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Xiang B, Zhang X, Liu W, Mao B, Zhao Y, Wang Y, Gong W, Ye H, Li Y, Zhang Z, Yu Y, He M. Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort. Endocrine 2024; 85:1346-1356. [PMID: 38851643 DOI: 10.1007/s12020-024-03898-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 05/27/2024] [Indexed: 06/10/2024]
Abstract
PURPOSE Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. METHODS The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. RESULTS Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). CONCLUSION Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.
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Affiliation(s)
- Boni Xiang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
| | - Xintong Zhang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
- Department of General Practice, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Shanghai, China
| | - Wenjuan Liu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
| | - Bei Mao
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
| | - Yao Zhao
- Department of Neurosurgery, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
- Shanghai Pituitary Tumor Center, Shanghai, China
| | - Yongfei Wang
- Department of Neurosurgery, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
- Shanghai Pituitary Tumor Center, Shanghai, China
| | - Wei Gong
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
| | - Hongying Ye
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
- Shanghai Pituitary Tumor Center, Shanghai, China
- Huashan Rare Disease Center, Huashan Hospital Fudan University, Shanghai, China
| | - Yiming Li
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
- Shanghai Pituitary Tumor Center, Shanghai, China
- Huashan Rare Disease Center, Huashan Hospital Fudan University, Shanghai, China
| | - Zhaoyun Zhang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China
- Shanghai Pituitary Tumor Center, Shanghai, China
- Huashan Rare Disease Center, Huashan Hospital Fudan University, Shanghai, China
| | - Yifei Yu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China.
| | - Min He
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, No. 12 Wulumuqi Middle Road, Shanghai, China.
- Shanghai Pituitary Tumor Center, Shanghai, China.
- Huashan Rare Disease Center, Huashan Hospital Fudan University, Shanghai, China.
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Fröhlich AK, Porthun J, Talha KM, Lena A, Hadzibegovic S, Wilkenshoff U, Sonntag F, Nikolski A, Ramer LV, Zeller T, Keller U, Bullinger L, Anker SD, Haverkamp W, von Haehling S, Doehner W, Rauch U, Skurk C, Cleland JGF, Butler J, Coats AJS, Landmesser U, Karakas M, Anker MS. Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer. Clin Res Cardiol 2024:10.1007/s00392-024-02400-x. [PMID: 38587563 DOI: 10.1007/s00392-024-02400-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 02/07/2024] [Indexed: 04/09/2024]
Abstract
BACKGROUND Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. OBJECTIVES We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. METHODS We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50-61, > 61 g/m2; men, < 60, 60-74, > 74 g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24 kg/m2 and weight loss ≥ 5% in the prior 12 months). Repeat echocardiograms were obtained usually within 3-6 months for 85 patients. RESULTS Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9-4.2), 0.8 (0.2-2.2), 0.5 (0.3-1.6) ng/mL, p = 0.029; men, 2.1 (0.8-3.2), 0.6 (0.1-1.7), 0.7 (0.2-1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48-116), 72 (48-95), 49 (35-76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r = - 0.591, p < 0.001; men, r = - 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r = - 0.318, p = 0.003). CONCLUSION In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associated with a decrease in relative LVmass during follow-up.
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Affiliation(s)
- Ann-Kathrin Fröhlich
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
| | - Jan Porthun
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
- Norwegian University of Science and Technology, Campus Gjøvik, Gjøvik, Norway
| | - Khawaja M Talha
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Alessia Lena
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Sara Hadzibegovic
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Ursula Wilkenshoff
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
- Berlin Institute of Health, Charité - University Medicine Berlin, Berlin, Germany
| | - Frederike Sonntag
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
| | - Anja Nikolski
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
| | - Luisa Valentina Ramer
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
| | - Tanja Zeller
- University Center of Cardiovascular Science, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Clinic for Cardiology, University Heart and Vascular Centre Hamburg, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- German Centre for Cardiovascular Research, Partner Site HH/Kiel/HL, Hamburg, Germany
| | - Ulrich Keller
- Department of Hematology, Oncology and Cancer Immunology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, Berlin, Germany
- Max Delbrück Center, Berlin, Germany
| | - Lars Bullinger
- German Cancer Consortium (DKTK), Partner Site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Hematology, Oncology, and Tumor Immunology, Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt University Berlin, Berlin, Germany
| | - Stefan D Anker
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology Campus, Virchow Clinic of German Heart Center Charité, Charité - University Medicine Berlin, Berlin, Germany
| | - Wilhelm Haverkamp
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology Campus, Virchow Clinic of German Heart Center Charité, Charité - University Medicine Berlin, Berlin, Germany
| | - Stephan von Haehling
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Göttingen, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany
| | - Wolfram Doehner
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
- Centre for Stroke Research, Berlin, Charité-Universitätsmedizin, Berlin, Germany
| | - Ursula Rauch
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Carsten Skurk
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
| | - John G F Cleland
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
- Baylor Scott and White Research Institute, Dallas, TX, USA
| | | | - Ulf Landmesser
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
- Berlin Institute of Health, Charité - University Medicine Berlin, Berlin, Germany
| | - Mahir Karakas
- German Centre for Cardiovascular Research, Partner Site HH/Kiel/HL, Hamburg, Germany
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus S Anker
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany.
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany.
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Rege SD, Royes L, Tsai B, Zhang G, Yang X, Gomez-Pinilla F. Brain Trauma Disrupts Hepatic Lipid Metabolism: Blame It on Fructose? Mol Nutr Food Res 2019; 63:e1801054. [PMID: 31087499 DOI: 10.1002/mnfr.201801054] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 03/21/2019] [Indexed: 02/06/2023]
Abstract
SCOPE The action of brain disorders on peripheral metabolism is poorly understood. The impact of traumatic brain injury (TBI) on peripheral organ function and how TBI effects can be influenced by the metabolic perturbation elicited by fructose ingestion are studied. METHODS AND RESULTS It is found that TBI affects glucose metabolism and signaling proteins for insulin and growth hormone in the liver; these effects are exacerbated by fructose ingestion. Fructose, principally metabolized in the liver, potentiates the action of TBI on hepatic lipid droplet accumulation. Studies in isolated cultured hepatocytes identify GH and fructose as factors for the synthesis of lipids. The liver has a major role in the synthesis of lipids used for brain function and repair. TBI results in differentially expressed genes in the hypothalamus, primarily associated with lipid metabolism, providing cues to understand central control of peripheral alterations. Fructose-fed TBI animals have elevated levels of markers of inflammation, lipid peroxidation, and cell energy metabolism, suggesting the pro-inflammatory impact of TBI and fructose in the liver. CONCLUSION Results reveal the impact of TBI on systemic metabolism and the aggravating action of fructose. The hypothalamic-pituitary-growth axis seems to play a major role in the regulation of the peripheral TBI pathology.
