bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Decrease in Luteinizing Hormone Secretion in Response to Weight Reduction Is Inversely Related to the Severity of Insulin Resistance in Overweight Women*
Authors: Bützow Tarja L. , Lehtovirta Mikko , Siegberg Rita , Hovatta Outi , Koistinen Riitta , Seppälä Markku , Apter Dan 
Published: January 2014

AbstractControversial effects of weight reduction on gonadotropin secretion in obesity have been reported. As a result of pulsatility, single serum samples or frequent sampling studies are somewhat limited with regard to monitoring LH and FSH concentrations. We studied follicular phase nocturnal urinary (nu) LH and FSH secretion and glucose metabolism (150-min euglycemic hyperinsulinemic clamp) during 1 menstrual cycle/30-day period before and after weight reduction in 10 severely overweight infertility patients (age, 29 ± 3.1 yr; body mass index, 37.1 ± 3.3 kg/m2; ±sem). A 6-week very low calorie diet was followed by a 4-week normocaloric period. The urinary LH and FSH results reported represent samples taken 12 to 2 days before the LH surge, or 10 consecutive samples in the case of amenorrhea.We observed a decrease of 8% (P &lt; 0.001) in percent body fat mass and a 5% (P &lt; 0.005) reduction in waist to hip ratio. Mean nu-LH decreased by 45%[ 6.06 ± 1.05 (±sem) to 3.22 ± 0.71 IU/L], whereas mean nu-FSH remained unchanged. Insulin-stimulated glucose uptake increased by 41% (P &lt; 0.01), which was accounted for by a significant increase in nonoxidative glucose disposal (P = 0.003). Serum sex hormone-binding globulin concentrations increased by 39% (P &lt; 0.01), and insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) levels increased by 46% (P &lt; 0.05). Fasting serum insulin concentrations decreased by 38%, those of leptin by 37%, those of androstenedione by 32%, those of testosterone by 20% (all P &lt; 0.01), and those of dehydroepiandrosterone sulfate by 13% (P &lt; 0.05). The percent change in nu-LH correlated negatively with glucose uptake (r = −0.76; P &lt; 0.01) and the increase in serum sex hormone-binding globulin (r = −0.85; P &lt; 0.005) and positively with the percent change in waist to hip ratio (r = 0.79; P &lt; 0.01). The absolute nu-LH levels after weight reduction correlated significantly with fasting insulin concentrations (r = 0.88; P &lt; 0.001) and negatively with glucose uptake (r = −0.67; P &lt; 0.05). No significant relationships were found between absolute levels or changes in nu-LH concentrations and leptin, IGF-I, IGFBP-3, or IGFBP-1 concentrations. Our findings suggest that weight reduction with a very low calorie diet results in a decrease in nu-LH concentrations, a reduction in the LH/FSH ratio, and FSH predominance favoring folliculogenesis. The decrease in LH concentrations is inversely related to the severity of insulin resistance. It is possible that the decrease in LH secretion with weight reduction is more dependent on the absolute levels of insulin sensitivity than on the degree of general adiposity.
Heterogeneity of Nuclear Lamin A Mutations in Dunnigan-Type Familial Partial Lipodystrophy*
Authors: Hegele Robert A. , Cao Henian , Anderson Carol M. , Hramiak Irene M. 
Published: January 2014

AbstractWe previously identified a novel mutation, namely LMNA R482Q, that was found to underlie Dunnigan-type partial lipodystrophy (FPLD) and diabetes in an extended Canadian kindred. We have since sequenced LMNA in five additional Canadian FPLD probands and herein report three new rare missense mutations in LMNA: V440M, R482W, and R584H. One severely affected subject was a compound heterozygote for both V440M and R482Q. The findings indicated that 1) a spectrum of LMNA mutations underlies FPLD; 2) aberrant lamin A, and not lamin C, is likely to underlie FPLD, as R584H occurs within LMNA sequence that is specific for lamin A; 3) the V440M mutation may not cause lipodystrophy on its own; 4) compound heterozygosity for V440M and R482Q is associated with a relatively more severe FPLD phenotype, but not with complete lipodystrophy; and 5) variation in the severity of the phenotype might be related to environmental factors.
Mutation of Three Critical Amino Acids of the N-Terminal Domain of IGF-Binding Protein-3 Essential for High Affinity IGF Binding
Authors: Buckway C. K. , Wilson E. M. , Ahlsén M. , Bang P. , Oh Y. , Rosenfeld R. G. 
Published: January 2014

