Adiponectin before and after weight loss in obese children

Adiponectin is decreased in obesity and seems to be involved in insulin resistance. The influences of age, gender, puberty, and weight loss on adiponectin have not been studied in obese children. We measured body fat mass based on skinfold thickness, age, pubertal stage, gender, adiponectin, and insulin resistance (homeostasis model assessment) in 42 obese children. We analyzed adiponectin and homeostasis model assessment 1 yr later in these obese children and separated them into two groups according to degree of weight loss (decrease in sd score for body mass index, >or=0.5 vs. <0.5). Adiponectin was negatively correlated to percentage body fat (r = -0.44; P = 0.002), insulin resistance (r = -0.33; P = 0.016), and age (r = -0.41; P = 0.003). Adiponectin levels were significantly (P = 0.017) higher in pubertal girls compared with boys, but there was no significant difference in prepubertal children in respect to gender (P = 0.833). Adiponectin was significantly (P < 0.001) lower in pubertal compared with prepubertal children. The significant weight loss in 16 children was associated with a significant increase in adiponectin (P = 0.010) and a decrease in insulin resistance (P = 0.013), whereas there were no changes in the 26 children without significant weight loss. Adiponectin levels in obese children were negatively correlated to age, body fat, and insulin resistance and were decreased in puberty. Significant weight loss led to an increase in adiponectin levels and an improvement of insulin resistance.     

Effect of growth hormone therapy on serum adiponectin and resistin levels in short, small-for-gestational-age children and associations with cardiovascular risk parameters

BACKGROUND: Adiponectin and resistin are fat cell-derived hormones, which are thought to be respectively protective and disadvantageous with regard to the development of cardiovascular disease and diabetes mellitus type 2. Low birth weight has been associated with increased risks for the development of these diseases. In short, small-for-gestational-age (SGA) children, GH therapy has several positive effects regarding cardiovascular risk factors. On the other hand, concern has been expressed about the effects of GH therapy on insulin sensitivity. METHODS: We measured adiponectin and resistin levels in 136 short prepubertal children born SGA and their association with cardiovascular risk parameters and growth factors. Also, we compared the levels with normal-statured controls. The effect of GH treatment was evaluated in 50 short SGA children vs. baseline and vs. an untreated sex- and age-matched SGA control group. RESULTS: Short SGA children had similar adiponectin and lower resistin levels, compared with normal-statured controls. In GH-treated SGA children, neither adiponectin nor resistin levels changed significantly during 2 yr of GH treatment. Compared with untreated sex- and age-matched SGA controls, GH-treated SGA children had similar adiponectin and lower resistin levels. Adiponectin correlated inversely with age but not any cardiovascular risk parameter or growth factor. Higher IGF-I levels in GH-treated children were associated with lower resistin levels. CONCLUSIONS: Compared with normal-statured controls, short prepubertal SGA children had similar adiponectin and lower resistin levels. Two years of GH treatment had no effect on their adiponectin and resistin levels.     

Serum adiponectin levels in adults with Prader-Willi syndrome are independent of anthropometrical parameters and do not change with GH treatment

OBJECTIVE: Obesity and growth hormone (GH) deficiency are common in Prader-Willi syndrome (PWS) and these patients are at risk of metabolic diseases in adult life and of reduced life span. Low adiponectin values are associated with obesity and the metabolic syndrome. We therefore found it of interest to measure adiponectin levels in PWS. PATIENTS AND METHODS: 17 adults, nine men and eight women, 17 to 32 years of age, with a mean body mass index (BMI) of 35+/-3.2 kg/m2 participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin) for six months, and subsequently all received GH for 12 months. At baseline, serum total adiponectin levels in the PWS patients were compared with 25 lean and 34 obese controls. Body composition and various metabolic parameters, including adiponectin, were studied every six months in the PWS group. RESULTS: Serum adiponectin levels in PWS subjects were significantly lower (P<0.001) compared with lean and significantly higher (P<0.001) compared with obese controls. In PWS patients, no correlation was found between adiponectin and anthropometrical parameters or measures of insulin sensitivity (e.g. fasting insulin and insulin sensitivity as estimated by the homeostasis model assessment), or between adiponectin and IGF binding protein-1 or IGF-I. Adiponectin did not change during GH intervention. CONCLUSION: In this study of adults with PWS serum total adiponectin levels were higher than in controls with simple obesity and were independent of anthropometrical parameters. In accordance with this the metabolic syndrome is not necessarily present in all PWS patients. Correction of GH deficiency had no effect on serum adiponectin levels.     

