Exercise training improves autonomic function and inflammatory pattern in women with polycystic ovary syndrome (PCOS)

Background Polycystic ovary syndrome (PCOS) is a common female reproductive‐age endocrine disease predominantly characterized by chronic anovulation, hyperandrogenism, insulin‐resistance and low‐grade inflammatory status. Exercise training (ET) favourably modulates cardiopulmonary function and insulin‐sensitivity markers in PCOS women. The present study investigated the effects of ET on autonomic function and inflammatory pattern in PCOS women. Study design Prospective baseline uncontrolled clinical study. Methods One‐hundred and eighty five PCOS women referred to our department were screened for the inclusion into the study protocol from March 2004 to July 2007. One‐hundred and twenty four PCOS women met the criteria for the inclusion into the study protocol and were subdivided into two groups each composed of 62 patients: PCOS‐T (trained) group underwent 3‐month ET program, whereas PCOS‐UnT (untrained) group did not. At baseline and at 3‐month follow‐up, hormonal and metabolic profile, cardiopulmonary parameters, autonomic function (as expressed by heart rate recovery, HRR) and inflammatory pattern [as expressed by C‐reactive protein (CRP) and white blood cells (WBCs) count] were evaluated. Results PCOS‐T showed a significant (P < 0·05) improvement in maximal oxygen consumption (VO_2max) and in post‐exercise HRR, and a significant (P < 0·001) decrease in CRP and WBCs; whereas no statistically significant changes of the same parameters were observed in PCOS‐UnT. Multiple linear regression analysis showed that 3‐month HRR is linearly related to the inclusion in training group (β = 0·316, P < 0·001), VO_2max (β = 0·151, P = 0·032) and the ratio between glucose and insulin area under curve (AUC) (β = 0·207, P = 0·003), and inversely related to body mass index (β = –0·146, P = 0·046), insulin AUC (β = –0·152, P = 0·032), CRP (β = –0·165, P < 0·021), and WBCs count (β = –0·175, P = 0·039). Conclusions Exercise training improves autonomic function and inflammatory pattern in PCOS women.     

The serum levels of the EGF-like homeotic protein dlk1 correlate with different metabolic parameters in two hormonally different children populations in Spain

Background The Dlk1 gene encodes for dlk1, a transmembrane protein belonging to the EGF‐like repeat‐containing family. Dlk1 has been shown to act as a regulator of adipogenesis. Fc‐dlk1 transgenic mice show a decrease in adipose tissue and glucose tolerance, hypertriglyceridaemia and lower insulin sensitivity. Dlk1‐deficient mice show growth retardation, increased serum lipid metabolites and develop obesity. These data advocate for a role of dlk1 in the maintenance of lipid homeostasis, and suggest that dlk1 levels may influence the development of cardiovascular disease. Aim and methods In this study, we analysed whether dlk1 serum levels could be indicative of the different hormonal or metabolic status shown by two Spanish children populations (6–8 years‐old), Orense and Murcia. We determined dlk1 serum levels by ELISA assay, using an antibody raised against the recombinant protein, and performed a correlation analysis against measurements of several hormonal and biochemical parameters in samples from 494 subjects. Results We found a statistically significant positive correlation between serum levels of dlk1 and those of glucose (P < 0·05), total cholesterol (P < 0·01) and high‐density lipoprotein‐cholesterol (HDL‐C) (P < 0·01) in children from Murcia, but not from Orense's population, where dehydroepiandrosterone‐sulphate (DHEA‐S) levels were significantly higher (P < 0·01) and dlk1 correlated positively with insulin (P < 0·01), homeostasis model assessment (HOMA) (P < 0·01) and free fatty acids (FFA) (P < 0·05). Conclusions dlk1 serum levels appear related to the anabolic status of the children in association with changes in the levels of DHEA‐S, which have been associated with hyperinsulinaemia and diabetes. Monitoring dlk1 levels may be important to evaluate the metabolic and hormonal stage of child development.     

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.     

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.     