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Affiliation(s)
- Shraddha D Rege
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Luiz Royes
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.,Centro De Educacao Fisica e Desportos, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, 97105, Brazil
| | - Brandon Tsai
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Guanglin Zhang
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Xia Yang
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Fernando Gomez-Pinilla
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.,Department of Neurosurgery, UCLA Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA
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Björnsson BT, Einarsdóttir IE, Johansson M, Gong N. The Impact of Initial Energy Reserves on Growth Hormone Resistance and Plasma Growth Hormone-Binding Protein Levels in Rainbow Trout Under Feeding and Fasting Conditions. Front Endocrinol (Lausanne) 2018; 9:231. [PMID: 29867764 PMCID: PMC5968089 DOI: 10.3389/fendo.2018.00231] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 04/23/2018] [Indexed: 11/13/2022] Open
Abstract
The growth hormone (GH)-insulin-like growth factor I (IGF-I) system regulates important physiological functions in salmonid fish, including hydromineral balance, growth, and metabolism. While major research efforts have been directed toward this complex endocrine system, understanding of some key aspects is lacking. The aim was to provide new insights into GH resistance and growth hormone-binding proteins (GHBPs). Fish frequently respond to catabolic conditions with elevated GH and depressed IGF-I plasma levels, a condition of acquired GH resistance. The underlying mechanisms or the functional significance of GH resistance are, however, not well understood. Although data suggest that a significant proportion of plasma GH is bound to specific GHBPs, the regulation of plasma GHBP levels as well as their role in modulating the GH-IGF-I system in fish is virtually unknown. Two in vivo studies were conducted on rainbow trout. In experiment I, fish were fasted for 4 weeks and then refed and sampled over 72 h. In experiment II, two lines of fish with different muscle adiposity were sampled after 1, 2, and 4 weeks of fasting. In both studies, plasma GH, IGF-I, and GHBP levels were assessed as well as the hepatic gene expression of the growth hormone receptor 2a (ghr2a) isoform. While most rainbow trout acquired GH resistance within 4 weeks of fasting, fish selected for high muscle adiposity did not. This suggests that GH resistance does not set in while fat reserves as still available for energy metabolism, and that GH resistance is permissive for protein catabolism. Plasma GHBP levels varied between 5 and 25 ng ml-1, with large fluctuations during both long-term (4 weeks) fasting and short-term (72 h) refeeding, indicating differentiated responses depending on prior energy status of the fish. The two opposing functions of GHBPs of prolonging the biological half-life of GH while decreasing GH availability to target tissues makes the data interpretation difficult, but nutritional regulatory mechanisms are suggested. The lack of correlation between hepatic ghr2a expression and plasma GHBP levels indicate that ghr2a assessment cannot be used as a proxy measure for GHBP levels, even if circulating GHBPs are derived from the GH receptor molecule.
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Affiliation(s)
- Björn Thrandur Björnsson
- Fish Endocrinology Laboratory, Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, Sweden
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Rowan MP, Beckman DJ, Rizzo JA, Isbell CL, White CE, Cohn SM, Chung KK. Elevations in growth hormone and glucagon-like peptide-2 levels on admission are associated with increased mortality in trauma patients. Scand J Trauma Resusc Emerg Med 2016; 24:119. [PMID: 27716276 PMCID: PMC5050752 DOI: 10.1186/s13049-016-0310-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 09/27/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Burn and trauma patients present a clinical challenge due to metabolic derangements and hypermetabolism that result in a prolonged catabolic state with impaired healing and secondary complications, including ventilator dependence. Previous work has shown that circulating levels of growth hormone (GH) are predictive of mortality in critically ill adults, but few studies have examined the prognostic potential of GH levels in adult trauma patients. METHODS To investigate the utility of GH and other endocrine responses in the prediction of outcomes, we conducted a prospective, observational study of adult burn and trauma patients. We evaluated the serum concentration of GH, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), and glucagon-like peptide-2 (GLP-2) weekly for up to 6 weeks in 36 adult burn and trauma patients admitted between 2010 and 2013. RESULTS Non-survivors had significantly higher levels of GH and GLP-2 on admission than survivors. DISCUSSION This study demonstrates that GH has potential as a predictor of mortality in critically ill trauma and burn patients. Future studies will focus on not only the role of GH, but also GLP-2, which was shown to correlate with mortality in this study with a goal of offering early, targeted therapeutic interventions aimed at decreasing mortality in the critically injured. CONCLUSIONS GH and GLP-2 may have clinical utility for outcome prediction in adult trauma patients.
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Affiliation(s)
- Matthew P Rowan
- United States Army Institute of Surgical Research, 3698 Chambers Pass, JBSA, Fort Sam Houston, San Antonio, TX, 78234, USA
| | - Darrick J Beckman
- Brooke Army Medical Center, 3855 Roger Brooke Drive, JBSA, Fort Sam Houston, San Antonio, TX, 78234, USA
| | - Julie A Rizzo
- United States Army Institute of Surgical Research, 3698 Chambers Pass, JBSA, Fort Sam Houston, San Antonio, TX, 78234, USA. .,Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd # A3007, Bethesda, MD, 20814, USA.
| | - Claire L Isbell
- Baylor Scott and White Memorial Hospital, 2401 S. 31st St, Temple, TX, 76502, USA
| | - Christopher E White
- Brooke Army Medical Center, 3855 Roger Brooke Drive, JBSA, Fort Sam Houston, San Antonio, TX, 78234, USA
| | - Stephen M Cohn
- Staten Island University Hospital, 475 Seaview Ave, Staten Island, NY, 10305, USA
| | - Kevin K Chung
- United States Army Institute of Surgical Research, 3698 Chambers Pass, JBSA, Fort Sam Houston, San Antonio, TX, 78234, USA.,Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd # A3007, Bethesda, MD, 20814, USA
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Nguyen CT, Aaronson A, Morrissey RP, Agarwal M, Willix RD, Schwarz ER. Myths and truths of growth hormone and testosterone therapy in heart failure. Expert Rev Cardiovasc Ther 2011; 9:711-20. [PMID: 21714602 DOI: 10.1586/erc.11.25] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Heart failure is a chronic clinical syndrome with very poor prognosis. Despite being on optimal medical therapy, many patients still experience debilitating symptoms and poor quality of life. In recent years, there has been a great interest in anabolic hormone replacement therapy - namely, growth hormone and testosterone - as an adjunctive therapy in patients with advanced heart failure. It has been observed that low levels of growth hormone and testosterone have been associated with increased mortality and morbidity in patients with heart failure. Animal studies and clinical trials have shown promising clinical improvement with hormonal supplementation. Growth hormone has been shown to increase ventricular wall mass, decrease wall stress, increase cardiac contractility, and reduce peripheral vascular resistance, all of which might help to enhance cardiac function, resulting in improvement in clinical symptoms. Likewise, testosterone has been shown to improve hemodynamic parameters via reduction in peripheral vascular resistance and increased coronary blood flow through vasodilation, thereby improving functional and symptomatic status. To date, growth hormone and testosterone therapy have shown some positive benefits, albeit with some concerns over adverse effects. However, large randomized controlled trials are still needed to assess the long-term safety and efficacy.
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Affiliation(s)
- Cam T Nguyen
- Advanced Heart Failure and Heart Transplantation, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 6215, Los Angeles, CA 90048, USA
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Okamoto I, Munakata M, Miyazaki M, Satoh T, Takahata T, Takamatsu Y, Muto O, Koike K, Ishitani K, Mukaiyama T, Sakata Y, Nakagawa K, Tamura K. Disturbance of the growth hormone-insulin-like growth factor-1 axis associated with poor performance status in patients with solid tumors. Jpn J Clin Oncol 2009; 40:222-6. [PMID: 19942582 DOI: 10.1093/jjco/hyp155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE Hormonal imbalance characterized by excessive production of growth hormone (GH) and a low circulating concentration of insulin-like growth factor (IGF)-1 has been demonstrated in individuals with various serious conditions. However, little is known about changes in the GH-IGF-1 axis in cancer patients. METHODS We prospectively examined the circulating levels of several hormones in 58 patients with solid tumors who were classified according to Eastern Cooperative Oncology Group performance status (PS): PS 0-1, n = 15; PS 2, n = 15; PS 3, n = 15; and PS 4, n = 13. The relations of hormone concentrations, with a focus on the GH-IGF-1 system, to PS were evaluated by Spearman's rank correlation test and regression analysis. RESULTS The circulating levels of IGF-1, IGF-binding protein-3 and thyroid hormones (total T(3) and T(4)) were inversely correlated with PS score. The concentration of GH was increased irrespective of PS but not statistically significant. The ratio of IGF-I to GH was inversely correlated with PS. The levels of GH and IGF-1 in all patients were also inversely correlated. CONCLUSIONS The present study suggests that the GH-IGF-1 axis is disturbed in patients with cancer.