Glucose metabolism and body composition in young adults treated with TBI during childhood

After SCT in childhood, survivors may develop disorders of glucose metabolism. The role of obesity is controversial. We measured insulin sensitivity using the homeostasis model assessment (HOMA) and the frequently sampled i.v. glucose tolerance test (FSIVGTT), as well as body composition using dual-energy X-ray absorptiometry in 18 young adults median 18.2 years after SCT and compared them with matched controls. We also measured growth hormone (GH) secretion, and levels of leptin and adiponectin. HOMA showed insulin resistance in eight patients (44%), as opposed to none of the controls (P=0.008) and FSIVGTT showed a decreased sensitivity index in the patients (2.98 vs 4.54?mU/L/min, P=0.042). Dual energy X-ray absorptiometry showed a higher percentage fat mass in the patients (34.9 vs 24.3%, P=0.011), which correlated inversely with the sensitivity index (r=-0.52, P=0.032). The patients had a lower peak value of GH (GH(max) 9 vs 20.7?mU/L, P=0.002). Time post SCT correlated with percentage fat mass and inversely with GH(max). The patients had higher levels of leptin and lower levels of adiponectin, even after adjustment for fat mass. We propose that the decreased insulin sensitivity may primarily be explained by the adverse body composition, which may owe to long-standing GH deficiency.     

Early metabolic derangements in daughters of women with polycystic ovary syndrome

CONTEXT: Polycystic ovary syndrome (PCOS) is a familial endocrine-metabolic dysfunction, increasingly recognized in adolescent girls with hyperandrogenism. However, it is difficult to establish whether the metabolic abnormalities described in PCOS are present before the onset of hyperandrogenism. In children, a strong association of adiponectin levels with metabolic parameters of insulin resistance has been described. OBJECTIVE: The objective of the study was to evaluate adiponectin serum concentrations and metabolic parameters in prepubertal and pubertal daughters of women with PCOS to identify girls with increased metabolic risk. DESIGN: Fifty-three prepubertal and 22 pubertal (Tanner stages II-V) daughters of PCOS women (PCOSd) and 32 prepubertal and 17 pubertal daughters of control women (Cd) were studied. In both groups, an oral glucose tolerance test was performed with measurement of glucose and insulin. Adiponectin, leptin, C-reactive protein, SHBG, sex steroids, and lipids were determined in the fasting sample. RESULTS: Both groups had similar chronological ages, body mass index sd score, and Tanner stage distribution. In the prepubertal girls, 2-h insulin was higher (P = 0.023) and adiponectin levels were lower (P = 0.004) in the PCOSd group, compared with the Cd group. In the pubertal girls, triglycerides (P = 0.03), 2-h insulin (P = 0.01), and serum testosterone concentrations were higher (P = 0.012) and SHBG lower (P = 0.009) in PCOSd, compared with Cd, but adiponectin levels were similar in both groups. CONCLUSIONS: Some of the metabolic features of PCOS are present in daughters of PCOS women before the onset of hyperandrogenism. Adiponectin appears to be one of the early markers of metabolic derangement in these girls.     

The postprandial response of adiponectin to a high-fat meal in normal and insulin-resistant subjects

