growth hormone response among the remaining indices of insulin secretion/resistance. CONCLUSION: We conclude from these findings that hyperinsulinaemia in obesity is an important association with altered hypothalamic-pituitary function indicated by impaired prolactin and growth hormone secretion to insulin-induced hypoglycaemia.     

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.     

Alteration of ghrelin-neuropeptide Y network in obese patients with polycystic ovary syndrome: role of hyperinsulinism

Objective Insulin, ghrelin, neuropeptide Y (NPY) and leptin interact in the regulation of energy homeostasis. Most of these signals are altered in polycystic ovary syndrome (PCOS), which is characterized by a high prevalence of obesity. The present study was conducted to evaluate ghrelin–NPY and ghrelin–leptin interplays in relation to insulin secretion in obese PCOS subjects. Design Pilot prospective study. Patients Seven obese PCOS women and seven age–weight matched controls. Measurements Hormonal measurements, oral glucose tolerance test (OGTT) and a ghrelin test (1 µg/kg i.v. bolus). PCOS patients repeated the clinical work‐up after 4 months of metformin treatment (1500 mg/day orally). Results At baseline, PCOS women showed a significantly higher insulinaemic response to the OGTT compared to controls (P < 0·05). In basal conditions, PCOS women exhibited lower NPY levels than controls (P < 0·01). Ghrelin injection markedly increased NPY in controls (P < 0·01), whereas PCOS women showed a deeply blunted NPY response to the stimulus (area under the curve – AUC–NPY: P < 0·01 vs. controls.). Metformin treatment induced a significant decrease in insulin levels (P < 0·01) and the concomitant recovery of NPY secretory capacity in response to ghrelin (AUC–NPY: P < 0·05 vs. baseline) in PCOS women. Leptin levels, which were similar in the two groups, were not modified by ghrelin injection; metformin did not affect this pattern. Conclusion Hyperinsulinaemia seems to play a pivotal role in the alteration of NPY response to ghrelin in obese PCOS women. This derangement could be implicated in the physiopatology of obesity in these patients.     

Polymorphism of glycogen synthetase gene in polycystic ovary syndrome

OBJECTIVE Polycystic ovary syndrome is a heterogeneous disorder associated with a moderate degree of insulin resistance and a higher risk of developing NIDDM. The exact mechanism of insulin resistance is unclear. This study examines the frequency of an Xbal polymorphism of the glycogen synthetase gene (A2 allele) as a marker of insulin resistance and seeks to relate the presence of the A2 allele to indices of insulin sensitivity in women with polycystic ovary syndrome (PCOS). METHODS Insulin sensitivity was assessed by fasting insulin measurements, as well as following oral glucose tolerance test. An i.v. insulin tolerance test was performed to measure the rate of endogenous blood glucose disposal following an i.v. bolus of insulin. Restriction fragment length polymorphism was performed with Xbal digestion of PCR amplified product to detect the presence of A1 and A2 allele. PATIENTS Seventy-one obese (BMI > 25.1) and 19 non-obese (BMI < 25) women with PCOS, and 62 controls (33 obese and 29 non-obese) participated in the study. RESULTS Obese PCOS had significantly higher fasting insulin ( P = 0.002) compared to obese controls. There was no difference between non-obese PCOS and controls. Twenty per cent of obese PCOS had impaired glucose tolerance. The A1A2 genotype was detected in 16 of the 150 (10.7%) subjects examined. Of these, 11/88 (12.5%) were PCOS and 5/62 (8%) were controls. The A2A2 genotype was not present in any of the subjects. The A1A2 genotype was not detected in any of the subjects with impaired glucose tolerance. There was no significant difference in the incidence of the A1A2 genotype between PCOS and controls or between the individual groups. There was no association between the presence of the A1A2 genotype and indices of insulin sensitivity. CONCLUSION The Xbal polymorphism (A2 allele) of the glycogen synthetase gene was not over represented in the PCOS subject and did not relate to the indices of insulin sensitivity or glucose intolerance.     