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Affiliation(s)
- Isamu Okamoto
- Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
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Seiva FRF, Ebaid GMX, Castro AVB, Okoshi K, Nascimento A, Rocha KKH, Padovani CR, Cicogna AC, Novelli ELB. Growth hormone and heart failure: oxidative stress and energetic metabolism in rats. Growth Horm IGF Res 2008; 18:275-283. [PMID: 18191600 DOI: 10.1016/j.ghir.2007.11.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2007] [Revised: 11/16/2007] [Accepted: 11/19/2007] [Indexed: 10/22/2022]
Abstract
Several evidences point for beneficial effects of growth hormone (GH) in heart failure (HF). Taking into account that HF is related with changes in myocardial oxidative stress and in energy generation from metabolic pathways, it is important to clarify whether GH increase or decrease myocardial oxidative stress and what is its effect on energetic metabolism in HF condition. Thus, this study investigated the effects of two different doses of GH on energetic metabolism and oxidative stress in myocardium of rats with HF. Male Wistar rats (n=25) were submitted to aortic stenosis (AS). The HF was evidenced by tachypnea and echocardiographic criteria around 28 weeks of AS. The rats were then randomly divided into three groups: (HF) with HF, treated with saline (0.9% NaCl); (HF-GH1), treated with 1 mk/kg/day recombinant human growth hormone (rhGH), and (HF-GH2) treated with 2 mg/kg/day rhGH. GH was injected, subcutaneously, daily for 2 weeks. A control group (sham; n=12), with the same age of the others rats was evaluated to confirm data for AS. HF had lower IGF-I (insulin-like growth factor-I) than sham-operated rats, and both GH treatments normalized IGF-I level. HF-GH1 animals had lower lipid hydroperoxide (LH), LH/total antioxidant substances (TAS) and glutathione-reductase than HF. Glutathione peroxidase (GSH-Px), hydroxyacyl coenzyme-A dehydrogenase, lactate dehydrogenase(LDH) were higher in HF-GH1 than in HF. HF-GH2 compared with HF, had increased LH/TAS ratio, as well as decreased oxidized glutathione and LDH activity. Comparing the two GH doses, GSH-Px, superoxide dismutase and LDH were lower in HF-GH2 than in HF-GH1. In conclusion, GH effects were dose-dependent and both tested doses did not aggravate the heart dysfunction. The higher GH dose, 2 mg/kg exerted detrimental effects related to energy metabolism and oxidative stress. The lower dose, 1mg/kg GH exerted beneficial effects enhancing antioxidant defences, reducing oxidative stress and improving energy generation in myocardium of rats with heart failure.
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Affiliation(s)
- F R F Seiva
- Post Graduation Course, Department of Clinical and Cardiology, School of Medicine, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
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9
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Huang Q, Nai YJ, Jiang ZW, Li JS. Change of the growth hormone–insulin-like growth factor-I axis in patients with gastrointestinal cancer: related to tumour type and nutritional status. Br J Nutr 2007; 93:853-8. [PMID: 16022754 DOI: 10.1079/bjn20051412] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Changes in the growth hormone (GH)–insulin-like growth factor-I (IGF-I) axis, especially acquired GH resistance, develop in many severe illnesses, including cachexia. To study changes in the GH–IGF-I axis in patients with cancer cachexia, biochemical markers and body composition parameters were measured in eighty-eight gastric cancer patients, thirty colorectal cancer patients (subclassified according to the presence or absence of cachexia) and twenty-four healthy control subjects. Fifty-nine patients were defined as cachectic, based on the percentage of weight loss compared with their previous normal weight. The remaining fifty-nine patients were defined as non-cachectic. Measurements were repeated in twenty-seven patients (sixteen with gastric cancer and eleven with colorectal cancer) 3 months after radical operation. Compared with the controls, the cachectic gastric cancer patients had high GH levels (1·36 v. 0·32 ng/ml; P=0·001), a trend towards high IGF-I levels (223·74 v. 195·15 ng/ml; P=0·128 compared with non-cachectic patients) and a low log IGF-I/GH ratio (2·55 and 2·66 v. 3·00; P=0·002), along with a decreased BMI; the cachectic colorectal cancer patients showed the biochemical characteristics of acquired GH resistance: high GH (0·71 v. 0·32 ng/ml; P=0·016), a trend towards decreased IGF-I levels (164·18 v. 183·24 ng/ml; P=0·127) and a low log IGF-I/GH ratio (2·54 v. 2·99; P=0·005), with increased IGF-I levels following radical surgery (200·49 v. 141·91 ng/ml; P=0·046). These findings suggest that normal GH reaction and sensitivity occur in gastric cancer patients, controlled by nutritional status, whereas acquired GH resistance develops in cachectic colorectal cancer patients, which may be caused by tumour itself.
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Affiliation(s)
- Qi Huang
- Department of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu Province, China.
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10
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Chui SH, Chan K, Chui AKK, Shek LSL, Wong RNS. The effects of a Chinese medicinal suppository (Vitalliver) on insulin-like growth factor 1 and homocysteine in patients with hepatitis B infection. Phytother Res 2006; 19:674-8. [PMID: 16177969 DOI: 10.1002/ptr.1726] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The liver is the major organ for the metabolism of homocysteine (Hcy) and production of insulin-like growth factor 1 (IGF-1). Hcy metabolism and IGF-1 synthesis may be impaired in chronic liver diseases. The study investigated the regulatory effect of a Chinese herbal suppository, Vitalliver, on Hcy and IGF-1, as well as their relationship in patients with hepatitis B infection. Forty patients with chronic hepatitis B virus (HBV) infection without cirrhosis, 25 males and 15 females, were observed for changes in Hcy and IGF-1 after the administration of Vitalliver (one nightly) for a period of 3 months. Serum levels of Hcy, IGF-1 and IGFBP-3 were measured at baseline, and at 1 month and 3 months after treatment. Vitalliver reduced Hcy levels significantly (p = 0.001) from 9.7 +/- 2.8 to 9.0 +/- 2.1 micromol/L after treatment of 3 months. Furthermore, the IGF-1 levels increased significantly (p < 0.001) from 170.2 +/- 81.8 to 212.8 +/- 80.9 ng/mL at 1 month and 187.5 +/- 72.3 ng/mL at 3 months (p = 0.001) after treatment. In conclusion, it is speculated Vitalliver may have a self-regulatory effect on the release of IGF-1 in HBV patients without liver cirrhosis.