Metabolic and cardiopulmonary effects of detraining after a structured exercise training programme in young PCOS women

Objective The aim of the present study was to determine if the favourable cardiopulmonary and metabolic benefits induced by exercise training (ET) programme are maintained after its cessation. Patients Thirty‐two young overweight polycystic ovary syndrome (PCOS) women matched for age and body mass index (BMI) with other 32 PCOS patients was enrolled. The first group [PCOS‐T (trained)] underwent 24‐week ET programme, whereas the second [PCOS‐DT (detrained)] underwent 12‐week ET programme followed by 12‐week detraining period. Methods At baseline, after 12‐ and 24‐week follow‐up, all PCOS women were studied for their hormonal (ovarian and adrenal androgens), metabolic (glucose and insulin) and lipid profile, and underwent cardiopulmonary exercise test. Results After the initial 12‐week ET programme, both PCOS‐T and PCOS‐DT groups, without differences between groups, showed a similar significant (P < 0·05) improvement in BMI, fasting insulin, areas under curve insulin (AUC_INS), glucose and insulin AUC (AUC_GLU/INS), high‐density lipoprotein‐cholesterol (HDL‐C), low‐density lipoprotein‐cholesterol (LDL‐C) and maximal oxygen consumption at cardiopulmonary exercise test (VO_2max). At 24‐week follow‐up, PCOS‐T group showed a significant (P < 0·05) improvement in BMI, fasting insulin, AUC_INS, AUC_GLU/INS, LDL‐C, HDL‐C and VO_2max, in comparison to baseline and 12‐week follow‐up. At same follow‐up visit, the all parameters resulted significantly (P < 0·05) worsened in PCOS‐DT group in comparison to 12‐week follow‐up and PCOS‐T group. In PCOS‐DT group, no parameter assessed at 24‐week follow‐up was significantly different in comparison with baseline. Conclusion In young PCOS women, 12‐week detraining resulted in a complete loss of the favourable adaptations obtained after ET.     

Metformin increases fasting plasma peptide tyrosine tyrosine (PYY) in women with polycystic ovarian syndrome (PCOS)

Objective The beneficial effects of metformin in patients with type 2 diabetes mellitus (T2DM) and polycystic ovarian syndrome (PCOS) are thought to be in part due to weight reduction. However, the mechanisms by which metformin causes weight loss are unclear. We sought to determine whether circulating levels of the anorectic gut hormone peptide tyrosine tyrosine (PYY) show any correlation with metformin‐induced weight loss. Design and patients We examined the acute effects of orally administrated metformin on fasting PYY levels in eight healthy normal‐weight female subjects. Subsequently, we evaluated the effects of 6 months metformin treatment on fasting PYY levels and anthropometric measurements in 20 women with PCOS. Results In normal‐weight females 10 days’ metformin treatment increased fasting PYY levels (P < 0·01). Similarly, in PCOS subjects metformin treatment increased fasting PYY concentrations (P < 0·05). In both groups a marked variation in PYY increase in response to metformin was observed. Long‐term metformin treatment was associated with improvements in weight (P < 0·05), BMI (P < 0·05), fasting glucose (P < 0·05) and menstrual frequency (P < 0·01). Interestingly, change in PYY levels were correlated with change in waist circumference (r = 0·55, P < 0·05). Conclusions Acute and chronic oral metformin administration increase fasting PYY levels and may contribute to metformin's weight loss effect. Further studies are now required to clarify whether changes in circulating PYY levels in response to metformin treatment can be used to predict which patients will subsequently lose weight long‐term and gain cycle restoration.     

The evaluation of metabolic parameters and insulin sensitivity for a more robust diagnosis of the polycystic ovary syndrome