The N-terminal domain is conserved in all members of the IGF-binding protein superfamily. Most recently, studies have demonstrated the importance of an IGF-binding protein N-terminal hydrophobic pocket for IGF binding. To examine more critically the amino acids important for IGF binding within the full-length IGF-binding protein-3 protein while minimizing changes in the tertiary structure, we targeted residues I56, L80, and L81 within the proposed hydrophobic pocket for mutation. With a single change at these sites to the nonconserved glycine there was a notable decrease in binding. A greater reduction was seen when both L80 and L81 were substituted with glycine, and complete loss of affinity for IGF-I and IGF-II occurred when all three targeted amino acids were changed to glycine. Furthermore, the ability of the IGF-binding protein-3 mutants to inhibit IGF-I-stimulated phosphorylation of its receptor was a reflection of their affinity for IGF, with the lowest affinity mutants having the least inhibitory effect.These studies, thus, support the hypothesis that an N-terminal hydrophobic pocket is the primary site of high affinity binding of IGF to IGF-binding protein-3. The mutants provide a tool for future studies directed at IGF-dependent and IGF-independent actions of IGF-binding protein-3.
Assessment of Growth Hormone Dynamics in Human Immunodeficiency Virus-Related Lipodystrophy1
Authors: Rietschel Petra , Hadigan Colleen , Corcoran Colleen , Stanley Takara , Neubauer Gregory , Gertner Joseph , Grinspoon Steven 
Published: January 2014

Human immunodeficiency virus (HIV) lipodystrophy (LIPO) is characterized by increased visceral adiposity, peripheral fat atrophy, dyslipidemia, and insulin resistance. GH concentrations are known to vary inversely with excess weight and body fat but have not been investigated in HIV lipodystrophy. Twenty-one subjects with HIV LIPO, 20 HIV-infected nonlipodystrophy subjects (NONLIPO), and 20 control (C) subjects were prospectively recruited for this study and compared.
Subjects in the three groups were all male, age-matched [median, 47 yr old (interquartile range, 37–50) LIPO; 41 (37–44) NONLIPO; and 43 (37–49) C], and body mass index-matched [median, 24.3 kg/m2 (interquartile range, 22.2–26.6) LIPO; 24.4 (23.3–25.9) NONLIPO; and 24.8 (22.7–26.1) C] (P&gt; 0.05 for all comparisons). Visceral abdominal fat [16,124 mm2 (11,246–19,790) LIPO; 7,559 (5,134–11,201) NONLIPO; and 8,803 (6,165–11,623) C; P &lt; 0.01 LIPO vs. NONLIPO and LIPO vs. C] and the ratio of visceral abdominal fat to sc abdominal fat [1.37 (0.71–2.44) LIPO vs. 0.57 (0.47–0.78) NONLIPO vs. 0.55 (0.41–0.71) C, P &lt; 0.01 LIPO vs. NONLIPO and LIPO vs. C] were significantly increased in the LIPO subjects but were not significantly different between NONLIPO and C. The mean overnight GH concentration, determined from frequent sampling every 20 min (from 2000 h to 0800 h) was decreased in the LIPO subjects [0.38 μg/L (0.13–0.67) LIPO vs. 0.96 (0.53–1.30) NONLIPO vs. 0.81 (0.49–1.03) C, P &lt; 0.05 LIPO vs. NONLIPO and LIPO vs. C] and not significantly different between NONLIPO and C. Pulse analysis demonstrated decreased baseline GH [0.08 μg/L (0.06–0.21) LIPO vs. 0.19 (0.10–0.32) NONLIPO vs. 0.17 (0.12–0.57) C, P &lt; 0.05 LIPO vs. NONLIPO and LIPO vs. C] and GH peak amplitude [1.06μ g/L (0.46–1.94) LIPO vs. 2.47 (1.22–3.43) NONLIPO and 2.27 (1.36–4.25) C, P &lt; 0.05 LIPO vs. NONLIPO and LIPO vs. C] in the LIPO subjects but no significant difference in pulse frequency. No significant differences were observed between NONLIPO and C for any GH parameter. Insulin-like growth factor-I was not different between the groups. Total body fat (r = −0.40, P = 0.01) and visceral fat (r = −0.58, P = 0.0001) correlated inversely with mean overnight GH concentrations in the HIV-infected patients. In a multivariate regression model, controlling for age, body mass index, body fat, and visceral fat, only visceral fat was a significant predictor of mean GH concentrations (P = 0.0036, r2 for model = 0.40).
These data demonstrate normal GH pulse frequency and insulin-like growth factor-I concentrations but reduced mean GH concentrations, basal GH concentrations, and GH pulse amplitude in patients with HIV lipodystrophy. Increased visceral adiposity is the strongest predictor of reduced GH concentrations in HIV lipodystrophy. Further studies are necessary to determine the clinical significance of reduced GH in patients with HIV lipodystrophy.
The Expression of the Growth Hormone Secretagogue Receptor Ligand Ghrelin in Normal and Abnormal Human Pituitary and Other Neuroendocrine Tumors1
Authors: Korbonits Márta , Bustin Stephen A. , Kojima Masayasu , Jordan Suzanne , Adams Eric F. , Lowe David G. , Kangawa Kenji , Grossman Ashley B. 
Published: January 2014