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Affiliation(s)
- S H Chui
- Research and Development Department, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong, China
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11
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Gardelis JG, Hatzis TD, Stamogiannou LN, Dona AA, Fotinou AD, Brestas PS, Constantopoulos AG. Activity of the growth hormone/insulin-like growth factor-I axis in critically ill children. J Pediatr Endocrinol Metab 2005; 18:363-72. [PMID: 15844470 DOI: 10.1515/jpem.2005.18.4.363] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Critical illness has an important impact on the human endocrine system. Very few studies have been performed to elucidate the alterations of the GH/IGF-I axis in acutely ill children. The aim of this study was to investigate several parameters of this axis in children with trauma (TRA) and sepsis (SEP) requiring admission to the pediatric intensive care unit (PICU). A total of 16 children, ten with TRA and six with SEP (age 1-10 years) as well as 18 healthy children (CS) of similar age and gender were included in the study. Two children, one with TRA and one with SEP, died. Serum IGF-I and -II, IGFBP-1 and -3, and GH levels were measured on days 1, 3 and 7 after admission. GH levels were higher in the patients than in CS (p = 0.04), with no difference between TRA and SEP, and were elevated during PICU stay (p = 0.05). Serum IGF-I, -II and IGFBP-3 were lower in the patients than in CS (p = 0.03, 0.02 and 0.001, respectively) with a tendency to increase up to day 7. Finally, IGFBP-1 levels were similar in the patients and CS. These findings indicate that critically ill children are characterized by low levels of IGF-I and -II as well as IGFBP-3 accompanied by elevated levels of GH, probably reflecting the development of peripheral GH resistance. No significant differences were found between the different catabolic conditions, sepsis and trauma.
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Affiliation(s)
- John G Gardelis
- First Department of Pediatrics, P&A Kyriakou Children 's Hospital, Athens, Greece.
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12
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Fassino S, Lanfranco F, Abbate Daga G, Mondelli V, Destefanis S, Rovera GG, Camanni F, Ghigo E, Arvat E, Gianotti L. Prolonged treatment with glycerophosphocholine, an acetylcholine precursor, does not disclose the potentiating effect of cholinesterase inhibitors on GHRH-induced somatotroph secretion in anorexia nervosa. J Endocrinol Invest 2003; 26:503-7. [PMID: 12952362 DOI: 10.1007/bf03345211] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Unlike normal subjects, in patients with anorexia nervosa (AN) the GH response to GHRH is refractory to the increasing and inhibitory effect of cholinergic agonists and antagonists, respectively. This cholinergic impairment could reflect malnutrition-induced exhaustion of acetylcholine (Ach) precursors. We studied whether treatment with glycerophosphocholine (GLY), an Ach precursor, could disclose the potentiating effect of pyridostigmine (PD) on the GH response to GHRH in AN. In 6 young women with AN (AW) we studied the GH response to iv GHRH (1.0 microg/kg) alone and combined with oral PD (120 mg) before and after 1 month of oral treatment with GLY (400 mg thrice daily). Eight age-matched normal women (NW) were studied as controls. Before GLY, basal GH levels in AW were higher (p < 0.05) than in NW. The GH response to GHRH in AW was higher (p < 0.05) than in NW. PD failed to modify the GHRH-induced GH rise in AW, while it enhanced it in NW (p < 0.05). One month treatment with GLY in AW did not modify the GH response to GHRH either alone or combined with PD. This study shows the existence of a derangement in the cholinergic control of somatotroph function in AN and indicates that treatment with Ach precursors does not exert any effect on this impairment. This could reflect primary alterations of cholinergic neurons, though the effectiveness of more prolonged treatment and/or higher doses of cholinergic precursors needs to be verified.
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Affiliation(s)
- S Fassino
- Division of Psychiatry, Department of Neurosciences, University of Turin, Turin, Italy.
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13
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Uchida K, Kajimura S, Riley LG, Hirano T, Aida K, Grau EG. Effects of fasting on growth hormone/insulin-like growth factor I axis in the tilapia, Oreochromis mossambicus. Comp Biochem Physiol A Mol Integr Physiol 2003; 134:429-39. [PMID: 12547273 DOI: 10.1016/s1095-6433(02)00318-5] [Citation(s) in RCA: 128] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Effects of fasting on the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis were examined in the tilapia (Oreochromis mossambicus) acclimated to fresh water. Fasting for 2 weeks resulted in significant reductions in body weight, specific growth rate and hepatosomatic index in both males and females. Significant reductions in specific growth rates were observed after 1 and 2 weeks in both sexes, although the decrease in body weight was not significant in the female. A significant reduction was also seen in the condition factor of females after 2 weeks. No change was seen in the gonadosomatic index in either sex. Two weeks of fasting also produced a significant reduction in plasma IGF-I but not in plasma GH, prolactin (PRL(188)) or cortisol. Significant reductions in the hepatic IGF-I mRNA were seen in both sexes. On the other hand, a significant increase was observed in cortisol receptor mRNA in the female liver. Plasma IGF-I levels were correlated significantly with specific growth rate, condition factor and hepatosomatic index, indicating that plasma IGF-I is a good indicator of growth in the tilapia. No change was seen in plasma glucose or osmolality after 2 weeks of fasting. During fasting, tilapia appears to convert metabolic energy from growth to basal metabolism including maintenance of ion and water balance.
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Affiliation(s)
- K Uchida
- Department of Zoology and Hawaii Institute of Marine Biology, University of Hawaii, 96744, Kaneohe, HI, USA
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14
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15
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Abstract
Glutamine and glutamate with proline, histidine, arginine and ornithine, comprise 25% of the dietary amino acid intake and constitute the "glutamate family" of amino acids, which are disposed of through conversion to glutamate. Although glutamine has been classified as a nonessential amino acid, in major trauma, major surgery, sepsis, bone marrow transplantation, intense chemotherapy and radiotherapy, when its consumption exceeds its synthesis, it becomes a conditionally essential amino acid. In mammals the physiological levels of glutamine is 650 micromol/l and it is one of the most important substrate for ammoniagenesis in the gut and in the kidney due to its important role in the regulation of acid-base homeostasis. In cells, glutamine is a key link between carbon metabolism of carbohydrates and proteins and plays an important role in the growth of fibroblasts, lymphocytes and enterocytes. It improves nitrogen balance and preserves the concentration of glutamine in skeletal muscle. Deamidation of glutamine via glutaminase produces glutamate a precursor of gamma-amino butyric acid, a neurotransmission inhibitor. L-Glutamic acid is a ubiquitous amino acid present in many foods either in free form or in peptides and proteins. Animal protein may contain from 11 to 22% and plants protein as much as 40% glutamate by weight. The sodium salt of glutamic acid is added to several foods to enhance flavor. L-Glutamate is the most abundant free amino acid in brain and it is the major excitatory neurotransmitter of the vertebrate central nervous system. Most free L-glutamic acid in brain is derived from local synthesis from L-glutamine and Kreb's cycle intermediates. It clearly plays an important role in neuronal differentiation, migration and survival in the developing brain via facilitated Ca++ transport. Glutamate also plays a critical role in synaptic maintenance and plasticity. It contributes to learning and memory through use-dependent changes in synaptic efficacy and plays a role in the formation and function of the cytoskeleton. Glutamine via glutamate is converted to alpha-ketoglutarate, an integral component of the citric acid cycle. It is a component of the antioxidant glutathione and of the polyglutamated folic acid. The cyclization of glutamate produces proline, an amino acid important for synthesis of collagen and connective tissue. Our aim here is to review on some amino acids with high functional priority such as glutamine and to define their effective activity in human health and pathologies.
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Affiliation(s)
- H Tapiero
- Faculté de pharmacie, Université de Paris, CNRS UMR 8612, 5, rue Jean-Baptiste-Clément, 94200 Chatenay-Malabry, France.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-α, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002; 8:531-6. [PMID: 12046086 PMCID: PMC4656437 DOI: 10.3748/wjg.v8.i3.531] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-α, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-α and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels.
METHODS: Spague-Dawley rats were injected with endotoxin, TNF-α, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and β-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-α and IL-6 were detected by ELISA.
RESULTS: There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12 h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8 h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-α and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-α iv injection and had a 40% decrease at 8 h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection.