Background Polycystic ovary syndrome (PCOS) is considered predominantly as a hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. Context PCOS diagnostic criteria [National Institute of Health (NIH), Rotterdam Consensus (ROT), Androgen Excess Society (AES)] are unanimous recognized. We aimed to assess in women with suspected PCOS whether the application of the three diagnostic criteria differently characterizes the metabolic profile and insulin sensitivity. Design Retrospective study in a cohort of women admitted to our Outpatient Clinic for suspected PCOS. Patients Two hundred and four women with suspected PCOS in comparison to a group of normal, age‐matched Sicilian women (N = 34) without signs of metabolic syndrome. Measurements We evaluated hyperandrogenaemia and clinical hyperandrogenism, ovarian morphology, hypothalamo–hypophyseal axis and metabolic syndrome parameters. An oral glucose tolerance test (OGTT; 75 g glucose) measured areas under the curve (AUC) for insulin, C peptide and homeostasis model assessment of insulin‐resistance (HOMA‐IR) were performed. Results The prevalence of PCOS was 51% according to NIH, 83% to ROT and 70·6% to AES, and only 100 patients were qualified simultaneously under these three criteria. The prevalence of the metabolic syndrome in PCOS women was 26·92% (NIH), 21·77% (ROT) and 23·61% (AES), respectively. In comparison to healthy women, PCOS women showed increased fasting insulinaemia (PCOS/ROT: P = 0·028; PCOS/NIH: P = 0·007; PCOS/EAS: P = 0·023), 120 min insulin after OGTT insulinaemia (for the three criteria: P < 0·001), AUC_2h insulin (for the three criteria: P < 0·001) and AUC_2h C peptide (for the three criteria: P < 0·001). Conclusions Our study highlights the fact that regardless of the diagnostic criteria used, evaluation of the metabolic parameters and insulin sensitivity is important for a correct diagnosis of PCOS and a therapeutic approach.     

Inflammatory markers and visceral fat are inversely associated with maximal oxygen consumption in women with polycystic ovary syndrome (PCOS)

Background We investigated whether several different inflammatory markers including C‐reactive protein (CRP) and fibrinogen and white blood cells (WBCs) count, are associated with maximal oxygen consumption (VO_2max) in women with polycystic ovary syndrome (PCOS). Methods In PCOS women (n = 124, 24·1 ± 4·5 year‐old) VO_2max was measured during symptom‐limited cardiopulmonary exercise test. Abdominal fat distribution was determined by ultrasound. Physical activity level was assessed by a standardized questionnaire. CRP was measured by immunoassays, fibrinogen by the Clauss method, and WBCs count with a Coulter counter. Results Pearson's analysis showed a significant correlation between VO_2max and logCRP (r = –0·437, P < 0·001), fibrinogen (r = –0·479, P < 0·001), and WBCs count (r = –0·438, P < 0·001). Multivariable logistic regression model showed that age (β = –0·127, P = 0·005), AUC_INS (β = –0·335, P < 0·001), HDL‐C (β = 0·390, P < 0·001), physical activity score (β = 0·238, P = 0·002), visceral fat (β =–0·184), P = 0·023), FAI (β = –0·291, P = 0·028); CRP (β = –0·216, P = 0·011), fibrinogen (β = –0·113, P = 0·008) and WBCs count (β = –0·177, P < 0·001) were significantly associated with VO_2max. Conclusions Acute‐phase reactants, such as CRP and fibrinogen, and WBCs count were independently and inversely associated with a direct measure of cardiorespiratory fitness (VO_2max) in women with PCOS, even after adjustment for physical activity level and other potential confounding factors. These findings add to the growing body of evidence linking inflammation to cardiorespiratory fitness in PCOS women.     

The transition to menopause reinforces adiponectin production and its contribution to improvement of insulin-resistant state

Objective To evaluate the influence of menopausal status on the serum adiponectin concentration and investigate whether the contribution of adiponectin to insulin resistance is modified by menopausal status. Subjects We conducted a population‐based, cross‐sectional study of 207 premenopausal and 206 postmenopausal Japanese women. Measurements Data on anthropometric characteristics, fasting serum adiponectin, glucose and insulin concentrations were used. Insulin resistance (homeostasis model assessment of insulin resistance: HOMA‐IR) was calculated. Results Postmenopausal women had significantly higher HOMA‐IRs than premenopausal women [1·50 (1·42, 1·59) vs 1·18 (1·12, 1·24), geometric mean (1 standard error range), P = 0·005]. Paradoxically, adiponectin levels in postmenopausal women were also significantly higher than those in premenopausal women [10·3 (9·95, 10·7) vs 9·04 (8·71, 9·39), P = 0·028]. Multiple regression analysis showed that body mass index (BMI) was the only significantly independent predictor [standardized partial regression coefficients (sβ) = 0·319, P < 0·001] for HOMA‐IR among premenopausal women, whereas both BMI and adiponectin were the significant predictors among postmenopausal (sβ = 0·334 and ?0·141, P < 0·001 and < 0·05, respectively). When the subjects were restricted to those without metabolic disorders including high blood pressure, hypertriglyceridaemia, hypo‐HDL cholesterolaemia and high fasting glucose, adiponectin (sβ = ?0·249, P < 0·05) was the only significant predictor for HOMA‐IR among postmenopausal women but BMI was not significant (sβ = 0·223, P = 0·075). Conclusions The transition to menopause increases serum adiponectin concentrations. And the significant and negative association between adiponectin and HOMA‐IR was observed only after menopause. Therefore, adiponectin may play a role in the improvement of an incipient insulin‐resistant state after, rather than before, menopause.     

