Effects of Short-Term Insulin-Like Growth Factor-I (IGF-I) or Growth Hormone (GH) Treatment on Bone Metabolism and on Production of 1,25-Dihydroxycholecalciferol in GH-Deficient Adults

Gram-negative sepsis with release of endotoxin is a frequent cause of cachexia that develops partly because of resistance to growth hormone (GH) with reduced insulin-like growth factor-I (IGF-I) expression. We set out to more fully characterize the mechanisms for the resistance and to determine whether in addition to a defect in the janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) 5b pathway, required for GH-induced IGF-I expression, there might also be a more distal defect. Conscious rats were given endotoxin and studied 4 h later. In liver of these animals, GH-induced JAK2 and STAT5 phosphorylation was impaired and appeared to be caused, at least in part, by a marked increase in hepatic tumor necrosis factor-α and interleukin-6 mRNA expression accompanied by elevated levels of inhibitors of GH signaling, namely cytokine-inducible suppressors of cytokine signaling-1 and -3 and cytokine-inducible SH2 protein (CIS). Nuclear phosphorylated STAT5b levels were significantly depressed to 61% of the control values and represent a potential cause of the reduced GH-induced IGF-I expression. In addition, binding of phosphorylated STAT5b to DNA was reduced to an even greater extent and averaged 17% of the normal control value. This provides a further explanation for the impaired IGF-I gene transcription. Interestingly, when endotoxin-treated rats were treated with GH, there was a marked increase in proinflammatory cytokine gene expression in the liver. If such a response were to occur in humans, this might provide a partial explanation for the adverse effect of GH treatment reported in critically ill patients.

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Effects of Short-Term Insulin-Like Growth Factor-I (IGF-I) or Growth Hormone (GH) Treatment on Bone Metabolism and on Production of 1,25-Dihydroxycholecalciferol in GH-Deficient Adults1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.1.4484 ◽

1998 ◽

Vol 83 (1) ◽

pp. 81-87 ◽

Cited By ~ 1

Author(s):

Tarcisio Bianda ◽

Yvonne Glatz ◽

Roger Bouillon ◽

Ernst Rudolf Froesch ◽

Christoph Schmid

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Bone Formation ◽

Bone Turnover ◽

Type I ◽

Insulin Like Growth Factor ◽

Gh Treatment ◽

Factor I ◽

Igf I ◽

Growth Factor I

Administration of insulin-like growth factor-I (IGF-I) or growth hormone (GH) is known to stimulate bone turnover and kidney function. To investigate the effects of IGF-I and GH on markers of bone turnover, eight adult GH-deficient patients (48 ± 14 yr of age) were treated with IGF-I (5 μg/kg/h in a continuous sc infusion) and GH (0.03 IU/kg/daily sc injection at 2000 h) in a randomized cross-over study. We monitored baseline values for three consecutive days before initiating the five-day treatment period, as well as the wash-out period of ten weeks. Serum osteocalcin, carboxyterminal and aminoterminal propeptide of type I procollagen (PICP and PINP, respectively) increased significantly within 2–3 days of both treatments (P < 0.02) and returned to baseline levels within one week after the treatment end. The changes in resorption markers were less marked as compared with formation markers. Total 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) rose significantly, whereas PTH and calcium levels remained unchanged during either treatment. Conclusions: Because the rapid increase in markers of bone formation was not preceded by an increase in resorption markers, IGF-I is likely to stimulate bone formation by a direct effect on osteoblasts. Moreover, because PTH, calcium, and phosphate remained unchanged, IGF-I appears to stimulate renal 1α-hydroxylase activity in vivo.

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Expression of human or bovine growth hormone gene with a mouse metallothionein-1 promoter in transgenic swine alters the secretion of porcine growth hormone and insulin-like growth factor-I

Journal of Endocrinology ◽

10.1677/joe.0.1200481 ◽

1989 ◽

Vol 120 (3) ◽

pp. 481-488 ◽

Cited By ~ 29

Author(s):

K. F. Miller ◽

D. J. Bolt ◽

V. G. Pursel ◽

R. E. Hammer ◽

C. A. Pinkert ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

General Pattern ◽

Biologically Active ◽

Growth Hormone Gene ◽

Insulin Like Growth Factor ◽

Short Term ◽

Factor I ◽

Igf I ◽

Growth Factor I

ABSTRACT Endocrine profiles were examined in swine that had integrated and expressed a fusion gene consisting of mouse metallothionein-1 (MT) promoter fused to either a human (h) or bovine (b) GH structural gene. Eleven of 18 pigs that had integrated MT-hGH and eight of nine pigs that had integrated MT-bGH expressed the genes. The level of expression varied widely among pigs (14–4551 μg/l for MT-hGH and 23–1578 μg/l for MT-bGH). The level of expression varied over time within each pig with no general pattern. Concentrations of porcine GH (pGH) were lower in MT-hGH pigs that expressed the gene than in non-expressors or in littermate controls. Insulin-like growth factor-I (IGF-I) concentrations increased with age in all pigs and were raised threefold in pigs expressing either the MT-hGH or MT-bGH genes. Measurement of the foreign GH in samples taken at 15-min intervals failed to reveal any short-term fluctuations in concentration. Administration of hGH releasing factor (GRF) to pigs expressing MT-bGH resulted in attenuated release of pGH compared with that of contemporary controls. Concentrations of bGH did not change after GRF injection. Human and bovine GH expressed in transgenic pigs appear to be biologically active in that they induce IGF-I and suppress endogenous pGH secretion. The failure to find short-term fluctuations and the lack of response to GRF injections are consistent with a non-pituitary and non-GRF regulatable site of production. Journal of Endocrinology (1989) 120, 481–488

