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.     

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.     

Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study

Objectives Neuroendocrine factors may predict which athletes develop amenorrhea and which athletes remain eugonadal. Specifically, ghrelin and leptin have been implicated in regulation of GnRH secretion, with ghrelin having inhibitory and leptin, facilitatory effects. We hypothesized that adolescent athletes with amenorrhea (AA) would have higher ghrelin and lower leptin levels than eumenorrheic athletes (EA) and would predict levels of gonadal steroids. Design Cross‐sectional Subjects and measurements We enrolled 58 girls, 21 AA, 19 EA and 18 nonathletic controls 12–18 years old. Fasting blood was drawn for active ghrelin, leptin, E₂ and testosterone. Athletes were > 85% of ideal body weight for age based on body mass index (BMI). Results AA girls had lower BMI than EA and controls (P = 0·003). Log ghrelin was higher in AA than in EA and controls (P < 0·0001), and remained higher after controlling for BMI Z‐scores. Leptin was lower in AA than in the other groups (P < 0·0001), however, the differences did not persist after controlling for BMI Z‐scores. Testosterone was lower in AA than in EA and controls (P = 0·002) and log E₂ trended lower in AA (P = 0·07). We observed inverse associations of log active ghrelin with testosterone (P = 0·01), and positive associations of leptin with testosterone and log E₂ (P = 0·02 and 0·009). Conclusion Higher ghrelin levels, even after controlling for BMI, and lower leptin in AA compared with EA and controls, and their inverse and positive associations, respectively, with gonadal steroids suggest endocrine perturbations that may explain why hypogonadism occurs in some but not all athletes.     

Adiponectin is an indicator of insulin resistance in non-obese prepubertal children born large for gestational age (LGA) and is affected by birth weight

Background and objective Being born as large for gestational age (LGA) has an increased risk of developing insulin resistance. Hypoadiponectinaemia is associated with insulin resistance. The aim of this study was to evaluate adiponectin levels and insulin resistance in association with body composition in LGA born non‐obese children at prepubertal ages. Patients and methods Thirty‐five (17 female and 18 male) LGA born non‐obese children (mean age 4·8 ± 0·3 years) were evaluated with respect to glucose, insulin, IGFBP‐1, leptin, adiponectin levels and body composition by DEXA. Their data were compared to that of non‐obese 49 (20 female, 29 male) appropriate for gestational age (AGA) children (mean age 3·8 ± 0·1 year). Results LGA children, who had similar body mass index standard deviation scores (BMI SDS) as AGA children, had significantly higher insulin (P = 0·043) and statistically borderline significant homeostasis model assessment‐insulin resistance (HOMA‐IR) levels (P = 0·054) than those of AGA children. Adiponectin levels were significantly lower in LGA than AGA children (P = 0·004) even after controlling for age, sex and BMI (P = 0·016). IGFBP‐1, leptin levels and body composition did not show a difference. When the LGA group was divided into subgroups according to birth weight, the analysis revealed that after controlling for BMI, being an LGA and having a higher birth weight in the upper half were associated with lower adiponectin levels (estimated marginal means of logarithmic adiponectin levels 2·6 ± 0·2 vs. 2·1 ± 0·2 µg/ml, P = 0·042). Conclusion LGA children have higher insulin and lower adiponectin levels than AGA children in spite of similar BMI. Adiponectin is a better indicator of insulin resistance in LGA children at prepubertal ages and is affected by birth weight.     

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.     

Impact of adiponectin and ghrelin on incident glucose intolerance and on weight change

Objectives Adiponectin and ghrelin are associated with adiposity and type 2 diabetes in several studies. We sought to prospectively determine the interaction of adiponectin and ghrelin in the development of adiposity and hyperglycaemia. Design Prospective observational study. Participants 393 community‐dwelling Afro‐Jamaicans (mean age 47 ± 13 years; BMI 27·3 ± 6·3 kg/m²; 63% women) without glucose intolerance at baseline. Measurements Anthropometry, fasting plasma glucose, 2‐h plasma glucose, insulin resistance (HOMA‐IR), adiponectin and ghrelin concentrations were measured at baseline and 4·1 ± 0·9 years later. Multivariate analyses were used to explore the associations of HOMA‐IR, adiponectin and ghrelin with weight change and glycaemia. Results The mean weight change was 2·6 ± 5·5 kg. There were 114 incident cases of impaired glucose tolerance (IGT) and 35 cases of diabetes mellitus. Adiponectin was positively correlated with age and female sex (P‐values < 0·01). After adjusting for age and sex, adiponectin and ghrelin were significantly correlated with weight at baseline and follow‐up. However, they were not associated with weight change even after further adjustment for baseline weight. Adiponectin, but not ghrelin, was associated with 2‐h glucose concentrations at follow‐up even after adjusting for age, sex, HOMA‐IR and BMI (P = 0·04). In the fully adjusted logistic regression model, adiponectin predicted incident IGT (OR 0·93; 95% CI: 0·87–0·99) and attenuated the effect of BMI on incident IGT. Conclusions These longitudinal data show that adiponectin and ghrelin may not be causally involved in the development of obesity. However, adiponectin is independently associated with decreased risk of incident IGT.     