Serum retinol-binding protein 4 is not increased in obesity or obesity-associated type 2 diabetes mellitus, but is reduced after relevant reductions in body fat following gastric bypass

Objective Controversy exists regarding the elevation of serum retinol‐binding protein 4 (RBP4) in human obesity and type 2 diabetes mellitus (T2DM). In the present study, we have compared serum RBP4 in lean and obese patients with or without T2DM, and analysed the effect of weight loss on serum RBP4. Design Forty‐two Caucasian subjects were included in the study. Serum RBP4 was measured by ELISA and Western blot. In addition, serum RBP4 was measured in 21 morbidly obese patients before and after 4, 8 and 15 months of weight loss following Roux‐en‐Y gastric bypass (RYGBP). Results No significant effect of either obesity or diabetes on serum RBP4 was observed. Serum RBP4 concentrations (measured by either ELISA or Western blot) did not correlate with body mass index (BMI), body fat or any indicator of glucose metabolism or insulin resistance. Weight loss following RYGBP did not modify serum RBP4 at 15 months (P = 0·472). However, the variations in serum RBP4 were significantly associated with the reduction in body fat (r = 0·48; P = 0·026). Patients loosing over 20% of fat mass (n = 11) showed significantly different RBP4 concentrations compared to those individuals exhibiting smaller adiposity reductions (n = 10) (–11·0 ± 6·4 vs.+5·8 ± 3·6 mg/l; P = 0·036). Furthermore, RBP4 levels were significantly reduced at 4 (P = 0·006) and 8 (P = 0·015) months only in those patients loosing over 20% of fat mass. Conclusion Serum RBP4 concentrations are not increased in obese patients with or without T2DM. A decrease in RBP4 levels was only observed after surgically induced weight loss accompanied by relevant reductions in body fat. RBP4 might be considered as a dynamic marker of negative energy balance being reduced during weight loss when a negative energy balance threshold is reached. Furthermore, RBP4 variation in the first month after RYGBP may be a predictor of weight loss success.     

Increased arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS) without comorbidities: one more characteristic inherent to the syndrome?

Background Polycystic ovary syndrome (PCOS) is associated with adverse metabolic effects. Some cardiovascular disease (CVD) risk markers are increased in women with PCOS. However, early markers of atherosclerosis are also associated with obesity and insulin resistance, which are related to PCOS. These markers may result either directly from PCOS or indirectly as a consequence of the comorbidities associated with the syndrome. Context To assess the presence of early CVD markers in young, nonobese women with PCOS. Patients Forty women with PCOS and 50 healthy women with regular menstrual cycles, matched for age and body mass index (BMI). Measurements The following CVD markers were assessed by ultrasonography: common carotid artery (CCA) stiffness index (β), distensibility and intima–media thickness (IMT), and brachial artery flow‐mediated dilatation (FMD). Inflammatory markers, including interleukin (IL)‐6, tumour necrosis factor (TNF)‐α, homocysteine, C‐reactive protein (CRP), glycaemia, lipid profile and insulin, were also assessed. Results CCA β was higher in PCOS than in control women (3·72 ± 0·96 vs. 3·36 ± 0·96, P = 0·04) and CCA distensibility was lower (0·31 ± 0·08 vs. 0·35 ± 0·09 mmHg^?1, P = 0·02). Waist circumference, total testosterone and the Free Androgen Index (FAI) were higher in PCOS patients than in controls (78·2 ± 10·0 vs. 71·5 ± 7·2 cm, P = 0·001; 88·1 ± 32·4 vs. 57·1 ± 21·2 ng/dl, P < 0·01; 12·7 ± 15·7%vs. 4·7 ± 2·3%, P < 0·01, respectively), while SHBG was reduced (37·9 ± 19·1 vs. 47·8 ± 18·3 nmol/l, P = 0·01). The remaining variables did not differ between the groups. Conclusions Young women with PCOS exhibit changes in vascular elasticity even in the absence of classical risk factors for CVD, such as hypertension and obesity.     