OBJECTIVE: Adiponectin is an adipose-specific protein with short-term effects in vivo on glucose and fatty acid levels. We studied the plasma concentration and the proteolytic activation status of adiponectin following the consumption of a high-fat, low-carbohydrate meal. DESIGN: Analysis of adiponectin concentration and polypeptide structure after consumption of a fat meal. SUBJECTS: Normal subjects (n=24) and first-degree relatives of patients with type II diabetes (n=20). MEASUREMENTS: All subjects had a normal fasting plasma glucose and glucose tolerance. Blood was collected for the determination of plasma insulin, adiponectin, triglyceride, and free fatty acids. Body composition was assessed with dual-energy X-ray absorptiometry and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Postprandial response over 6 h was determined for plasma adiponectin, glucose, insulin, triglyceride, and free fatty acids. Adiponectin was measured by commercial RIA and its polypeptide structure examined by Western blotting. RESULTS: The relatives were more insulin resistant and had increased adiposity compared with control subjects. There was no significant difference in postprandial response in fatty acids, triglyceride, or insulin between the groups. Postprandial levels of adiponectin measured by radioimmunoassay were not significantly different from fasting levels, and no breakdown products of adiponectin were detectable in postprandial samples by Western blotting. CONCLUSIONS: Levels of circulating adiponectin do not alter in response to a fat meal, despite evidence in mice that acute changes in adiponectin significantly affect postprandial fatty acid flux. Moreover, a fat meal challenge did not lead to significant activation of adiponectin by proteolytic conversion.     

Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices

HIV-related lipodystrophy is characterized by adipose redistribution, dyslipidemia, and insulin resistance. Adiponectin is an adipose-derived peptide thought to act as a systemic regulator of glucose and lipid metabolism. We investigated adiponectin concentrations in 10 HIV-infected patients during acute HIV infection (viral load, 2.0 x 10(6) +/- 1.0 x 10(6) copies/ml) and then 6-8 months later, as well as cross-sectionally in 41 HIV-infected patients (21 with evidence of fat redistribution and 20 without evidence of fat redistribution) in comparison with 20 age- and body mass index-matched healthy control subjects. Circulating adiponectin concentrations did not change with treatment of acute HIV infection (5.8 +/- 0.4 vs. 5.9 +/- 0.7 micro g/ml, P = 0.96) but were reduced in patients with chronic HIV infection and fat redistribution (7.8 +/- 0.9 micro g/ml), compared with age- and body mass index-matched HIV-infected patients without fat redistribution (12.7 +/- 1.7 micro g/ml) and healthy control subjects (11.9 +/- 1.7 micro g/ml, P < 0.05 vs. HIV-infected patients without fat redistribution and vs. control subjects). Adiponectin concentrations correlated with body composition [correlation coefficient (r) = -0.47, P = 0.002 vs. trunk fat:total fat; r = 0.51, P < 0.001 vs. extremity fat:total fat], insulin response to glucose challenge (r = -0.36, P = 0.03), triglyceride (r = -0.39, P = 0.01), and high-density lipoprotein (r = 0.37, P = 0.02) among the HIV-infected patients. Adiponectin remained a significant correlate of insulin response to GTT, controlling for medication use and body composition changes in HIV-infected patients. These data suggest a strong relationship between adiponectin and body composition in HIV-infected patients. Changes in adiponectin may contribute to the metabolic dysregulation in this group of patients.     

Sleep-related breathing disorders in prepubertal children with Prader-Willi syndrome and effects of growth hormone treatment

CONTEXT: Recently, several cases of sudden death in GH-treated and non-GH-treated, mainly young Prader-Willi syndrome (PWS), patients were reported. GH treatment in PWS results in a remarkable growth response and an improvement of body composition and muscle strength. Data concerning effects on respiratory parameters, are however, limited. OBJECTIVE: The objective of the study was to evaluate effects of GH on respiratory parameters in prepubertal PWS children. DESIGN: Polysomnography was performed before GH in 53 children and repeated after 6 months of GH treatment in 35 of them. PATIENTS: Fifty-three prepubertal PWS children (30 boys), with median (interquartile range) age of 5.4 (2.1-7.2) yr and body mass index of +1.0 sd score (-0.1-1.7). INTERVENTION: Intervention included treatment with GH 1 mg/m2.d. RESULTS: Apnea hypopnea index (AHI) was 5.1 per hour (2.8-8.7) (normal 0-1 per hour). Of these, 2.8 per hour (1.5-5.4) were central apneas and the rest mainly hypopneas. Duration of apneas was 15.0 sec (13.0-28.0). AHI did not correlate with age and body mass index, but central apneas decreased with age (r = -0.34, P = 0.01). During 6 months of GH treatment, AHI did not significantly change from 4.8 (2.6-7.9) at baseline to 4.0 (2.7-6.2; P = 0.36). One patient died unexpectedly during a mild upper respiratory tract infection, although he had a nearly normal polysomnography. CONCLUSIONS: PWS children have a high AHI, mainly due to central apneas. Six months of GH treatment does not aggravate the sleep-related breathing disorders in young PWS children. Our study also shows that monitoring during upper respiratory tract infection in PWS children should be considered.     