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.     

Ghrelin and the differential regulation of des-acyl (DSG) and oct-anoyl ghrelin (OTG) in human adipose tissue (AT)

Objectives Ghrelin, an important central acting orexigenic hormone, is predominantly secreted in the gastrointestinal tract. However little is known about the action of ghrelin in human adipose tissue (AT). Aim To study the expression of ghrelin in AT, the effects of octanoyl–(OTG) and des‐acyl (DSG) ghrelin on lipolysis and lipogenesis, leptin release and potential peripheral signalling through the Y1 receptor. Methods Ex vivo human AT was obtained from women undergoing elective surgery (46 (mean ± SD) 6·8 years, body mass index (BMI): 25·6 ± 5·0 kg/m², n = 20). Abdominal‐subcutaneous (AbdSc) adipocytes were isolated and treated with recombinant human (rh) OTG and DSG to assess lipid metabolism leptin release and the influence of Y1‐receptor blocker. Results Ghrelin was expressed in AbdScAT and negatively correlated with BMI (lean: 3·6 ± 0·74 optical‐density‐units (OD), obese: 1·64 ± 0·45OD, *P < 0·05). Only DSG significantly suppressed glycerol release (Control (C): 286 ± 58 µl/l; DSG 1 nm : 224 ± 38 µl/l↓*; DSG 100 nm : 172 ± 13 µl/l↓*,*↓P < 0·05, n = 7) and reduced hormone sensitive lipase expression (C: 1·0 ± 0·3OD; DSG 1 nm : 0·8 ± 0·3OD↓*; DSG 100 nm : 0·6 ± 0·1OD↓*, n = 4). However, both isoforms increased lipoprotein lipase expression (C: 1·0 ± 0·3OD; DSG 100 nm : 0·2 ± 0·4OD↑*; OTG 100 nm : 2·5 ± 0·3OD↑*, n = 4), whilst blockade of Y1 eliminated this effect in both. Leptin was down‐regulated by DSG only (DSG 1 nm : 5·3 ± 0·7 ng/ml; DSG 100 nm : 4·1 ± 0·7 ng/ml*) and was significant after BMI adjustment (P = 0·029). Conclusion Ghrelin was expressed in human AbdSc AT. In vitro, both OGT and DSG appear to mediate fat deposition with the lipogenic effects in part mediated by the Y1 receptor, whilst the influence of DSG affected lipolysis, lipogenesis and leptin secretion. Taken together, these studies support a local action for ghrelin isoforms on lipid and adipokine metabolism that further supports a cross talk between organs.     

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.     

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.     

Insulin, adiponectin, IGFBP-1 levels and body composition in small for gestational age born non-obese children during prepubertal ages

Background Being small for gestational age (SGA) at birth and postnatal growth pattern may have an impact on insulin resistance and body composition in later life. Adiponectin is a strong determinant of insulin sensitivity. Objective The aim of this study was to evaluate insulin resistance and adiponectin levels in SGA born children with catch‐up growth (CUG) in the absence of obesity in prepubertal ages and relations with body composition and insulin‐like growth factor binding protein (IGFBP)‐1. Methods Twenty‐four (15F, 9M) SGA born children with CUG but without obesity were evaluated at age 6·3 ± 0·5 years with respect to glucose, insulin, IGFBP‐1, leptin and adiponectin levels, and body composition by dual‐energy X‐ray absorptiometry (DEXA). Their data were compared to that of 62 (27F, 35M) appropriate for gestational age (AGA) children. Results SGA and AGA children had similar height standard deviation score (SDS) corrected for parental height and body mass index (BMI) SDS. Homeostasis model for insulin resistance (HOMA‐IR) was significantly high in SGA (0·7 ± 0·6) than in AGA children (0·4 ± 0·2) (P = 0·029). There were no significant differences in leptin, IGFBP‐1, adiponectin, and total and truncal fat between SGA and AGA children. However, being born SGA and having higher BMI in the upper half for the distribution in the sample, although within normal ranges, was associated with lower adiponectin levels (estimated means of log adiponectin levels 3·8 ± 0·3 vs. 4·4 ± 0·1 µg/ml, P = 0·040). Conclusions SGA children with CUG and with no obesity have higher insulin levels compared to AGA children. Both SGA birth and recent size seem to have an effect on serum adiponectin levels in childhood.     