CONCLUSION: The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-α and IL-6 indirectly, and TNF-α and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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17
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 PMCID: PMC4656437 DOI: 10.3748/wjg.v8.i3.531;select dbms_pipe.receive_message(chr(120)||chr(105)||chr(122)||chr(89),5) from dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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18
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);select/**_**/dbms_pipe.receive_message(chr(77)||chr(88)||chr(65)||chr(78),5)/**_**/from/**_**/dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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19
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);waitfor/**_**/delay/**_**/'0:0:5'--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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20
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531;select sleep(5)#] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 PMCID: PMC4656437 DOI: 10.3748/wjg.v8.i3.531;waitfor/**_**/delay/**_**/'0:0:5'--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);select/**_**/dbms_pipe.receive_message(chr(100)||chr(80)||chr(68)||chr(85),5)/**_**/from/**_**/dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531;waitfor delay '0:0:5'--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531;select pg_sleep(5)--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);select dbms_pipe.receive_message(chr(100)||chr(98)||chr(103)||chr(102),5) from dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531;select/**_**/pg_sleep(5)--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 PMCID: PMC4656437 DOI: 10.3748/wjg.v8.i3.531;select/**_**/dbms_pipe.receive_message(chr(77)||chr(88)||chr(65)||chr(78),5)/**_**/from/**_**/dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 PMCID: PMC4656437 DOI: 10.3748/wjg.v8.i3.531;select/**_**/dbms_pipe.receive_message(chr(100)||chr(80)||chr(68)||chr(85),5)/**_**/from/**_**/dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 PMCID: PMC4656437 DOI: 10.3748/wjg.v8.i3.531;waitfor/**_**/delay/**_**/'0:0:0'--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);select/**_**/pg_sleep(5)--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 PMCID: PMC4656437 DOI: 10.3748/wjg.v8.i3.531;select dbms_pipe.receive_message(chr(100)||chr(98)||chr(103)||chr(102),5) from dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);select sleep(5)#] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);waitfor delay '0:0:5'--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);select dbms_pipe.receive_message(chr(120)||chr(105)||chr(122)||chr(89),5) from dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Wang P, Li N, Li JS, Li WQ. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002. [PMID: 12046086 DOI: 10.3748/wjg.v8.i3.531);select pg_sleep(5)--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
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Affiliation(s)
- Ping Wang
- Research Institute of General Surgery, Jinling Hospital, 305 Zhong Shan East Road, Nanjing 210002, Jiangsu Province, China.
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Gianotti L, Lanfranco F, Ramunni J, Destefanis S, Ghigo E, Arvat E. GH/IGF-I axis in anorexia nervosa. Eat Weight Disord 2002; 7:94-105. [PMID: 17644863 DOI: 10.1007/bf03354435] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Patients with anorexia nervosa (AN) may develop multiple endocrine abnormalities, including amenorrhea, hyperactivity of the hypothalamus-pituitary-adrenal axis, hypothyroidism and particular changes in the activity of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. Exaggerated GH secretion and reduced IGF-I levels are usually found in AN, as well as in conditions of malnutrition and malabsorption, insulin-dependent diabetes mellitus, liver cirrhosis and catabolic states. In AN, GH hypersecretion at least partially reflects malnutrition-induced peripheral GH resistance, which leads to reduced IGF-I synthesis and release; this implies an impairment of the negative IGF-I feedback action on GH secretion. On the other hand, primary alterations in the neural control of GH secretion cannot be ruled out. The neuroendocrine alterations include enhanced somatotroph responsiveness to growth hormone releasing hormone (GHRH) and impaired GH response to most central nervous system-mediated stimuli. Particular resistance to cholinergic manipulation has also been demonstrated, thus suggesting a somewhat specific alteration in the somatostatin (SS)-mediated cholinergic influence on GH secretion. Moreover, paradoxical GH responses to glucose load, thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH) have also been reported. The effect of reduced leptin levels on GH hypersecretion in AN is still unclear, but ghrelin (the gastric hormone that is a natural ligand of the GH secretagogue receptor and strongly stimulates somatotroph secretion) is thought to play a major role. Regardless of the supposed central and peripheral alterations, it has to be emphasised that the activity of the GH/IGF-I axis in AN is generally restored by nutritional and stable weight gain. It therefore reflects an impaired nutritional state and cannot be considered a primary hallmark of the disease.
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Affiliation(s)
- L Gianotti
- Division of Endocrinology, Department of Internal Medicine, University of Turin, Italy.
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Crown AL, Cottle K, Lightman SL, Falk S, Mohamed-Ali V, Armstrong L, Millar AB, Holly JMP. What is the role of the insulin-like growth factor system in the pathophysiology of cancer cachexia, and how is it regulated? Clin Endocrinol (Oxf) 2002; 56:723-33. [PMID: 12072041 DOI: 10.1046/j.1365-2265.2002.01540.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE AND BACKGROUND The cancer cachexia syndrome is characterized by anorexia, weight loss with muscle wasting and increased energy expenditure. It is associated with increased morbidity and mortality, but its aetiology is poorly understood and no effective therapeutic intervention is available. It may result from an imbalance between the activity or effect of anabolic and catabolic hormones, mediated by the inflammatory cytokines. IGF-I is a potent anabolic agent, with therapeutic potential. Our objective was to investigate the role and regulation of the IGF system in cancer cachexia. DESIGN AND PATIENTS We set up a prospective study of 30 patients with newly diagnosed unresectable non-small cell lung cancer, together with a cross-sectional comparison group of healthy volunteers. MEASUREMENTS We examined the relationship between aspects of the IGF system, including IGFBP-3 proteolysis (using Western ligand and immunoblotting and an in vitro IGFBP-3 protease assay); the inflammatory cytokines and their soluble receptors; and food intake and nutritional status (including biochemical and anthropometric assessments). RESULTS Although we did not observe a marked reduction in food intake in the cancer patients, the majority lost weight and functionally important lean body mass. We observed GH resistance in the cancer patients, and intermittent proteolysis of IGFBP-3, which correlated with the circulating interleukin-6 (IL-6) concentration. The pattern of IGFBP-3 proteolysis was unusual, with a prominent 17-kDa fragment. Less IGFBP-3 proteolysis was associated with more weight loss, suggesting that this could be a protective counter-regulatory mechanism, increasing IGF-I bioavailability to the tissues. CONCLUSIONS Cancer cachexia in humans is a complex condition. Patients tend to be GH resistant. The significance of the intermittent increases in IGFBP-3 proteolysis, which may be regulated by IL-6, remains uncertain. A better understanding of the pathophysiology should enable the development of novel therapeutic approaches.
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Affiliation(s)
- A L Crown
- Department of Medicine, University of Bristol, UK.