The effect of growth hormone on the response of total and acylated ghrelin to a standardized oral glucose load and insulin resistance in children with Prader-Willi syndrome

CONTEXT: Fasting levels of plasma ghrelins are grossly elevated in children with Prader-Willi syndrome (PWS). The cause of this elevation and the regulation of ghrelins in PWS is largely unknown. The regulatory role of individual nutritional components and of GH is not well characterized. OBJECTIVE: We investigated the influence of GH on acylated (aGhr) and total ghrelin (tGhr) concentrations before and after an oral glucose load, and on insulin resistance in PWS children. DESIGN, PATIENTS, AND INTERVENTIONS: In a clinical follow-up study, plasma ghrelins were measured during an oral glucose tolerance test, and parameters of insulin resistance were determined in 28 PWS children before and/or 1.18 (0.42-9.6) yr (median, range) after start of GH therapy (0.035 mg/kg body weight per day). MAIN OUTCOME MEASURES: Fasting and postglucose concentrations of aGhr and tGhr and homeostasis model assessment 2 insulin resistance were the main outcome measures. SETTING: The study was conducted in a single center (University Children's Hospital). Results: High fasting [1060 +/- 292 (sd) pg/ml; n = 12] and postglucose trough (801 +/- 303 pg/ml; n = 10) tGhr concentrations in GH-untreated PWS children were found to be decreased in the GH-treated group (fasting 761 +/- 247 pg/ml, n = 24, P = 0.006; postglucose 500 +/- 176 pg/ml, n = 20; P = 0.006). In contrast, aGhr concentrations and insulin resistance were not changed by GH treatment. Both aGhr and tGhr concentrations were decreased by oral carbohydrate administration, independent of the GH treatment status. CONCLUSIONS: Our results indicate that, in PWS children, aGhr and tGhr are differentially regulated by GH.     

Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels

Adiponectin is an adipocytokine with profound antidiabetic and antiatherogenic effects that is decreased in obesity. With the increasing prevalence of obesity and the emergence of related disorders, including type 2 diabetes in children, the regulation of adiponectin and its relationship to childhood obesity is of great interest. In this study we aimed to elucidate the impact of gender, pubertal development, and obesity on adiponectin levels in children. We investigated two phenotypically characterized cohorts of 200 normal weight and 135 obese children and adolescents covering a wide range of age (3.4-17.9 yr) and body mass index (-2.1 to +4.8 sd score). In healthy lean boys, adiponectin levels significantly declined in parallel with physical and pubertal development, subsequently leading to significantly reduced adiponectin levels in adolescent boys compared with girls (5.6 +/- 0.5 vs. 7.1 +/- 0.5 mg/liter; P = 0.03). This decline was inversely related to testosterone (r = -0.42; P < 0.0001) and dehydroepiandrosterone sulfate (r = -0.20; P = 0.0068) serum concentrations and may account for the gender differences seen in adults. Using a stepwise forward multiple regression model, pubertal stage was the strongest independent predictor of adiponectin (r(2) = 0.206; P < 0.0001), with additional influences of body mass index sd score and testosterone. Adiponectin levels were decreased in obese children and adolescents compared with lean peers of corresponding age and pubertal stage (5.18 vs. 7.13 mg/liter; P = 0.015). In obese children, adiponectin levels were closely associated with parameters related to the metabolic syndrome, such as insulin resistance, hyperinsulinemia, blood pressure, and uric acid, in univariate and multivariate analyses, with the insulin sensitivity index being the strongest independent parameter identified by stepwise forward multiple regression (r(2) = 0.226; P < 0.0001). Hence, there is a strong association of adiponectin serum concentrations with obesity, pubertal development, and metabolic parameters in children indicating epidemiological and pathophysiological relevance already in childhood.     

Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity

Plasma levels of adiponectin are decreased in patients with nonalcoholic fatty liver disease (NAFLD), but the relationship among plasma adiponectin, insulin sensitivity, and histological features is unclear. In 174 NAFLD patients and 42 controls, we examined plasma adiponectin concentrations in relation to 1) lipid profile, indices of insulin resistance, and features of the metabolic syndrome (n = 174); 2) hepatic insulin resistance (clamp technique with tracer infusion) (10 patients); and 3) histological features at liver biopsy (n = 116). When the data from all subjects were combined, plasma adiponectin levels were positively associated with increased age, female gender, and plasma high-density lipoprotein levels, and negatively associated with waist circumference, body mass index, triglycerides, indices of insulin resistance, and aminotransferase levels, and also predicted the presence of the metabolic syndrome. In step-wise regression, increased age, female gender, waist circumference, triglyceride levels, and homeostasis model assessment independently associated with adiponectin (adjusted R(2), 0.329). In NAFLD, adiponectin was only associated with increased age, female gender, and triglycerides (adjusted R(2), 0.245). When the measured histological parameters were included in the model, plasma adiponectin levels were also inversely proportional to the percentage of hepatic fat content (adjusted R(2), 0.221), whereas necroinflammation and fibrosis did not fit in the model. Adiponectin was negatively correlated with insulin-suppressed endogenous glucose production during the clamp (P = 0.011). The results demonstrate that decreased levels of circulating adiponectin in NAFLD are related to hepatic insulin sensitivity and to the amount of hepatic fat content. Hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.     

Mature subcutaneous and visceral adipocyte concentrations of adiponectin are highly correlated in prepubertal children and inversely related to body mass index standard deviation score

CONTEXT: Adiponectin is an adipocyte-specific protein with insulin-sensitizing properties. Several studies have examined the expression of adiponectin mRNA or tissue/secreted protein levels in fat obtained from adults, but none has assessed tissue levels in childhood. PATIENTS: Paired subcutaneous (Sc) and visceral (V) fat samples were obtained from 12 normal-weight children. MAIN OUTCOME MEASURES: Mature adipocytes were isolated and total adiponectin levels determined by ELISA. Insulin sensitivity and lipid parameters were assessed in fasting blood samples taken at the time of biopsy collection. RESULTS: A positive correlation was seen between the adiponectin concentration within the Sc and V mature adipocytes derived from each child (r = 0.924; P < 0.001). After logarithmic transformation of the Sc and V adiponectin concentrations (log-Sc and log-V) to render the data Gaussian, both log-Sc and log-V were found to be lower in those children with higher body mass index sd score (r = -0.621 and r = -0.357 respectively), although this reached statistical significance only in the Sc adipocytes (P = 0.03). Age was not related to either log-Sc or log-V adiponectin levels, although a significant negative association was seen with serum adiponectin (r = -0.589; P = 0.04). Log-Sc or log-V did not correlate with serum adiponectin concentrations, markers of insulin sensitivity, or circulating lipid levels. CONCLUSIONS: These data indicate a relationship between total adiponectin levels in different tissue compartments, suggesting either some form of interaction or coregulation by systemic factors, possibly related to body size/fat mass. Serum concentrations of total adiponectin were inversely related to age but showed no relationship with either tissue levels or body mass index sd score.     

Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa

BACKGROUND: Adolescents with anorexia nervosa (AN) have low bone mineral density (BMD). Adipokines and insulin play an important role in bone metabolism in healthy individuals. However, their association with bone metabolism in AN is unknown. OBJECTIVE: The aim of the study was to determine whether adipokines and insulin are independently associated with measures of BMD in adolescents with AN and controls. DESIGN/METHODS: Levels of adiponectin and insulin, fasting and after oral glucose, were evaluated in 17 AN patients and 19 controls (age, 12-18 yr), in whom hormonal parameters [GH, IGF-I, cortisol, estradiol, leptin, ghrelin, and peptide YY (PYY)] had been previously determined. Body composition, bone mineral content, and BMD at the lumbar spine, hip, femoral neck, and total body were assessed by dual energy x-ray absorptiometry. Two bone formation and bone resorption markers were examined. SETTING: The study was conducted at a General Clinical Research Center. RESULTS: Adiponectin differed between AN subjects and controls after controlling for fat mass and decreased in both after oral glucose (P = 0.02 and 0.07). On regression modeling, independent associations were observed of: 1) body mass index and adiponectin with lumbar spine bone mineral apparent density Z-scores (r(2) = 0.45); 2) lean mass, PYY, and ghrelin with hip Z-scores (r(2) = 0.55); 3) adiponectin and lean mass with femoral neck-bone mineral apparent density Z-scores (r(2) = 0.34); and 4) lean mass, PYY, GH, and ghrelin with total body-bone mineral content/height Z-scores (r(2) = 0.64), for the combined group. Adiponectin was also independently associated with BMD, and insulin was associated with bone turnover markers in the groups considered separately. CONCLUSIONS: Adiponectin contributes significantly to the variability of bone density, and insulin contributes to bone turnover markers in adolescent girls.     