Ghrelin is a recently identified endogenous ligand of the GH secretagogue (GHS) receptor. It was originally isolated from the stomach, but has also been shown to be present in the rat hypothalamus. It is a 28-amino acid peptide with an unusual octanoylated serine 3 at the N-terminal end of the molecule, which is crucial for its biological activity. Synthetic GHSs stimulate GH release via both the hypothalamus and the pituitary, and the GHS receptor (GHS-R) has been shown by us and others to be present in the pituitary. We investigated whether ghrelin messenger ribonucleic acid (mRNA) and peptide are present in the normal human hypothalamus and in normal and adenomatous human pituitary.RNA was extracted from pituitary tissue removed at autopsy and transsphenoidal surgery (n = 62), and ghrelin and GHS-R type 1a and 1b mRNA levels were investigated using real-time RT-PCR. Both ghrelin and GHS-R mRNA were detected in all samples. Corticotroph tumors showed significantly less expression of ghrelin mRNA, whereas GHS-R mRNA levels were similar to those in normal pituitary tissue. Gonadotroph tumors showed a particularly low level of expression of GHS-R mRNA. Immunohistochemistry, using a polyclonal antibody against the C-terminal end of the ghrelin molecule, revealed positive staining in the homolog of the arcuate nucleus in the human hypothalamus and in both normal and abnormal human pituitary. Pituitary tumor ghrelin peptide content was demonstrated using two separate RIA reactions for the N-terminal and C-terminal ends of the molecule. Both forms were present in normal and abnormal pituitaries, with 5 ± 2.5% octanoylated (active) ghrelin (mean ± sd) present as a percentage of the total. We suggest that the presence of ghrelin mRNA and peptide in the pituitary implies that the locally synthesized hormone may have an autocrine/paracrine modulatory effect on pituitary hormone release.
Insulin Inhibits Intranuclear Nuclear Factor κB and Stimulates IκB in Mononuclear Cells in Obese Subjects: Evidence for an Anti-inflammatory Effect?
Authors: Dandona Paresh , Aljada Ahmad , Mohanty Priya , Ghanim Husam , Hamouda Wael , Assian Ezzat , Ahmad Shakeel 
Published: January 2014

In view of the fact that insulin resistance is associated with atherogenesis and that troglitazone, an insulin sensitizer, has anti-inflammatory effects, which may be potentially antiatherogenic in the long term, we have now investigated whether insulin has potential anti-inflammatory effects. We infused 2.0 to 2.5 IU/h in 5% dextrose (100 mL/h) iv into 10 obese subjects for 4 h followed by 5% dextrose alone for 2 h. The rate of insulin infusion was varied to maintain glucose concentrations as close to the baseline as possible. Blood samples were obtained before and at 2, 4, and 6 h. Subjects were also infused with 5% dextrose without insulin and with saline on separate occasions. Intranuclear nuclear factor κB (NFκB) in mononuclear cells fell at 2 and further at 4 h, reverting toward the baseline at 6 h (P &lt; 0.05). IκB increased significantly at 2 h, increasing further at 4 h and remaining elevated at 6 h (P &lt; 0.001). Reactive oxygen species (ROS) generation by mononuclear cells fell significantly at 2 h and fell further at 4 h; it partially reverted to baseline at 6 h (P &lt; 0.005). p47phox subunit, the key protein of nicotinamide adenine dinucleotide phosphate oxidase also fell at 2 h and 4 h, reverting toward the baseline at 6 h (P &lt; 0.05). In addition, soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) fell significantly following insulin infusion. Glucose or saline infusions without insulin caused no alteration in NFκB, IκB, ROS generation, p47phox subunit, sICAM-1, MCP-1, or PAI-1.
We conclude that insulin has a potent acute anti-inflammatory effect including a reduction in intranuclear NFκB, an increase in IκB, and decreases in ROS generation, p47phox subunit, plasma soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1. This acute anti-inflammatory effect, if demonstrated in the long term, may have implications for atherosclerosis and its complications.
Metabolism of Orally Administered Androstenedione in Young Men
Authors: Leder Benjamin Z. , Catlin Don H. , Longcope Christopher , Ahrens Brian , Schoenfeld David A. , Finkelstein Joel S. 
Published: January 2014