Altered distribution of adiponectin isoforms in children with Prader-Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones

Objective Prader–Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones. Design, patients and measurements We measured total adiponectin and its isoforms [high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin] and satiety hormones in 14 children with PWS [median age 11·35 years, body mass index (BMI) Z‐score 2·15] and 14 BMI‐matched controls (median age 11·97 years, BMI Z‐score 2·34). Results Despite comparable BMI Z‐scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA‐IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z‐score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0·05), HOMA‐IR (P < 0·01), BMI Z‐score (P < 0·05), insulin (P < 0·01) and leptin (P < 0·05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls. Conclusions Relative to controls of similar age and BMI Z‐score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI‐matched controls.     

Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease

Objective Retinol‐binding protein 4 (RBP4) is a recently identified adipokine that is elevated in the serum in several insulin‐resistant states. We investigated the relationship between non‐alcoholic fatty liver disease (NAFLD) and serum RBP4 in nondiabetic adults. Methods One hundred and fifty‐nine nondiabetic, non‐alcoholic subjects (95 males and 64 females) participated in this study. Division of subjects into a NAFLD group (n = 73; 45 males and 28 females) or a normal group (n = 86; 50 males and 36 females) was based on the presence of fatty liver disease determined by sonography. Results Serum RBP4 levels in the NAFLD group were significantly higher than those in the normal group (62·8 ± 16·0 mg/l vs. 51·7 ± 14·6 mg/l, P < 0·0001). Multiple logistic regression analysis revealed that the RBP4 level was an independent factor associated with NAFLD (P = 0·0042). In addition, serum RBP4 levels were positively correlated with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ‐glutamyltranspeptidase (GGT) levels. The significant association between serum RBP4 and GGT levels remained even after adjusting for age, gender, body mass index, the homeostasis model of assessment (HOMA) value and the presence of NAFLD (r = 0·3097, P = 0·0002). Conclusion Serum RBP4 levels are significantly associated with NAFLD and liver enzymes.     

Insulin resistance and body composition in preterm born children during prepubertal ages

Background Premature born children may show insulin resistance in childhood which may be due to intrauterine or postnatal adverse environmental factors. Objective Aim of this study was to evaluate insulin resistance and body composition in preterm born children born appropriate for gestational age (AGA) or small for gestational age (SGA) and relations with IGF‐I, IGFBP‐3 axis. Methods Ninety‐three preterm born children grouped as premature SGA (n = 30) and premature AGA (n = 63) were evaluated at age 4·6 ± 0·2 years and 4·7 ± 0·1 years with respect to their glucose, insulin, IGF‐I, IGFBP‐3, IGFBP‐1, leptin levels and body composition by dual‐energy X‐ray absorptiometry. Their data were compared to that of body mass index (BMI) matched term SGA (n = 42) and term AGA (n = 44) children of age 4·5 ± 0·2 and 3·8 ± 0·1 years. All children had height appropriate for their target height. Insulin resistance was evaluated by basal insulin and homeostasis model assessment for insulin resistance (HOMA‐IR). Results Basal insulin level was similar in preterm AGA (4·3 ± 1·4 pmol/l) and term AGA (7·9 ± 6·4 pmol/l) children at similar and normal BMI levels. Preterm SGA children had insulin levels (5·0 ± 3·6 pmol/l) similar to preterm AGA children but significantly lower than that in term SGA children (23·7 ± 20·8 pmol/l) (P = 0·001). Similar results were obtained for HOMA‐IR. Term SGA children had also significantly lower IGFBP‐1 levels. Body composition, leptin and IGFBP‐3 did not differ between the respective groups. IGF‐I was lower in preterm AGA (5·0 ± 0·6 nmol/l) than in term AGA (8·3 ± 1·2 nmol/l) (P < 0·001) children. Conclusions Premature born AGA and SGA children do not have insulin resistance when compared to term children if they have made a catch‐up growth appropriate for their target height and have normal BMI. The similar insulin levels in preterm SGA and preterm AGA children together with increased insulin levels in term SGA children points to the fact that it is the intrauterine restriction in the third trimester that has an adverse effect on future adverse metabolic outcome.     