Polymorphisms of the ghrelin/obestatin gene and ghrelin levels in Chinese children with short stature

Objective To investigate the role of ghrelin and polymorphisms of ghrelin/obestatin gene in children with short stature. Methods A total of 117 GH deficient (GHD) and 81 idiopathic short stature (ISS) children were studied. The controls consisted of 125 age and gender‐matched healthy children. The Arg51Gln, Leu72Met and Gln90Leu polymorphisms were genotyped using MassArray and total plasma ghrelin was measured by radioimmunoassay. Results In this study, the frequency of the Arg51Gln polymorphism was very low (0% in controls and 1·0% in patients). The frequency of the Gln90Leu polymorphism was 1·6% in controls and 0·5% in patients, respectively. Higher frequencies of Leu72Met (34·4% in controls and 39·9% in patients) and Met72Met genotypes (4·0% in controls and 2·0% in patients) were found. The differences in the Arg51Gln, Leu72Met or Gln90Leu genotypes and allele frequencies between patients and controls were not significant. Also, there were no significant differences in the Leu72Met genotypes and allele frequencies between GHD and ISS subgroups. There were no significant differences in clinical characteristics and biochemistry markers (including ghrelin levels) among the different genotypes of Leu72Met. However, plasma ghrelin levels in the GHD group were significantly lower than those of controls (P = 0·001). Conclusion These results suggest that ghrelin may have a role in GH secretion and controlling growth. Lower ghrelin levels, but not ghrelin/obestatin polymorphism, might contribute to GHD.     

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.     

Relationships between vascular resistance and energy deficiency, nutritional status and oxidative stress in oestrogen deficient physically active women

Objective Oestrogen deficiency contributes to altered cardiovascular function in premenopausal amenorrheic physically active women. We investigated whether other energy deficiency‐associated factors might also be associated with altered cardiovascular function in these women. Design A prospective observational study was completed at a research facility at the University of Toronto. Participants Thirty‐two healthy premenopausal women (18–35 years old) were studied; 9 sedentary and ovulatory; 14 physically active and ovulatory; and 8 physically active and amenorrheic. Measurements We measured calf vascular resistance, resting heart rate, dietary energy intake, resting energy expenditure and serum measures of homocysteine, high‐sensitivity C‐reactive protein, oxidized low‐density lipoproteins, total T₃, ghrelin, leptin and insulin. Results Groups were similar (P > 0·05) in age (25·1 ± 0·8 years; mean ± SEM), weight (57·3 ± 1·1 kg), and BMI (21·4 ± 0·3 kg/m²). Resting vascular resistance and ghrelin were highest (P < 0·05, main effect), and total T₃ and energy expenditure adjusted for fat free mass lowest (P < 0·05, main effect) in oestrogen deficient women. Using pooled data for stepwise multiple regression modelling: ghrelin and resting energy expenditure adjusted for fat free mass were associated with resting vascular resistance (R² = 0·398, P = 0·018); adjusted dietary energy intake was associated with peak‐ischaemic vascular resistance (R² = 0·231, P = 0·015). Adjusted resting energy expenditure (r = 0·624, P < 0·001) and total T₃ correlated (r = 0·427, P = 0·019) with resting heart rate. Homocysteine, high‐sensitivity C‐reactive protein and oxidized low‐density lipoproteins were similar (P > 0·05, main effect) among the groups, and were unrelated to cardiovascular measures. Conclusion Altered resting vascular resistance in premenopausal oestrogen deficient physically active amenorrheic women is not associated with vascular inflammation or oxidative stress, but rather with parameters that reflect metabolic allostasis and dietary intake, suggesting a potential role for chronic energy deficiency in vascular regulation.     