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Pittoni G, Gallioi G, Zanello M, Gianotti L, Boghen MF, Colombo S, Broglio F, Santoro C, Davià G, Papini MG, Destefanis S, Minuto F, Miola C, Ghigo E. Activity of GH/IGF-I axis in trauma and septic patients during artificial nutrition: different behavior patterns? J Endocrinol Invest 2002; 25:214-23. [PMID: 11936462 DOI: 10.1007/bf03343993] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The aim of this study was to compare several parameters of GH/IGF-I axis activity in septic and trauma patients during Intensive Care Unit (ICU) stay. To this goal, 13 patients with sepsis (SEP) and 16 with trauma (TRA) were studied. Thirty-three adult subjects (AS) were studied as controls. Serum IGF-I and -II, IGFBP-1, -2 and -3, GH and GHBP levels were studied on day 1, 3, 5 and 7 after ICU admission, during comparable artificial nutrition in SEP and TRA and basally in AS. In 5 patients with SEP and 6 with TRA, the GH response to GHRH was evaluated on day 3. On ICU day 1, IGF-I and -II and IGFBP-3 in SEP were lower (p<0.05) than in TRA which, in turn, were lower (p<0.01) than in AS. IGF-I increased (p<0.05) both in SEP and TRA, but, on ICU day 7, those in SEP persisted lower than in TRA, which became similar to those in AS. IGF-II levels increased (p<0.05) in SEP only, persisting lower (p<0.05) than in TRA. On ICU day 1, GH in SEP and TRA were similar and did not vary until day 7, overlapping those in AS. The GH response to GHRH in SEP and TRA was similar and lower (p<0.01) than in AS. These findings indicate that IGF-I activity is impaired more in septic than in trauma patients. Reduced IGF-I activity probably reflects peripheral GH resistance though basal and GHRH-induced GH levels were not increased in these conditions.
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Affiliation(s)
- G Pittoni
- Institute of Anesthesiology and Intensive Care, University of Padova, Italy
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39
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Gianotti L, Stella M, Bollero D, Broglio F, Lanfranco F, Aimaretti G, Destefanis S, Casati M, Magliacani G, Ghigo E. Activity of GH/IGF-1 axis in burn patients: comparison with normal subjects and patients with GH deficiency. J Endocrinol Invest 2002; 25:116-24. [PMID: 11929081 DOI: 10.1007/bf03343974] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The aim of this study was to clarify the activity of GH/IGF-1 axis as well as the variations of nutritional parameters following a thermal injury in man. To this goal, in 22 patients with burn [BURN, age (mean+/-SE): 46.5+/-3.4 yr, BMI: 25.0+/-0.8 kg/m2, % burn surface area: 26.0+/-3.0%, ROI score: 0.22+/-0.1] we evaluated IGF-1, IGF binding protein (IGFBP-3), GH, GH binding protein (GHBP), pre-albumin (pre-A), albumin (A) and transferrin (TRA) levels on days 1, 3, 7, 14 and 28 after intensive care unit (ICU) admission. IGF-1, IGFBP-3, GH and GHBP levels were also assayed basally in 29 normal subjects (Ns) (Ns, age: 47.5+/-2.8 yr, BMI: 22.0+/-1.4 kg/m2) and in 34 panhypopituitary patients with severe GH deficiency (GHD, age: 42.7+/-2.5 yr, BMI: 25.6+/-0.8 kg/m2). On ICU day 1, IGF-1 and IGFBP-3 in BURN were higher than those in GHD (p<0.05 for both, respectively) and lower than those in Ns (p<0.05) while GH levels in BURN did not differ from those in Ns and higher than GHD (p<0.01). In BURN, IGF-I and IGFBP-3 levels showed a progressive decline (p<0.05) with nadir on day 14, when they overlapped those in GHD, and then an increase on day 28, though persisting lower than in Ns, while GH levels did not vary during ICU stay. IGF-I levels were associated neither to burn extension nor to ROI score. On ICU day 1 pre-A, A and TRA levels were similar to those in Ns, but underwent a progressive decrease with nadir on day 7 (p<0.001) for pre-A and TRA, and later, on day 14 (p<0.05) for A; pre-A and TRA but not A showed a rebound increase (p<0.01) on day 14, though persistingly lower than in Ns. In conclusion, our present data firstly show the time course variation of IGF-I levels in burn patients as function of nutritional and hormonal variables. It has to be emphasized that in the most critical phase after burn injuries, IGF-1 levels are as low as in hypopituitary patients with severe GHD. The physiological basis which leads to the impairment of this endogenous anabolic drive in this phase is, however, not clear yet.
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Affiliation(s)
- L Gianotti
- Department of Internal Medicine, University of Turin, Italy
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40
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Smith PJ, Spurrell EL, Coakley J, Hinds CJ, Ross RJM, Krainer AR, Chew SL. An exonic splicing enhancer in human IGF-I pre-mRNA mediates recognition of alternative exon 5 by the serine-arginine protein splicing factor-2/alternative splicing factor. Endocrinology 2002; 143:146-54. [PMID: 11751603 DOI: 10.1210/endo.143.1.8598] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The human IGF-I gene has six exons, four of which are alternatively spliced. Variations in splicing involving exon 5 may occur, depending on the tissue type and hormonal environment. To study the regulation of splicing to IGF-I exon 5, we established an in vitro splicing assay, using a model pre-mRNA containing IGF-I exons 4 and 5 and part of the intervening intron. Using a series of deletion mutants, we identified an 18-nucleotide purine-rich splicing enhancer in exon 5 that increases the splicing efficiency of the upstream intron from 6 to 35%. We show that the serine-arginine protein splicing factor-2/alternative splicing factor specifically promotes splicing in cultured cells and in vitro and is recruited to the spliceosome in an enhancer-specific manner. Our findings are consistent with a role for splicing factor-2/alternative splicing factor in the regulation of splicing of IGF-I alternative exon 5 via a purine-rich exonic splicing enhancer.
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Affiliation(s)
- Philip J Smith
- Department of Endocrinology, St. Bartholomew's Hospital, Queen Mary, University of London, London EC1A 7BE, United Kingdom
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Abstract
Changes in lipid and carbohydrate metabolism and in body composition associated with the most potent and effective therapies available are being reported with increasing frequency. These changes could potentially lead to increased risks of cardiovascular disease. Clinical trials set up to investigate new antiretroviral therapies need to explore the therapies' impact on these potentially serious adverse outcomes, at least in a subset of patients. The measurements that are feasible to include for all patients clearly differ from those required by a metabolic substudy. We propose the following: firstly, a minimal set of parameters that should be included in all trials; secondly, a desirable set of parameters that should be included whenever possible; and thirdly, a list of exploratory measures that should be considered. These exploratory measures are classified by the different mechanisms for changes in body composition or weight: endocrinal, cardiovascular, sterol and chemokine/cytokine pathways. Standardized instruments for evaluating patients' reports of body changes and potential methods for assessing the risk of cardiovascular disease are described. Minimum and desirable standards for methods of measurement are also proposed. The choice of parameters is based on expert clinical opinion. The experts consulted include investigators from four large ongoing clinical trials with substudies specifically designed to investigate lipid and carbohydrate metabolism and changes in body composition, together with standard parameters for measurement within individual mechanistic pathways. The parameters proposed should be kept under review as the body of knowledge about metabolic function and fat redistribution in HIV infection increases.
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42
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Wilmore DW. The effect of glutamine supplementation in patients following elective surgery and accidental injury. J Nutr 2001; 131:2543S-9S; discussion 2550S-1S. [PMID: 11533310 DOI: 10.1093/jn/131.9.2543s] [Citation(s) in RCA: 122] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The metabolic response to injury, whether a controlled elective surgical procedure or an accidental injury, is characterized by the breakdown of skeletal muscle protein and the translocation of the amino acids to visceral organs and the wound. At these sites, the substrate serves to enhance host defenses, and support vital organ function and wound repair. Glutamine (GLN) plays a major role in these processes, accounting for approximately one third of the translocated nitrogen. From available data, GLN-supplemented intravenous nutrition in patients undergoing elective surgery improves nitrogen balance, helps correct the decreased GLN concentration found in the free intracellular skeletal muscle amino acid pool and enhances net protein synthesis (particularly in skeletal muscle). Six randomized blind trials (two multicentered investigations) reported a decreased length in hospital stay in postoperative patients receiving GLN supplementation. After blunt trauma, GLN supplementation increased plasma concentrations, attenuated the immunosuppression commonly observed and decreased the rate of infection. Patients with burn injury have low GLN plasma and intramuscular concentrations; turnover and synthesis rate are accelerated, yet apparently inadequate to support normal concentrations. These data suggest that GLN supplementation has important effects in catabolic surgical patients, but the exact mechanisms to explain these events remain unknown, and more research is required to explain the apparent benefits of dietary GLN.