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.     

Metabolic characteristics of subjects with normal glucose tolerance and 1-h hyperglycaemia

Objective Nondiabetic subjects with a 1‐h plasma glucose ≥ 11·1 mmol/l during an oral glucose tolerance test (OGTT) drew our attention to their somewhat confusing status and relative frequency among Chinese patients. The aim of this study was to clarify the metabolic characteristics of these subjects. Design and patients A total of 2549 Chinese subjects were included in this study. Based on results of OGTT, these subjects were classified into three groups: normal glucose tolerance (NGT), impaired glucose regulation (IGR) and diabetes mellitus (DM). Then, according to the level of 1‐h plasma glucose, the NGT and IGR groups were subclassified, respectively, as: NGT without 1‐h hyperglycaemia (NGTN), NGT with hyperglycaemia at 1 h (NGT1H), IGR without 1‐h hyperglycaemia (IGRN), and IGR with hyperglycaemia at 1 h (IGR1H). Results After adjustments for age and gender, the insulinogenic index (IGI) of NGT1H and IGR1H was found to be lower than for those with NGTN and of IGRN, respectively (P < 0·05). No statistical differences, however, were found in oral glucose insulin sensitivity (OGIS) between either of the 1‐h hyperglycaemic groups or of the corresponding NGTN or IGRN groups. Homeostasis model assessment for β‐cell function (HOMA‐B) of NGT1H was lower than that of NGTN (P < 0·05), while IGRN and IGR1H showed no difference. No differences in homeostasis model assessment for insulin resistance (HOMA‐IR) were found among NGTN, NGT1H, IGRN and IGR1H groups. The levels of triglycerides (TG) were not significantly different among NGT1H, IGRN and IGR1H, while TG in these groups were significantly higher than in NGTN (P < 0·05). LDL‐C was significantly higher and HDL significantly lower in NGT1H than in all other groups (P < 0·05).The IGR group was also subclassified as: isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined glucose intolerance (CGI). The IGI of the NGT1H group was similar to the IGI that of combined glucose intolerance group but lower than those of IFG and IGT (P < 0·05).The OGIS of the NGT1H group was the highest among all groups (P < 0·05). HOMA‐B of IGT and NGT1H were higher than that of IFG (P < 0·05). There was no difference among all groups in HOMA‐IR. Plasma lipid levels were not significantly different between NGT1H and any other group. Conclusions Chinese NGT subjects with a 1‐h plasma glucose ≥ 11·1 mmol/l are characterized by metabolic abnormalities, which may be caused by the impairment of early insulin release rather than aggravated insulin resistance.     

Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians

Objective Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the –420C>G putative gain‐of‐function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans. Design and methods We examined the association of three resistin polymorphisms, –852A>G, –420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C‐reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851). Results Resistin levels were higher, dose‐dependently, with the –420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The –852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor‐receptor 2 (sol‐TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol‐TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores. Conclusions Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.     

Pre-gravid physical activity and reduced risk of glucose intolerance in pregnancy: the role of insulin sensitivity

Objective Pre‐gravid physical activity has been associated with a reduced risk of gestational diabetes mellitus (GDM), although neither the types of exercise nor the physiologic mechanisms underlying this protective effect have been well‐studied. Thus, we sought to study the relationships between types of pre‐gravid physical activity and metabolic parameters in pregnancy, including glucose tolerance, insulin sensitivity and β‐cell function. Design/patients/measurements A total of 851 women underwent a glucose challenge test (GCT) and a 3‐h oral glucose tolerance test (OGTT) in late pregnancy, yielding four glucose tolerance groups: (i) GDM; (ii) gestational impaired glucose tolerance (GIGT); (iii) abnormal GCT with normal glucose tolerance on OGTT (abnormal GCT NGT); and (iv) normal GCT with NGT on OGTT (normal GCT NGT). Pre‐gravid physical activity was assessed using the Baecke questionnaire, which measures (i) total physical activity and (ii) its three component domains: work, nonsport leisure‐time, and vigorous/sports activity. Results Glucose tolerance status improved across increasing quartiles of pre‐gravid total physical activity (P = 0·0244). Whereas neither work nor nonsport leisure‐time activity differed between glucose tolerance groups, pre‐gravid vigorous/sports activity was significantly higher in women with normal GCT NGT compared to women with (i) abnormal GCT NGT (P = 0·0018) (ii) GIGT (P = 0·0025), and (iii) GDM (P = 0·0044). In particular, vigorous/sports activity correlated with insulin sensitivity (measured by IS_OGTT) (r = 0·21, P < 0·0001). Furthermore, on multiple linear regression analysis, pre‐gravid vigorous/sports activity emerged as a significant independent predictor of IS_OGTT in pregnancy (t = 4·97, P < 0·0001). Conclusions Pre‐gravid vigorous/sports activity is associated with a reduced risk of glucose intolerance in pregnancy, an effect likely mediated by enhanced insulin sensitivity.     