不同肥胖标准PCOS患者血清sICAM-1水平对比观察及意义

目的比较不同肥胖标准的多囊卵巢综合征(PCOS)患者血清可溶性细胞间黏附分子-1(sICAM-1)水平,并探讨其意义。方法选取PCOS患者54例,将体质量指数(BMI)≥24 kg/m~218例归为肥胖A组,<24 kg/m~2者36例归为非肥胖A组;腰臀比(WHR)≥0.8者29例归为肥胖B组,<0.8者25例归为非肥胖B组;WHR≥0.8且BMI≥24 kg/m~2的患者14例归为肥胖C组,BMI<24 kg/m~2且WHR<0.8的患者15例归为非肥胖C组。采用ELISA方法检测各组患者血清sICAM-1水平。结果肥胖A、B、C组血清sICAM-1水平分别高于非肥胖A、B、C组(P均<0.05);肥胖A、B、C组血清sICAM-1水平比较P均>0.05;非肥胖A组血清sICAM-1水平高于非肥胖B、C组(P均<0.05),非肥胖B、C组血清sICAM-1水平相比,P>0.05。患者血清sICAM-1水平与BMI、WHR均呈正相关(r=0.204,0.360,P均<0.05),sICAM-1与WHR的相关性高于sICAM-1与BMI的相关性(P<0.05)。结论 PCOS患者血清sICAM-1水平与BMI...     

多囊卵巢综合征患者血清对氧磷酯酶1活性、氧化应激与胰岛素抵抗的关系

目的探讨对氧磷酯酶1（PON-1）活性、氧化应激在多囊卵巢综合征（PCOS）患者发生胰岛素抵抗（IR）中的作用。方法41例PCOS患者分为肥胖组17例和非肥胖组24例,另有20名健康女性纳入正常对照组。所有研究对象均行口服糖耐量试验（OGTT）和胰岛素释放试验,使用稳态模型评价IR及胰岛B细胞分泌功能,空腹静脉取血检测丙二醛（MDA）、超氧化物歧化酶（SOD）活性及PON-1活性。结果（1）PCOS非肥胖组和PCOS肥胖组的空腹胰岛素、餐后2小时血糖及胰岛素、HOMA—IR及HOMA-β均高于正常组（P〈0．05）,且PCOS肥胖组的空腹胰岛素、餐后2小时血糖及胰岛素、HOMA—IR均高于PCOS非肥胖组（P％0．05）。（2）PCOS非肥胖组和PCOS肥胖组的MDA、SOD及PON-1与正常组比较差异有统计学意义（P〈0．05）;PCOS肥胖组的SOD显著低于PCOS非肥胖组（P％0．01）,而MDA及PON-1两组之间差异无统计学意义（P〉0．05）。（3）相关分析显示：在PCOS非肥胖组,SOD与PON—1正相关（r=0．417,P〈0．05）,SOD与IR负相关（r=0．492,P〈0．05）。结论PCOS患者无论肥胖与否,均存在餐后血糖升高、PON-1活性降低、氧化应激、IR,且肥胖患者更为严重;PCOS患者的氧化应激与IR相关。     

Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity.