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Aspects of Growth Hormone and Insulin-Like Growth Factor-I Related to Neuroprotection, Regeneration, and Functional Plasticity in the Adult Brain

The Scientific World JOURNAL ◽

10.1100/tsw.2006.22 ◽

2006 ◽

Vol 6 ◽

pp. 53-80 ◽

Cited By ~ 237

Author(s):

N. David Åberg ◽

Katarina Gustafson Brywe ◽

Jörgen Isgaard

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Signaling Pathway ◽

Cell Types ◽

Adult Brain ◽

Insulin Like Growth Factor ◽

Gh Treatment ◽

Factor I ◽

Igf I ◽

Growth Factor I

Apart from regulating somatic growth and metabolic processes, accumulating evidence suggests that the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is involved in the regulation of brain growth, development, and myelination. In addition, both GH and IGF-I affect cognition and biochemistry in the adult brain. Some of the effects of GH are attributable to circulating IGF-I, while others may be due to IGF-I produced locally within the brain. Some of the shared effects in common to GH and IGF-I may also be explained by cross-talk between the GH and IGF-I transduction pathways, as indicated by recent data from other cell systems. Otherwise, it also seems that GH may act directly without involving IGF-I (either circulating or locally). Plasticity in the central nervous system (CNS) may be viewed as changes in the functional interplay between the major cell types, neurons, astrocytes, and oligodendrocytes. GH and IGF-I affect all three of these cell types in several ways. Apart from the neuroprotective effects of GH and IGF-I posited in different experimental models of CNS injury, IGF-I has been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. It appears that the MAPK signaling pathway is required for IGF-Istimulated proliferationin vitro, whereas the PI3K/Akt or MAPK/Erk signaling pathway appears to mediate antiapoptotic effects. The increase of IGF-I on endothelial cell phenotype may explain the increase in cerebral arteriole density observed after GH treatment. The functional role of GH and IGF-I in the adult brain will be reviewed with reference to neurotransmitters, glucose metabolism, cerebral blood flow, gap junctional communication, dendritic arborization, exercise, enriched environment, depression, learning, memory, and aging.Briefly, these findings suggest that IGF-I functions as a putative regenerative agent in the adult CNS. Hitherto less studied regarding in these aspects, GH may have similar effects, especially as it is the main regulator of IGF-Iin vivo. Some of the positive cognitive features of GH treatment are likely attributable to the mechanisms reviewed here.

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Changes in insulin sensitivity induced by short-term growth hormone (GH) and insulin-like growth factor I (IGF-I) treatment in GH-deficient adults are not associated with changes in adiponectin levels

Growth Hormone & IGF Research ◽

10.1016/j.ghir.2005.06.012 ◽

2005 ◽

Vol 15 (4) ◽

pp. 300-303 ◽

Cited By ~ 12

Author(s):

Christoph Schmid ◽

Tarcisio Bianda ◽

Cornelia Zwimpfer ◽

Jürgen Zapf ◽

Peter Wiesli

Keyword(s):

Growth Hormone ◽

Insulin Sensitivity ◽

Growth Factor ◽

Insulin Like Growth Factor ◽

Short Term ◽

Factor I ◽

Igf I ◽

Growth Factor I

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Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

AJP Renal Physiology ◽

10.1152/ajprenal.00188.2009 ◽

2009 ◽

Vol 297 (3) ◽

pp. F639-F645 ◽

Cited By ~ 16

Author(s):

Helena Gil-Peña ◽

Enrique Garcia-Lopez ◽

Oscar Alvarez-Garcia ◽

Vanessa Loredo ◽

Eduardo Carbajo-Perez ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Mrna Expression ◽

Growth Plate ◽

Female Rats ◽

Insulin Like Growth Factor ◽

Gh Treatment ◽

Factor I ◽

Igf I ◽

Growth Factor I

Hypokalemic tubular disorders may lead to growth retardation which is resistant to growth hormone (GH) treatment. The mechanism of these alterations is unknown. Weaning female rats were grouped ( n = 10) in control, potassium-depleted (KD), KD treated with intraperitoneal GH at 3.3 mg·kg−1·day−1 during the last week (KDGH), and control pair-fed with KD (CPF). After 2 wk, KD rats were growth retarded compared with CPF rats, the osseous front advance (±SD) being 67.07 ± 10.44 and 81.56 ± 12.70 μm/day, respectively. GH treatment did not accelerate growth rate. The tibial growth plate of KD rats had marked morphological alterations: lower heights of growth cartilage (228.26 ± 23.58 μm), hypertrophic zone (123.68 ± 13.49 μm), and terminal chondrocytes (20.8 ± 2.39 μm) than normokalemic CPF (264.21 ± 21.77, 153.18 ± 15.80, and 24.21 ± 5.86 μm). GH administration normalized these changes except for the distal chondrocyte height. Quantitative PCR of insulin-like growth factor I (IGF-I), IGF-I receptor, and GH receptor genes in KD growth plates showed downregulation of IGF-I and upregulation of IGF-I receptor mRNAs, without changes in their distribution as analyzed by immunohistochemistry and in situ hybridization. GH did not further modify IGF-I mRNA expression. KD rats had normal hepatic IGF-I mRNA levels and low serum IGF-I values. GH increased liver IGF-I mRNA, but circulating IGF-I levels remained reduced. This study discloses the structural and molecular alterations induced by potassium depletion on the growth plate and shows that the lack of response to GH administration is associated with persistence of the disturbed process of chondrocyte hypertrophy and depressed mRNA expression of local IGF-I in the growth plate.

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