Relationship between ghrelin and the metabolic syndrome in the elderly: a longitudinal population-based study

Context Ghrelin regulates energy homeostasis and may contribute to the development of the metabolic syndrome (MS) in the elderly. Objective To study the relationship between ghrelin and the MS, IGF‐I and life style factors over a 2‐year follow‐up. Design Longitudinal population‐based study, starting from 2002; 2 years follow‐up. Participants Three hundred and thirteen (153 men/160 women) individuals living independently older than 70 years. Results MS was found in 54·9% of men and 61% of women. In the 229 subjects available at follow‐up, ghrelin was higher in men than in women at basal (P = 0·002) and 2‐year follow‐up (P = 0·004). Ghrelin decreased over time in both genders (P < 0·01). Ghrelin was lower in individuals showing MS compared to non‐MS (P = 0·08), but this difference was more evident at 2‐year follow‐up (P = 0·016), mostly due to men with MS (P = 0·002) and even after adjustment for BMI, gender and age. Individuals with MS had an OR of 1·67 (95% CI: 1·0–2·78) for low ghrelin (< first tertile); when adjusting by BMI, gender and age, only high triglycerides with OR 1·8 (1·0–3·3), remained statistically significant among the MS components. IGF‐I showed a positive correlation with ghrelin only in individuals without MS (r_s 0·403, P < 0·001) with no gender differences; this relationship was not found in MS (r_s 0·120, P = 0·129). A positive association of ghrelin was found with academic level, alcohol consumption and smoking. Conclusions Ghrelin is higher in old men in comparison to women and decreases over time with a steeper decline in subjects with MS; moreover, in these subjects ghrelin/IGF‐I correlation is lost.     

Abnormal heart rate recovery after maximal cardiopulmonary exercise stress testing in young overweight women with polycystic ovary syndrome

Objective Heart rate recovery (HRR) is a measure derived from exercise test, defined as the fall in heart rate during the first minute after maximal exercise. Abnormal HRR is a measure of autonomic dysfunction associated with an increased mortality. This study was performed to evaluate the HRR in polycystic ovary syndrome (PCOS). Design Prospective controlled clinical study. Patients Seventy‐five PCOS women compared to 75 healthy women matched for age (21·7 ± 2·1 years vs. 21·9 ± 1·8 years, respectively) and body mass index (BMI) (29·0 ± 2·6 kg/m² vs. 29·1 ± 2·9 kg/m², respectively). Measurements Subjects were studied for their hormonal and metabolic profile, and underwent cardiopulmonary exercise test (CPX). Results PCOS women showed a significantly reduced HRR (12·9 ± 1·8 vs. 20·4 ± 3·1 beats/min, P < 0·001) compared to healthy controls, an impairment in maximal oxygen consumption (18·0 ± 2·3 ml/kg/min vs. 29·3 ± 3·9 ml/kg/min) and in oxygen consumption at anaerobic threshold (13·6 ± 2·6 ml/kg/min vs. 24·2 ± 3·0 ml/kg/min). In PCOS women, abnormal HRR was inversely correlated to BMI (r = ?0·582, P < 0·001) and to the area under the curve for insulin (r = ?0·596, P < 0·001). Conclusions Our data demonstrate an abnormal HRR after maximal CPX in young overweight PCOS patients, and that HRR should be investigated as a further potential marker of increased cardiovascular risk in PCOS.