Fat tissue is a significant source of endogenous tumor necrosis factor alpha (TNFalpha), the pluripotent cytokine that plays an important role as a mediator of the peripheral insulin resistance found in obesity. The majority of evidence for this role of TNFalpha is from studies in animal models of obesity. To explore further the role of TNFalpha in the pathogenesis of obesity-related insulin resistance in humans, we compared plasma levels of TNFalpha and the other main endocrine cytokine, interleukin-6 ([IL-6] both measured by enzyme-linked immunosorbent assay), in 26 obese women (body mass index [BMI] > 30 kg/m2) and 13 female controls (BMI < 26 kg/m2) without a history of recent or active infection. Glucose and insulin levels were measured at 0, 1, and 2 hours after a 75-g oral glucose load. There was no significant difference in plasma TNFalpha or IL-6 levels between obese and non-obese subjects overall (2.10 +/- 0.19 v 1.65 +/- 0.18 pg/mL and 2.06 +/- 0.29 v 1.50 +/- 0.17 pg/mL, respectively). However, TNFalpha levels were significantly elevated in obese subjects with a 2-hour glucose level more than 140 mg/dL (n = 8) compared with the other obese subjects (n = 18) and the non-obese controls (2.88 +/- 0.46 v 1.75 +/- 0.10 and 1.65 +/- 0.18 pg/mL, respectively, P < .01). Furthermore, the TNFalpha level correlated significantly with the waist to hip ratio ([WHR] r = .53, P < .01) and fasting and post-oral glucose tolerance test (OGTT) insulin levels (r = .47, P < .02), but not with the BMI, and was higher in obese women with a WHR more than 0.90 (n = 14) in comparison to those with a WHR less than 0.90 (n = 12, 2.47 +/- 0.29 v 1.66 +/- 0.18 pg/mL, respectively, P < .03). The corresponding plasma leptin level was significantly higher in obese women versus the control group (41.6 +/- 2.5 v22.3 +/- 2.9 ng/mL, P < .001) and was related to the BMI (r = .60, P < .01) but not to TNFalpha or the WHR. There were no significant differences in the corresponding IL-6 concentration between groups, and IL-6 did not correlate with TNFalpha, leptin, BMI, WHR, or insulin levels. In conclusion, circulating TNFalpha levels are higher in abdominal obesity compared with peripheral obesity, and may contribute to the insulin resistance that more commonly complicates the former pattern of fat distribution.     

Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents

Approximately half of all women with polycystic ovary syndrome (PCOS) are overweight or obese, and studies have reported endocrine and metabolic differences between lean and obese women with PCOS. PCOS has not been as extensively investigated in the adolescent population. The objectives of our study were to further characterize early endocrine and metabolic alterations in adolescents with PCOS and to determine whether differences between nonobese and obese women with PCOS are present early in its course. We studied an ethnically heterogeneous group of 48 adolescents: 11 nonobese with PCOS [age, 16.1 +/- 1.9 yr; body mass index (BMI), 22.5 +/- 1.5 kg/m(2)], 22 obese with PCOS (age, 15.5 +/- 1.4 yr; BMI, 35.9 +/- 6.2 kg/m(2)), and 15 obese controls (age, 14.4 +/- 1.5 yr; BMI, 35.8 +/- 7.1 kg/m(2)). Fasting levels of glucose, insulin, proinsulin, hemoglobin A1c, testosterone, SHBG, Delta4-androstenedione (Delta4-A), dehydroepiandrosterone sulfate (DHEAS), LH, FSH, IGF-I, IGF binding protein-1, free IGF-I, and lipids were measured. Six of the 11 nonobese PCOS subjects, 11 of the 22 obese PCOS subjects, and six of the 15 controls underwent standard oral glucose tolerance testing. The insulin response to the oral glucose tolerance test was measured by the insulin area under the curve (I(AUC120)). Measures of insulin sensitivity were calculated as the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index. The nonobese adolescents with PCOS demonstrated higher levels of LH, SHBG, Delta4-A, DHEAS, dihydrotestosterone, free IGF-I, and high-density lipoprotein, and lower low-density lipoprotein, compared with the obese PCOS group. Fasting levels of insulin and proinsulin, I(AUC120), and log I(AUC120) were higher, and the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index were lower in the obese compared with the nonobese PCOS subjects. Greater levels of LH and androgens, including total and free testosterone, Delta4-A, and DHEAS, and lower SHBG levels were found in the obese PCOS group compared with the obese controls. Adolescents with PCOS manifest clinical, metabolic, and endocrine features similar to those of adult women, and differences between nonobese and obese women with PCOS may be detected in adolescence. Our findings indicate a more pronounced alteration in the hypothalamo-pituitary-adrenal axis in nonobese adolescents with PCOS and a more marked dysregulation of insulin levels and impairment of insulin sensitivity in their obese counterparts. Our data also suggest differences in the IGF system between nonobese and obese adolescents with PCOS.     

Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome

Since an increase in tumor necrosis factor alpha (TNFalpha) expression has been associated with insulin resistance, this study was undertaken to determine the status of circulating TNFalpha and the relationship of TNFalpha with insulin levels, body weight, or both in women with polycystic ovary syndrome (PCOS). Fasting serum samples were analyzed in 34 subjects with PCOS, of whom 22 were obese (body mass index [BMI]>27 kg/m2), and in 40 normal control women, of whom 20 were obese. Women with PCOS exhibited a significantly (P<.02) higher mean serum TNFalpha concentration compared with the controls. The serum TNFalpha level and BMI were directly correlated in women with PCOS (r=.48, P<.005) and highly correlated in controls (r=.78, P<.001). When subjects were classified by body weight, the mean serum TNFalpha concentration was significantly (P<.001) elevated in normal-weight women with PCOS compared with normal-weight controls. On the other hand, mean serum TNFalpha concentrations in obese women with PCOS and obese controls were similar and significantly (P<.02) higher than in normal-weight women with PCOS. A direct correlation between serum fasting insulin and TNFalpha was evident in controls (r=.35, P<.03), but not in women with PCOS. However, in the subgroup of obese women with PCOS, fasting insulin directly correlated (r=.49, P<.03) with TNFalpha and the median fasting serum insulin concentration was significantly (P<.05) higher compared with the level in normal-weight women with PCOS and all controls. Fasting insulin and TNFalpha were no longer correlated in controls as a group and in obese women with PCOS when controlling for body weight. Serum TNFalpha did not correlate with luteinizing hormone (LH), testosterone (T), or dehydroepiandrosterone sulfate (DHEAS) in women with PCOS. However, serum insulin was significantly correlated (r=.49, P<.0004) with T and the BMI exhibited a trend for correlation with serum T (r=.33, P=.05) in women with PCOS. Finally, the mean serum LH concentration was significantly (P<.02) higher in normal-weight women with PCOS versus obese women with PCOS, and serum LH levels exhibited a trend for an inverse correlation with the BMI (r=.31, P=.09) in women with PCOS. We conclude that (1) serum TNFalpha is increased in normal-weight women with PCOS and is even higher in obese individuals regardless of whether they have PCOS; (2) factors other than obesity are the cause of elevated serum TNFalpha in normal-weight women with PCOS; and (3) whereas increased circulating TNFalpha may mediate insulin resistance in obesity, which may in turn promote hyperandrogenism in obese women with PCOS, it remains to be demonstrated whether this is also the case in normal-weight women with PCOS.     

Phenotypic characteristics according to insulin sensitivity in non-obese Korean women with polycystic ovary syndrome

Over 50% of women with polycystic ovary syndrome (PCOS) have been reported to have varying degree of insulin resistance and it may contribute to hyperandrogenism. The aim of the study is to identify whether the insulin resistance is present in non-obese Korean women with PCOS and whether the phenotype is different according to insulin sensitivity. Seventy-three non-obese (BMI<23 kg/m(2)) women with PCOS and 34 age and BMI comparable control women with regular menstrual cycles were examined. Standard 75 g OGTT was performed to determine the status of glucose tolerance. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp technique. The fasting plasma glucose (p<0.01) and post-glucose load plasma insulin (p<0.01) of women with PCOS were higher than those of controls. Glucose disposal rate (M-value) was lower in women with PCOS compared to controls (p<0.05). Insulin resistant (IR) and insulin sensitive (IS) PCOS were divided by the M-value of 25-percentile (5.5mg/kg min) in controls. Between IR and IS groups, DHEAS (p<0.01), post-glucose load plasma insulin (p<0.05) showed differences after the adjustment for BMI. Our non-obese women with PCOS showed significant insulin resistance compared to their age and BMI comparable control subjects and their insulin resistance may contribute to hyperandrogenism especially via adrenal androgen overproduction.     