Interrelationship between insulin, leptin and growth hormone in growth hormone-treated children

OBJECTIVES: The aim of the study was to examine insulin homeostasis during growth hormone (GH) therapy, and to investigate the effect of GH treatment on insulin and leptin concentration in obese children. SUBJECTS: Nineteen obese children (8 with Prader-Willi Syndrome (PWS)) were treated with GH 0.1 IU/kg/day dose for 3 months and were compared with 29 non-treated age and sex matched obese children (9 PWS) and 49 GH treated non-obese short children. Mean age of the children was 10.3+/-1.8 (6.7-13.8) y, with body mass index of 23.6+/-10.4 (11.5-47) kg/m2. RESULTS: Leptin concentration decreased and was correlated inversely with initial leptin value (r2=-0.374, P<0.001) and decreased body mass (r2=0.338, P=0.001). Insulin sensitivity index was not significantly changed during therapy. Leptin decrease after 3 months of GH administration was correlated inversely with the increase in first phase insulin response to intravenous glucose tolerance test (IVGTT) (r2=-0.595, P<0.001). Results of long-term follow-up of treated patients demonstrated a decrease in insulin concentration after cessation of therapy. In GH-treated subjects, the glucose increase in response to glucose load appeared to be higher than in untreated subjects. CONCLUSION: The high insulin response to glucose load seen in GH-treated subjects was appropriate to their glucose concentration and the insulin sensitivity index was unchanged relative to the pretreatment period. Increased insulin dosage in our patients did not induce an increase in leptin concentrations as had been hypothesised.     

Circulating adiponectin levels, body composition and obesity-related variables in Prader-Willi syndrome: comparison with obese subjects

BACKGROUND: People with obesity and/or the metabolic syndrome have an increased risk for developing diabetes and cardiovascular disease and may have low adiponectin levels. The obesity associated with Prader-Willi syndrome (PWS) would be expected to have similar complications. However, it was recently reported that, despite their adiposity, people with PWS have reduced visceral fat and are less likely to develop diabetes mellitus or the metabolic syndrome compared with people with simple obesity. OBJECTIVE: To determine if plasma adiponectin levels and other variables relevant to diabetes and cardiovascular risk are different in a cohort of PWS subjects with known genetic subtypes compared with age-, sex- and weight-matched control subjects. RESULTS: Fasting plasma glucose, C-peptide, triglycerides, leptin and cholesterol levels were similar in PWS and obese subjects. Our 20 PWS subjects (mean age = 27.7 years) had higher percent body fat (54.1 vs 48.5%) determined by DEXA measurements and lower percent lean mass (45.9 vs 51.5%) compared with 14 obese controls (mean age = 26.9 year). Plasma adiponectin levels were significantly higher in PWS (15.5 +/- 8.2 microg/ml) than in obese controls (7.5 +/- 2.7 microg/ml). A significant positive correlation was found with insulin sensitivity in PWS subjects (r = 0.75, P = 0.0003) but not in obese controls (r = 0.36, P = 0.20). DISCUSSION: Our study confirmed an earlier observation of higher adiponectin levels in PWS subjects and less insulin resistance proportionate to their obesity status than found in subjects with simple obesity. Furthermore, no differences were seen in PWS subjects with the chromosome 15 deletion or maternal disomy 15. The reported excessive visceral adiposity in subjects with simple obesity compared with PWS may be associated with decreased production and lower circulating levels of adiponectin.     