Androstenedione is a steroid hormone and the major precursor to testosterone. It is available without prescription and taken with the expectation that it will be converted to testosterone endogenously and increase strength and athletic performance. The metabolism of orally administered testosterone has not been well studied.We randomly assigned 37 healthy men to receive 0, 100, or 300 mg oral androstenedione in a single daily dose for 7 d. Single 8-h urine collections were performed on the day before the start of the androstenedione administration and on d 1 and 7 to assess excretion rates of free and glucuronide- conjugated testosterone, androsterone, etiocholanolone, and dihydrotestosterone. Serum testosterone glucuronide concentrations were measured by frequent blood sampling over 8 h on d 1 in 16 subjects (5 each in the 0 and 100 mg group and 6 in the 300 mg group).In the control group, mean (±se) d 1 and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 3 ± 1, 215 ± 26, 175 ± 26, and 0.4 ± 0.1 μg/h, respectively. In the 100 mg group, mean d 1 and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 47 ± 11, 3,836 ± 458, 4,306 ± 458, and 1.6 ± 0.2 μg/h, respectively. In the 300 mg group, mean d 1 and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 115 ± 39, 8,142 ± 1,362, 10,070 ± 1,999, and 7.7 ± 1.5μ g/h, respectively. Urinary excretion rates of all metabolites were greater in both the 100 and 300 mg groups than in controls (P &lt; 0.0001). Urinary excretion rates of testosterone (P = 0.007), androsterone (P = 0.009), etiocholanolone (P= 0.0005), and dihydrotestosterone (P &lt; 0.0001) were greater in the subjects who received 300 mg androstenedione than in those who received 100 mg. In the treated groups, excretion of free testosterone accounted for less than 0.1% of the total excreted testosterone measured. Serum testosterone glucuronide levels increased significantly during frequent blood sampling in both the 100 and 300 mg groups compared with controls (P = 0.0005 for the 100 mg group; P &lt; 0.0001 for the 300 mg group). The net mean changes in area under the curve for serum testosterone glucuronide were −18 ± 25%, 579 ± 572%, and 1267 ± 1675% in the groups receiving 0, 100, and 300 mg/d androstenedione, respectively.We conclude that the administration of both 100 and 300 mg androstenedione increases the excretion rates of conjugated testosterone, androsterone, etiocholanolone, and dihydrotestosterone and the serum levels of testosterone glucuronide in men. The magnitude of these increases is much greater than the changes observed in serum total testosterone concentrations. These findings demonstrate that orally administered androstenedione is largely metabolized to testosterone glucuronide and other androgen metabolites before release into the general circulation.
The Role of IGF-Binding Proteins in Mediating the Effects of Recombinant Human IGF-I on Insulin Requirements in Type 1 Diabetes Mellitus
Authors: Crowne E. C. , Samra J. S. , Cheetham T. , Acerini C. L. , Watts A. , Holly J. M. P. , Dunger D. B. 
Published: January 2014

To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40μ g/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg·h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg·night) ensured identical GH levels.
After recombinant human IGF-I administration, IGF-I levels and the IGF-I/IGF-binding protein-3 ratio increased [mean ± sem:IGF-I, 401 ± 22 ng/ml; placebo, 256 ± 20 ng/ml (P = 0.0002); IGF-I, 0.108 ± 0.006; placebo, 0.074 ± 0.004 (P = 0.0003), respectively], and insulin requirements decreased (IGF-I, 0.12 ± 0.03; placebo, 0.23 ± 0.03 U/kg·min; P = 0.008). The normal within-individual inverse relationships between insulin and IGF-binding protein-1 levels were observed (lag time 2 h: r =− 0.34; P &lt; 0.01). Yet despite reduced free insulin levels (8.5 ± 1.5; placebo, 12.2 ± 1.2 mU/liter; P = 0.03), IGF-binding protein-1 levels were reduced after recombinant human IGF-I administration (53.7 ± 6.8; placebo, 82.2 ± 11.8 ng/ml; P = 0.008). The largest reductions in free insulin levels after recombinant human IGF-I and thus putative improvement in insulin sensitivity occurred in subjects with the smallest increase in the plasma IGF-I/IGF-binding protein-3 ratio (r = 0.7; P = 0.03). Taken together, these data are consistent with the hypothesis that transcapillary movement of IGF-I (perhaps mediated by IGF-binding protein-1), out of the circulation facilitates altered insulin sensitivity. These data have important implications for risk-benefit assessment of recombinant human IGF-I therapy in type 1 diabetes mellitus.
Differential Effects of GH Replacement on the Components of the Leptin System in GH-Deficient Individuals
Authors: Randeva Harpal S. , Murray Robert D. , Lewandowski Krzysztof C. , O’Callaghan Chris J. , Horn Rudiger , O’Hare Paul , Brabant Georg , Hillhouse Edward W. , Shalet Stephen M. 
Published: January 2014