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.     

Insulin sensitivity in women with polycystic ovary syndrome

The aim of our study was to compare insulin sensitivity in lean and obese European polycystic ovary syndrome (PCOS) women with lean healthy women. We performed the euglycemic hyperinsulinemic clamp in 83 women with PCOS [53 lean with body mass index (BMI) of 21.5 +/- 1.8 kg/m2 and 30 obese with BMI of 29.6 +/- 3.7 kg/m2] and in 15 healthy women with BMI of 21.6 +/- 1.8 kg/m2 to determine glucose disposal (M) and the insulin sensitivity index (ISI). Statistical evaluation was done using Kruskal-Wallis ANOVA followed by Kruskal-Wallis multiple-comparison z-value test. The basal blood glucose was significantly higher in lean and obese PCOS women than in controls (P < 0.02). Fasting insulin was significantly higher in both lean and obese PCOS women than in controls (P < 0.000001). Obese PCOS women were more insulin resistant than controls (P < 0.02 for M and P < 0.0008 for ISI); lean PCOS women did not differ from controls in M or ISI. Posthepatic insulin delivery was significantly higher in both lean and obese PCOS women compared with controls (P < 0.000008). We conclude that lean PCOS women are not more insulin resistant than healthy controls. Insulin hypersecretion, on the other hand, is present even in lean PCOS women.     

Evaluation of metabolic risk markers in polycystic ovary syndrome (PCOS). Adiponectin, ghrelin, leptin and body composition in hirsute PCOS patients and controls

OBJECTIVE: Polycystic ovary syndrome (PCOS) patients are abdominally obese and are at increased risk of developing the metabolic syndrome. Low adiponectin and ghrelin levels in PCOS patients could be caused by insulin resistance as well as high testosterone levels. DESIGN: Adiponectin and ghrelin levels were evaluated in 51 hirsute PCOS patients referred to the outpatient clinic of an academic, tertiary care medical centre and in 63 weight-matched female controls. Relationships between adiponectin, ghrelin, leptin, body composition, testosterone and insulin were examined. METHODS: Measurements of body composition including waist-hip-ratio (WHR), body mass index (BMI) and whole body dual-energy X-ray absorptiometry scan measures of body fat mass. Measurements of fasting levels of adiponectin, ghrelin, leptin, androgen status, oestradiol, lipid variables and insulin during follicular phase. RESULTS: Adiponectin levels were significantly decreased in obese PCOS patients compared with weight-matched controls (geometric mean (-2 to 2 s.d.) 5.3 (2.5-11.1) vs 7.3 (3.0-17.4) mg/l, P<0.05). Mean ghrelin was significantly lower in hirsute PCOS patients than in controls (0.6 (0.3 to 1.4) vs 0.8 (0.4 to 1.7) microg/l, P<0.001) and this remained significant after subdividing subjects according to waist circumference and BMI. During multiple regression analysis, testosterone correlated positively with adiponectin and negatively with ghrelin independent of BMI, WHR and total fat mass. CONCLUSION: Obese hirsute PCOS patients demonstrated significantly lower adiponectin levels than weight-matched controls suggesting a very high risk for the metabolic syndrome. Furthermore, ghrelin levels were decreased in hirsute PCOS patients and showed a significant, negative correlation with testosterone independent of body composition.     