Growth hormone treatment of adults with Prader-Willi syndrome and growth hormone deficiency improves lean body mass, fractional body fat, and serum triiodothyronine without glucose impairment: results from the United States multicenter trial

CONTEXT: GH replacement in Prader-Willi syndrome (PWS) children has well-defined benefits and risks and is used extensively worldwide. Its use in PWS adults has been limited by documentation of benefits and risks, as determined by larger multisite studies. OBJECTIVES: Our objective was to evaluate the effectiveness and safety of GH in GH-deficient genotype-positive PWS adults. DESIGN: We conducted a 12-month open-label multicenter trial with 6-month dose-optimization and 6-month stable treatment periods. Setting: The study was conducted at outpatient treatment facilities at four U.S. academic medical centers. PATIENTS: Lean and obese PWS adults with diverse cognitive skills, behavioral traits, and living arrangements were recruited from clinical populations. INTERVENTION: Human recombinant GH (Genotropin) was initiated at 0.2 mg/d with monthly 0.2-mg increments to a maximum 1.0 mg/d, as tolerated. MAIN OUTCOMES MEASURES: Lean body mass and percent fat were measured by dual-energy x-ray absorptiometry. RESULTS: Lean body mass increased from 42.65 +/- 2.25 (se) to 45.47 +/- 2.31 kg (P < or = 0.0001), and percent fat decreased from 42.84 +/- 1.12 to 39.95 +/- 1.34% (P = 0.025) at a median final dose of 0.6 mg/d in 30 study subjects who completed 6-12 months of GH. Mean fasting glucose of 85.3 +/- 3.4 mg/dl, hemoglobin A1c of 5.5 +/- 0.2%, fasting insulin of 5.3 +/- 0.6 microU/ml, area under the curve for insulin of 60.4 +/- 7.5 microU/ml, and homeostasis model assessment of insulin resistance of 1.1 +/- 0.2 were normal at baseline in 38 study initiators, including five diabetics, and remained in normal range. Total T(3) increased 26.7% from 127.0 +/- 7.8 to 150.5 +/- 7.8 ng/dl (P = 0.021) with normalization in all subjects, including six (20%) with baseline T(3) values at least 2 sd below the mean. Mildly progressive ankle edema was the most serious treatment-emergent adverse event (five patients). CONCLUSIONS: This multicenter study demonstrates that GH improves body composition, normalizes T(3), and is well tolerated without glucose impairment in PWS genotype adults.     

Longitudinal changes in insulin sensitivity and body composition of small-for-gestational-age adolescents after cessation of growth hormone treatment

Context: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, beta-cell function, and body composition change over time after stopping GH treatment. Objective: Our objective was to investigate longitudinal changes in Si, beta-cell function, and body composition after cessation of long-term GH treatment. Design and Patients: We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points. Outcome Measure: We took paired measurements of Si and beta-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry. Results: After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and beta-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher. Conclusions: The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.     

Plasma adiponectin and insulin sensitivity in overweight and normal-weight middle-aged premenopausal women

Adiponectin has been reported to regulate systemic insulin sensitivity as a part of a broader control mechanism in energy balance. However, it is not clear whether adiponectin exerts its positive effects on insulin sensitivity equally in a wide range of obesity. We investigated the association of plasma adiponectin concentration with insulin resistance (IR) in a cross-sectional sample of 98 middle-aged premenopausal women with a wide range of obesity. In addition, we studied the relationship between adiponectin, body composition, and blood biochemical and cardiorespiratory fitness variables. Body composition and fat distribution were measured via dual-energy x-ray absorptiometry in normal-weight (NW) (n = 41, body mass index [BMI] <25 kg/m²) and overweight (OW) (n = 57, BMI ≥25 kg/m²) women. Fasting blood samples were obtained; adiponectin, leptin, insulin, glucose, and insulin-like growth factor-I were measured; and IR index was calculated. The IR index from fasting plasma insulin and plasma glucose levels was estimated using the homeostasis model assessment (HOMA), as follows: fasting plasma insulin (in microliter units per milliliter) × fasting plasma glucose (in millimoles per liter)/22.5. Adiponectin was significantly higher (P = .0001) in NW (14.7 ± 4.7 μg/mL) compared with OW (9.9 ± 3.1 μg/mL) women. Significant differences (P < .003) in body mass, BMI, percentage of fat mass, fat mass, trunk fat, trunk fat-leg fat ratio, leptin, insulin, and HOMA were also observed between NW and OW groups. Leptin was independently related to plasma adiponectin (β = −.259, P = .001) in the overall study group. Plasma adiponectin was only related to trunk fat-leg fat ratio (β = −.242, P = .002) among NW subjects, whereas plasma adiponectin was related to fat-free mass (β = .182, P = .0001) and HOMA (β = −.576, P = .002) among OW women. The inverse relationship between adiponectin and leptin concentrations suggests that leptin may be involved in the regulation of adiponectin in middle-aged premenopausal women. Our data also demonstrate that adiponectin may play an important role in sustaining insulin sensitivity only in OW middle-aged premenopausal women.     