GH therapy is associated with a reduction in fat mass and an increase in lean mass in subjects with GH deficiency (GHD). Leptin, like GH, plays an important role in the regulation of body composition. GH treatment has been shown to reduce serum leptin; however, the physiological interactions between the leptin system (free leptin, bound leptin, and soluble leptin receptor) and the GH/IGF-I system largely remain unknown.Twenty-five patients with childhood (n = 10) and adult-onset (n = 15) GHD were studied. GH status had previously been determined using an insulin tolerance test and/or an arginine stimulation test. The following parameters were recorded at baseline (V1) and then after 3 months (V2) and 6 months (V3) on GH treatment: fat mass, body mass index (BMI), and waist/hip ratio (WHR); blood samples were taken after an overnight fast for free leptin, bound leptin, soluble leptin receptor, insulin, and IGF-I.At V2 and V3, respectively, a fall in free leptin (P &lt; 0.001 for each), and at V3 a fall in in percent fat mass (P &lt; 0.001) were observed. There were no significant changes in BMI or WHR. Simultaneously, there was a rise in insulin (P = 0.068 and P &lt; 0.001), IGF-I (P &lt; 0.001 and P &lt; 0.001), bound leptin (P = 0.005 and P &lt; 0.001), and soluble leptin receptor (P = 0.61 and P &lt; 0.001). A positive relationship was noted between free leptin and BMI (P &lt; 0.001) and between free leptin and fat mass (P &lt; 0.001), and a negative relationship was found between free leptin and IGF-I (P &lt; 0.001) and, within patient, between free leptin and insulin (P &lt; 0.001). There was no significant correlation between free leptin and WHR. Bound leptin had a positive association with IGF-I (P &lt; 0.001) and insulin (P = 0.002) and a negative relationship with percent fat mass (P = 0.023). Soluble leptin receptor was also positively related to IGF-I (P &lt; 0.001).In conclusion, our data suggest that the reduction in serum leptin with GH treatment, as noted by others, is mediated through a fall in free leptin. The fall in free leptin and in part the rise in bound leptin are most likely through a reduction in percent fat mass. However, the observed changes in free leptin and bound leptin and, more importantly, the rise in soluble leptin receptor, are not explained entirely by modifications in body composition and may be a direct result of GH/IGF-I.
Incomplete Modified Fast in Obese Early Pubertal Girls Leads to an Increase in 24-Hour Growth Hormone Concentration and a Lessening of the Circadian Pattern in Leptin
Authors: Kasa-Vubu Josephine Z. , Barkan Ariel , Olton Pamela , Meckmongkol Teerin , Carlson Nichole E. , Foster Carol M. 
Published: January 2014

AbstractWe studied nutrition and GH in eight obese girls, aged 6–11 yr. Blood was sampled every 15 min for 24 h. A 48-h diet providing 25% of assumed caloric needs was imposed, with repeat sampling during the last 24 h. Six nonfasting lean girls were also studied, and their mean GH was 3 times that of the obese girls in the fed state (P = 0.024). Dieting increased mean GH by 60% (P = 0.0028). There was no difference in pulse number for either group, but total secretion for lean girls was 3.9 times greater than that in obese girls during the fed state. With dieting, obese girls increased their total GH secretion by 60% (P = 0.010), but maintained lower total secretion, approximately 40% that of lean girls (P = 0.014). Mean leptin in obese girls in the fed state was 6.2 times greater than mean leptin in lean girls (P = 0.0001), with higher concentrations at night (P &lt; 0.05) and lowering of total mean leptin while dieting. We conclude that in early pubertal obese girls, short-term caloric restriction partially reverses the low GH state that is characteristic of obesity. The change is concomitant with a decrease in leptin and a lessening of circadian differences.