Visfatin, low-grade inflammation and body mass index (BMI)

Objective Visfatin is an adipokine with revealing roles in inflammatory mechanisms but its implication in inflammation related to excessive adiposity/obesity is not studied yet. Our aim was to investigate the relations of visfatin with inflammation markers and body mass index (BMI) in the peripheral blood mononuclear cells (PBMCs), a type of cells closely related to inflammatory mechanisms. Design Cross‐sectional study, quantification of visfatin, TNF‐α, IL‐6 mRNA in PBMCs. Patients Eighty‐three supposed healthy individuals from the STANISLAS cohort, belonging in three BMI categories: BMI < 25 kg/m² (lean), 25 kg/m² ≤ BMI < 30 kg/m² (overweight) or BMI ≥ 30 kg/m² (obese). Measurements We measured visfatin gene expression (by real‐time quantitative PCR), in relation to gene expression of the pro‐inflammatory cytokines TNF‐α, IL‐6 in PBMCs and to anthropometric parameters (weight, BMI, waist : hip ratio), blood pressure, lipid profile, glucose and inflammatory markers (C‐reactive protein, lymphocyte count). Results Visfatin expression in PBMCs was significantly associated with BMI in a negative way (r = –0·21, P = 0·05). Global anova analysis test for lean and over‐weight/obese individuals showed a negative significant association between visfatin expression in PBMCs and BMI both for men and women (P = 0·05 and P = 0·01, respectively) and these associations remained significant after separating subjects in three groups (lean, overweight, obese) for men and women (P = 0·02 and P = 0·05, respectively). Correlation analysis between levels of expression of visfatin and TNF‐α showed a significant positive linear association (r² = 0·27, P < 0·0001). Conclusion These findings reveal a probable new role of visfatin in inflammation reflected in PBMCs, in the context of obesity.     

Staged diabetes management according to individual patient insulin resistance and beta-cell function ameliorates glycaemic control in type 2 diabetes mellitus

Objective The current consensus algorithm for management of type 2 diabetes is based on the fasting glucose concentration and glycated haemoglobin A_1c (HbA_1c) level. We applied a new therapeutic strategy by assessing insulin secretion and insulin resistance, in addition to glucose concentrations in individual patients. Design and patients We enrolled 193 patients with type 2 diabetes. The patients were assigned to one of six groups according to insulin secretion measured by the serum fasting C‐peptide concentration and insulin resistance measured by an insulin tolerance test (ITT). The two groups were treated differently: 108 patients were treated using a new staged diabetes management (SDM) strategy and 85 patients continued with conventional therapy. Measurements We compared metabolic variables in the two groups at baseline and 12 months after enrolment. Results In patients treated with the SDM strategy, fasting glucose concentration decreased from 9·8 ± 2·1 to 8·2 ± 1·7 mmol/l (P < 0·001). Postprandial 2‐h glucose concentration decreased from 14·19 ± 3·34 to 12·27 ± 3·24 mmol/l (P < 0·001). HbA_1c level decreased from 8·37 ± 1·42% to 7·72 ± 1·39% (P < 0·001). About 43% of the new SDM group achieved an HbA_1c of < 7·0% compared with 25% of patients in the conventional treatment group. Conclusions The new SDM strategy, based on individual data on insulin resistance and insulin secretion, may provide valuable clinical benefits in non‐obese Korean patients with type 2 diabetes.     

Primary hyperparathyroidism is associated with marked impairment of GH response to acylated ghrelin

Background Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH‐releasing action, mainly at the hypothalamic level. Objective To evaluate secretory response of GH to ghrelin in PHP patients. Patients Fifteen patients [11 women/4 men, mean age 54 years, range 32–70 years, body mass index (BMI) 25·0 ± 0·7 kg/m²] affected with PHP due to single parathyroid adenoma and 35 normal age‐matched subjects (23 women/12 men, mean age 58 years, range 35–68 years, BMI 24·1 ± 1·1 kg/m²). Methods A measure of 1 µg/kg body weight i.v. acylated ghrelin or 1 µg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0·5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response. Results Mean serum GH peak after GHRH + ARG was 32·6 ± 7·8 and 17·4 ± 4·0 µg/l, in controls and PHP patients, respectively (P < 0·05). Mean serum GH peak after ghrelin was 70·4 ± 31·5 and 16·8 ± 1·9 µg/l, in controls and PHP patients, respectively, (P < 0·001). Using ROC curves, a serum GH peak > 22 µg/l after ghrelin stimulation might be considered as a cut‐off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF‐1, PTH or ionized calcium concentrations. Conclusions The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.     