A Comparative Study of Responses to Acute Hypoglycaemia Induced by Human and Porcine Insulins in Patients with Type 1 Diabetes

The effects of human and porcine insulins on the symptomatic, physiological, and counterregulatory hormonal responses to acute hypoglycaemia were compared in 40 patients with Type 1 diabetes, 20 of whom were newly diagnosed while 20 had been treated for between 5 and 20 years. In a double-blind, cross-over trial all patients were treated with human or porcine insulin, in random order, for two consecutive 3-month periods. At the end of each treatment period they were subjected to an acute episode of experimental hypoglycaemia induced by a continuous intravenous infusion (2.0 mU kg⁻¹ min⁻¹) of the same insulin species. Haemodynamic, sweating, and tremor responses were measured during both studies, symptom scores were recorded and the arterialized plasma glucose thresholds for autonomic activation and the onset of subjective symptoms were identified. In all patients the glycaemic thresholds for the initiation of the autonomic physiological responses to hypoglycaemia and the onset of the symptomatic response were concurrent and did not differ with insulin species (plasma glucose 1.94 vs 1.96 mmol l⁻¹, human vs porcine studies). The onset, temporal pattern, nature, and magnitude of the physiological responses (sweating, heart rate, blood pressure, and tremor) during acute experimental hypoglycaemia were also identical with each insulin species. The magnitude and temporal pattern of the response of counterregulatory hormones (adrenaline, noradrenaline, glucagon, ACTH, and GH) to hypoglycaemia as induced by human and porcine insulins were indistinguishable, as were the total and individual scores of autonomic and neuroglycopenic symptoms. In conclusion, in patients who had newly diagnosed and intermediate duration (5–20 years) of diabetes, the symptomatic, physiological, and counterregulatory hormonal responses to acute insulin-induced hypoglycaemia did not differ between human and porcine insulins, and the plasma glucose thresholds at which the symptomatic and autonomic responses were initiated were identical with both insulin species. This study does not support the hypothesis that treatment with human insulin modifies the symptomatic, physiological, and counterregulatory hormonal responses to acute hypoglycaemia.     

Obese but not normal-weight women with polycystic ovary syndrome are characterized by metabolic and microvascular insulin resistance

Context: Polycystic ovary syndrome (PCOS) and obesity are associated with diabetes and cardiovascular disease, but it is unclear to what extent PCOS contributes independently of obesity. Objective: The objective of the study was to investigate whether insulin sensitivity and insulin's effects on the microcirculation are impaired in normal-weight and obese women with PCOS. Design and Population: Thirty-five women with PCOS (19 normal weight and 16 obese) and 27 age- and body mass index-matched controls (14 normal weight and 13 obese) were included. Metabolic Insulin sensitivity (isoglycemic-hyperinsulinemic clamp) and microvascular insulin sensitivity [endothelium dependent (acetylcholine [ACh])] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation with laser Doppler flowmetry was assessed at baseline and during hyperinsulinemia. Main Outcome Measures: Metabolic insulin sensitivity (M/I value) and the area under the response curves to ACh and SNP curves were measured to assess microcirculatory function at baseline and during insulin infusion (microvascular insulin sensitivity). Results: Obese women were more insulin resistant than normal-weight women (P < 0.001), and obese PCOS women were more resistant than obese controls (P = 0.02). In contrast, normal-weight women with PCOS had similar insulin sensitivity, compared with normal-weight women without PCOS. Baseline responses to ACh showed no difference in the four groups. ACh responses during insulin infusion were significantly greater in normal-weight PCOS and controls than in obese PCOS and controls. PCOS per se had no significant influence on ACh responses during insulin infusion. During hyperinsulinemia, SNP-dependent vasodilatation did not significantly increase, compared with baseline in the four groups. Conclusion: PCOS per se was not associated with impaired metabolic insulin sensitivity in normal-weight women but aggravates impairment of metabolic insulin sensitivity in obese women. In obese but not normal-weight women, microvascular and metabolic insulin sensitivity are decreased, independent of PCOS. Therefore, obese PCOS women in particular may be at increased risk of metabolic and cardiovascular diseases.