The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children

Context  We previously reported that short, small for gestational age (SGA) children who were born preterm have a lower body fat percentage and a higher blood pressure, insulin secretion and disposition index than short SGA children born at term. Whether preterm birth also influences these parameters during GH treatment is unknown.
Objective  To compare blood pressure, insulin sensitivity, beta-cell function and body composition during 4 years of GH treatment, between preterm and term short SGA children.
Patients  A total of 404 prepubertal non-GH-deficient short SGA children were divided into 143 preterm (< 36 weeks) and 261 term children.
Outcome measures  Height, blood pressure ( n  = 404), body composition measured by dual energy X-ray absorptiometry (DXA) ( n  = 138) and insulin sensitivity and beta-cell function calculated from a frequent sampling intravenous glucose tolerance test (FSIGT) with tolbutamide ( n  = 74) or from the homeostasis model assessment of insulin resistance (HOMA-IR) ( n  = 204).
Results  In preterm and term children, GH treatment resulted in a similar decrease in systolic and diastolic blood pressure, body fat percentage, limb fat/total fat ratio and insulin sensitivity, and a similar increase in insulin secretion and disposition index. Lean body mass (LBM) corrected for gender and height increased in term children and did not change in preterm children. Multiple regression analysis revealed that this difference in GH effect on LBM was not associated with gestational age.
Conclusion  The effect of GH treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, SGA children.     

Growth hormone treatment improves body composition in adults with Prader-Willi syndrome

OBJECTIVE: Low growth hormone (GH) secretion and hypogonadism are common in patients with Prader-Willi syndrome (PWS). In this study we present the effects of GH treatment on body composition and metabolism in adults with PWS. PATIENTS AND MEASUREMENTS: Nineteen patients with clinical PWS were recruited, 13 had PWS genotype. They were randomised to treatment with placebo or GH (Genotropin, Pharmacia Corporation, Sweden) 0.8 IU (0.2 mg) daily for 1 month and then 1.6 IU (0.5 mg) daily for 5 months. Thereafter patients received open label treatment so that all had 12 months of active GH treatment. Doses were individually titrated to keep serum IGF-I within the normal range for age. Body composition using dual energy X-ray absorptiometry (DXA), metabolic and endocrinological parameters, including oral glucose tolerance test (OGTT), were studied every 6 months. Seventeen patients, nine men and eight women, 17-32 years of age, with a mean body mass index (BMI) of 35 +/- 3.2 kg/m2 completed the study. RESULTS: Compared to placebo, GH treatment increased IGF-I (P < 0.01) levels and decreased body fat (P = 0.04). When all patients recieved GH treatment a mean reduction in body fat of 2.5% (P < 0.01) concomitant with a mean increase in lean body mass of 2.2 kg (P < 0.05) was seen. Significant changes in body composition were only seen in the patients with the PWS genotype. Lipid profiles were normal in most patients before treatment and did not change. OGTT was impaired in five patients at 12 months, but two of these patients increased in fat mass. Insulin levels were unchanged. According to homeostasis model assessment (HOMA), insulin resistance did not change. Side-effects attributed to water retention occurred in three patients, one of whom had to be given increased diuretic therapy. CONCLUSION: This study shows beneficial effects of GH treatment on body composition in adult PWS patients without significant side-effects. Consequently, further studies are encouraged.