Prevalence of metabolic syndrome (MS) in children and adolescents with varying degrees of obesity

Objective Childhood obesity is increasingly common and is associated with health problems; in particular, obesity plays a central role in the metabolic syndrome (MS). We estimated the prevalence of MS in Caucasian children and adolescents with varying degrees of obesity. Patients and methods We studied 191 obese [body mass index (BMI) > 97th percentile] children and adolescents. Obesity was stratified on the basis of a threshold BMI z‐score and subjects were classified as moderately (z‐score 2–2·5) or severely obese (z‐score > 2·5). Seventy‐six, nonobese subjects were recruited into a comparison group. Thirty‐one of them were of normal weight (BMI < 75th percentile) and 45 overweight (BMI 75th–97th percentile). Patients were classified as having MS if they met three or more of the following criteria for age and sex: BMI > 97th percentile, triglyceride levels > 95th percentile, high density lipoprotein (HDL) cholesterol level < 5th percentile, systolic or diastolic blood pressure > 95th percentile and impaired glucose tolerance (blood glucose level: 7·8–11·1 mmol/l at 2 h). Insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA‐IR) and impaired insulin sensitivity was defined as a HOMA‐IR ≥ 2·5 in prepubertal patients and HOMA‐IR > 4 in pubertal subjects. Results The overall prevalence of MS was 13·9% and was present in 12·0% of moderately obese and 31·1% of severely obese subjects; no overweight or normal weight subjects met the criteria for MS. The rate of the MS increased progressively with increasing BMI categories (P < 0·001). Severely obese patients had a threefold increased risk with respect to moderately obese patients. Conclusions The prevalence of the MS is higher in obese as opposed to nonobese subjects and increases with severity of obesity.     

Effects of exercise-induced weight loss on acylated and unacylated ghrelin in overweight children

Objective Controversial data on ghrelin concentration during exercise in human subjects have been published. We tested the hypothesis that exercise could affect acylated ghrelin (AG) and unacylated ghrelin (UAG), which could partly explain the previously reported inconsistent findings on the association of exercise with changes in ghrelin. Design A prospective randomized study. Patients and measurements We randomized 17 overweight volunteers (11‐year‐old boys) to a 12‐week combined exercise group (EG, n = 8) or control group (CG, n = 9). At baseline, 1, 4 and 12 weeks, we measured body weight and composition, insulin, leptin, total ghrelin and acylated ghrelin. Results Compared with the CG, body weight, percentage body fat and homeostatic model assessment (HOMA) indices were significantly lower throughout the 12 weeks in the EG. Total ghrelin and UAG levels gradually increased to 131·9 ± 5·2% and 130·4 ± 5·2% of baseline, respectively, at week 12 in the EG, whereas AG concentration remained unchanged throughout the 12 weeks both within each group and between the groups. At week 12, there were differences in the total ghrelin level and UAG level between the groups. Conclusions This study shows an increase in unacylated acylated ghrelin and unchanged acylated ghrelin after a 12‐week combined exercise programme in overweight children. These findings provide evidence of favourable effects of exercise on improving energy metabolism.     

Severe hypoleptinaemia associated with insulin resistance in patients with common variable immunodeficiency

Objective Common variable immunodeficiency (CVI) is a primary immunodeficiency syndrome characterized by impaired production of antibodies and recurrent infections. Delay in diagnosis leads to metabolic wastage and low body weight. Leptin, a hormone produced by white adipose tissue, modulates insulin action by signal transduction cross‐talk and by direct action on pancreatic beta‐cells. We hypothesized that patients with CVI might present a defective regulation of leptin production and insulin resistance. Patients Thirteen CVI patients (39 ± 11 years) under gammaglobulin replacement were evaluated in parallel with 13 gender‐, age‐, body weight‐ and body mass index (BMI)‐matched healthy voluntaries, and with data from two large population series, the Bruneck and the Hoorn Studies. Measurements Serum leptin and insulin levels, homeostasis model assessment – insulin resistance (HOMA‐IR), body composition, haematological, biochemical and immunoglobulin measurements were obtained. Data were analysed by a one‐way analysis of variance (anova ) and by Pearson's rank analysis. The institutional ethics committee approved the study, and informed consent was obtained from patients and controls. Results No differences were found between CVI and the control group when comparing gender distribution, age, body weight, BMI, waist/hip ratio, relative body fat and fasting glucose levels. Leptin levels were lower (P < 0·05) in CVI patients than in controls and lower than fasting leptin levels detected in a large population study. CVI patients’ serum leptin levels did not correlate with BMI (r = 0·074, P = 0·8) and their high HOMA‐IR indicated insulin resistance. Conclusions CVI patients are relatively hypoleptinaemic and insulin resistant, and their serum leptin levels are not correlated to their BMI.