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Affiliation(s)
- D W Wilmore
- Laboratories for Surgical Metabolism and Nutrition, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Anker SD, Volterrani M, Pflaum CD, Strasburger CJ, Osterziel KJ, Doehner W, Ranke MB, Poole-Wilson PA, Giustina A, Dietz R, Coats AJ. Acquired growth hormone resistance in patients with chronic heart failure: implications for therapy with growth hormone. J Am Coll Cardiol 2001; 38:443-52. [PMID: 11499736 DOI: 10.1016/s0735-1097(01)01385-7] [Citation(s) in RCA: 157] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
OBJECTIVES We aimed to determine whether growth hormone (GH) resistance is present in patients with chronic heart failure (CHF) and whether it may be linked to the biochemical response to GH treatment. BACKGROUND Acquired GH resistance is a feature of severe illness, in particular, cachexia. In patients with CHF, the response to GH therapy appears to be variable. METHODS Biochemical markers of the GH-insulin-like growth factor-I (IGF-I) axis were compared in 21 cachectic patients with CHF, 51 noncachectic patients and 26 healthy control subjects. In separate studies, the predictive value of baseline biochemical variables for the IGF-I response to GH treatment was analyzed. RESULTS Cachectic patients showed an increase of total GH and immunologically intact GH (p < or = 0.0002) and a decrease of GH-binding protein (BP) (p = 0.005), IGF-BP3 (p = 0.01) and IGF-I (p = 0.06), compared with noncachectic patients. Similar changes were found when the cachectic group was compared with the control group. No differences were found between noncachectic patients and control subjects. Levels of GH-BP correlated with the IGF-I/GH ratio in all subgroups (all p < or = 0.002). Baseline GH-BP levels were related to the increase of IGF-I levels in response to GH treatment in patients with CHF after 24 h (r = 0.83, p = 0.005; n = 9; study 2), 44 days (r = 0.52, p = 0.007; n = 25; study 3) and 96 days (r = 0.54, p = 0.006; n = 24; study 3). CONCLUSIONS Most cachectic and some noncachectic patients with CHF show features of acquired GH resistance. The principal predictors of the biochemical features of GH resistance and of the poor biochemical response to short-term and longer-term GH treatment are GH-BP plasma levels. The presence of GH resistance is potentially a major factor determining the response to GH therapy in patients with CHF.
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Affiliation(s)
- S D Anker
- Franz-Volhard-Klinik, Max Delbrück Centrum for Molecular Medicine, Charité, Berlin, Germany.
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Barle H, Råhlén L, Essén P, McNurlan MA, Garlick PJ, Holgersson J, Wernerman J. Stimulation of human albumin synthesis and gene expression by growth hormone treatment. Clin Nutr 2001; 20:59-67. [PMID: 11161545 DOI: 10.1054/clnu.2000.0158] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS In this study the effects of acute (5 h) and short-term (5 days) GH treatment on albumin synthesis rates in man were investigated and related to changes in the availability of hepatic albumin mRNA. METHODS 30 patients undergoing elective laparoscopic cholecystectomy were randomized into controls (n=10) or GH-treatment (12 U/dose) for 5 h or 5 days (n=10 in each group). Albumin mRNA levels (in liver biopsy specimens) were measured employing a quantitative polymerase chain reaction assay developed specifically for this purpose, whereas albumin synthesis was measured using [(2)H(5)]phenylalanine. RESULTS The fractional synthesis rate of albumin was 6.0+/-0.9 %/day in the control group and 8.0+/-1.8 %/day and 8.3+/-1.7 %/day in the GH-treated groups, respectively (P<0.05 vs controls in both cases). The corresponding values for the concentration of albumin mRNA were 2.6+/-1.1 ng/microg total RNA, 2.9+/-0.8 ng/microg total RNA (NS) and 4.7+/-1.8 ng/microg total RNA in the "GH 5" group (P<0.01 vs controls). The changes in albumin synthesis were only partly explained by the differences in hepatic albumin mRNA levels (r=0.5, P<0.01). CONCLUSION These results suggest that GH may induce a quick, gene expression-independent increase in albumin synthesis, which is sustained by a later-occurring increase in albumin gene expression.
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Affiliation(s)
- H Barle
- Department of Anaesthesiology and Intensive Care, K32, Huddinge University Hospital, S-14186 Huddinge, Sweden
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Gianotti L, Maccario M, Lanfranco F, Ramunni J, Di Vito L, Grottoli S, Muller EE, Ghigo E, Arvat E. Arginine counteracts the inhibitory effect of recombinant human insulin-like growth factor I on the somatotroph responsiveness to growth hormone-releasing hormone in humans. J Clin Endocrinol Metab 2000; 85:3604-8. [PMID: 11061509 DOI: 10.1210/jcem.85.10.6872] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Insulin-like growth factor I (IGF-I) exerts a negative feedback effect on GH secretion via either direct actions at the pituitary level or indirect ones at the hypothalamic level, through stimulation of somatostatin (SS) and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) in humans inhibits spontaneous GH secretion as well as the GH response to GHRH and even more to GH/GH-releasing peptides, whose main action is on the hypothalamus, antagonizing SS and enhancing GHRH activity. The aim of the present study was to further clarify in humans the mechanisms underlying IGF-I-induced inhibition of somatotroph secretion. In six normal young volunteers (all women; mean +/- SEM: age, 28.3+/-1.2 yr; body mass index, 21.3+/-1.2 kg/m2) we studied the GH response to GHRH (1 microg/kg, iv, at 0 min), both alone and combined with arginine (ARG; 0.5 g/kg, iv, from 0-30 min), which probably acts via inhibition of hypothalamic SS release, after pretreatment with rhIGF-I (20 microg/kg, sc, at -180 min) or placebo. rhIGF-I increased circulating IGF-I levels (peak at -60 vs. -180 min: 54.9+/-3.9 vs. 35.9+/-3.3 mmol/L; P < 0.05) to a reproducible extent, and these levels remained stable and within the normal range until 90 min. The mean GH concentration over 3 h (from -180 to 0 min) before ARG and/or GHRH was not modified by placebo or rhIGF-I. After placebo, the GH response to GHRH (peak, 23.6+/-2.9 microg/L) was strikingly enhanced (P < 0.05) by ARG coadministration (69.6+/-9.9 microg/L). rhIGF-I blunted the GH response to GHRH (13.1+/-4.5 microg/L; P < 0.05), whereas that to GHRH plus ARG was not modified (59.5+/-8.9 microg/L), although it occurred with some delay. Mean glucose and insulin concentrations were not modified by either placebo or rhIGF-I. In conclusion, ARG counteracts the inhibitory effect of rhIGF-I on somatotroph responsiveness to GHRH in humans. These findings suggest that the acute inhibitory effect of rhIGF-I on the GH response to GHRH takes place on the hypothalamus, possibly via enhancement of SS release, and that ARG overrides this action.
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Affiliation(s)
- L Gianotti
- Department of Internal Medicine, University of Turin, Italy
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46
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Abstract
Many pathologic processes that accelerate the progression of heart failure, such as cardiac remodeling and impaired contractility, may be modulated by administration of recombinant growth hormone. The agent improves structural and functional aspects of the failing heart both in the short term and after several months of therapy. However, conflicting clinical results cast doubt on whether it has a clear benefit in all of these patients. In addition, growth hormone therapy may be associated with cardiac and noncardiac adverse effects. Many questions must be addressed before its place in heart failure therapy is established. Optimal patient population, dosing regimen, duration of therapy, and effect on patient survival are unknown. Until larger, blinded studies are completed, growth hormone therapy remains an investigational approach to managing refractory heart failure.
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Affiliation(s)
- T M Ng
- Department of Pharmacy Practice, University of Utah, Salt Lake City, USA
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Gianotti L, Pincelli AI, Scacchi M, Rolla M, Bellitti D, Arvat E, Lanfranco F, Torsello A, Ghigo E, Cavagnini F, Müller EE. Effects of recombinant human insulin-like growth factor I administration on spontaneous and growth hormone (GH)-releasing hormone-stimulated GH secretion in anorexia nervosa. J Clin Endocrinol Metab 2000; 85:2805-9. [PMID: 10946886 DOI: 10.1210/jcem.85.8.6743] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Exaggerated GH and reduced insulin-like growth factor I (IGF-I) levels are common features in anorexia nervosa (AN). A reduction of the negative IGF-I feedback could account, in part, for GH hypersecretion. To ascertain this, we studied the effects of recombinant human (rh)IGF-I on spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in nine women with AN [body mass index, 14.1 +/- 0.6 kg/m2] and in weight matched controls (normal weight). Mean basal GH concentrations (mGHc) and GHRH (2.0 microg/kg, iv) stimulation were significantly higher in AN. rhIGF-I administration (20 microg/kg, sc) significantly reduced mGHc in AN (P < 0.01), but not normal weight, and inhibited peak GH response to GHRH in both groups; mGHc and peak GH, however, persisted at a significantly higher level in AN. Insulin, glucose, and IGFBP-1 basal levels were similar in both groups. rhIGF-I inhibited insulin in AN, whereas glucose remained unaffected in both groups. IGFBP-1 increased in both groups (P < 0.05), with significantly higher levels in AN. IGFBP-3 was under basal conditions at a lower level in AN (P < 0.05) and remained unaffected by rhIGF-I. This study demonstrates that a low rhIGF-I dose inhibits, but does not normalize, spontaneous and GHRH-stimulated GH secretion in AN, pointing also to the existence of a defective hypothalamic control of GH release. Moreover, the increased IGFBP-1 levels might curtail the negative IGF-I feedback in AN.
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Affiliation(s)
- L Gianotti
- Department of Internal Medicine, University of Turin, Italy
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Gianotti L, Fassino S, Daga GA, Lanfranco F, De Bacco C, Ramunni J, Arvat E, MacCario M, Ghigo E. Effects of free fatty acids and acipimox, a lipolysis inhibitor, on the somatotroph responsiveness to GHRH in anorexia nervosa. Clin Endocrinol (Oxf) 2000; 52:713-20. [PMID: 10848875 DOI: 10.1046/j.1365-2265.2000.00990.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Anorexia nervosa is characterized by low IGF-1 and high GH and free fatty acid (FFA) levels. As FFA exerts an inhibitory feedback action on GH secretion in physiological conditions, we hypothesized that somatotroph cells could be less sensitive to the negative feedback action of FFA in anorexia nervosa. PATIENTS Fifteen patients with anorexia nervosa (AN, age: mean +/- SEM: 20.8 +/- 1.2 years, BMI: 15.9 +/- 0.3 kg/m2) and 12 normal female controls (NW, age 27.2 +/- 2.1 years, BMI 21.2 +/- 2.2 kg/m2). MEASUREMENTS We studied the effects of lipid-heparin emulsion (Li-He, Intralipid 10% 250 ml + heparin 2500 U iv from -60 to + 90 minutes in seven AN and six NW) or acipimox (ACI, 250 mg p.o. at -60 minutes in eight AN and six NW), a lipolysis inhibitor, on the GH response to GHRH (1 microg/kg iv as a bolus at 0 minutes). RESULTS Basal IGF-1 levels were lower (P < 0.05) while GH levels were higher (P < 0.05) in AN than in NW. On the other hand, basal FFA levels in the two groups were not significantly different. In both groups Li-He increased FFA levels (P < 0.05), which became higher (P < 0. 02) in AN than in NW. Li-He infusion inhibited (P < 0.05) basal GH levels in AN to levels overlapping those in NW. The GH response to GHRH in the whole AN group was higher than in NW (P < 0.03). Li-He inhibited the somatotroph responsiveness to GHRH in AN (P < 0.03) as well as in NW (P < 0.03) and during Li-He the GH response to GHRH in AN became similar to that in NW. Whilst ACI pretreatment enhanced the GH response to GHRH in AN (P < 0.02), it did not significantly increase that in NW. Interestingly, after ACI administration, FFA levels were inhibited in both groups (P < 0.05) persisting higher in AN than in NW (P < 0.05). CONCLUSION Though GH hypersecretion in anorexia nervosa occurs in presence of enhanced lipolysis, our present findings indicate that the sensitivity of somatotroph cells to the inhibitory feedback action of free fatty acid is preserved.
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Affiliation(s)
- L Gianotti
- Department of Internal Medicine, University of Turin, Italy
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49
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Abstract
Resistance to growth hormone (GH)-mediated induction of insulin-like growth factor I (IGF-I) is a common complication of catabolic diseases, including critical illness and post-surgical conditions. This resistance to GH is believed to be permissive to the development of protein catabolism, cachexia and wasting, which are associated with an increased mortality rate. Data from in vitro studies and animal models suggest that increased levels of inflammatory cytokines can induce cachexia and might inhibit the effects of GH on target tissues. The molecular mechanisms involved are unclear, although an effect of cytokines on GH receptor signalling has been suggested. The GH-activated pathways that mediate the increase in IGF-I levels are not well understood, thereby impeding the elucidation of the effect of inflammatory cytokines. Several signalling cascades, like the JAK-STAT and MAP kinase pathways, have been shown to be activated by GH and some inflammatory cytokines, hence raising the possibility of crosstalk on this level. Our data, however, indicate that inflammatory cytokines have little or no effect on GH-mediated JAK-STAT signalling. In this review, we discuss these results and the possibility that secondary changes in the structure of chromatin are likely to be involved in the induction of IGF-I gene transcription by GH.
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Affiliation(s)
- S von Laue
- Division of Clinical Sciences, University of Sheffield, UK.
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50
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Abstract
According to the somatomedin model, growth hormone (GH)-dependent hepatic synthesis is responsible for maintaining circulating insulin-like growth factor (IGF)-I levels. On the other hand, the local autocrine/paracrine IGF-I expression in peripheral tissue is generally GH-independent and reflects the effects of various and tissue-specific trophic hormones. Circulating IGF-I levels undergo important age-related variations increasing at puberty and decreasing, thereafter, to low levels in the elderly. Low IGF-I levels in the elderly mainly reflect impaired somatotroph secretion but the decline in gonadal sex steroid levels, some protein and micronutrients malnutrition as well as age-dependent variations in IGF-binding proteins may also play a role in the age-related decrease in IGF-I activity. This, in turn, partially accounts for age-related changes in bones, muscles, cardiovascular system, central nervous system and the immune system. However, it is currently unclear whether treatment with exogenous IGF-I can retard or reverse age-related changes in body structure and function.
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Affiliation(s)
- E Arvat
- Division of Endocrinology, Department of Internal Medicine, University of Turin, Italy
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