Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans

1994 ◽  
Vol 267 (4) ◽  
pp. E591-E598 ◽  
Author(s):  
D. L. Russell-Jones ◽  
A. M. Umpleby ◽  
T. R. Hennessy ◽  
S. B. Bowes ◽  
F. Shojaee-Moradie ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Insulin Infusion ◽  
Whole Body ◽  
Insulin Levels ◽  
Factor I ◽  
Anabolic Action ◽  
Human Volunteers ◽  
Igf I ◽  
Normal Humans ◽  
Normal Human

Insulin-like growth factor I (IGF-I) is thought to mediate the anabolic action of growth hormone. A glucose and amino acid clamp technique was used to investigate the effects of a 3-h intravenous infusion of either 43.7 pmol.kg-1.min-1 (20 micrograms.kg-1.h-1) IGF-I or 3.4 pmol.kg-1.min-1 (0.5 mU.kg-1.min-1) insulin on whole body leucine turnover in five normal human volunteers. During the IGF-I infusion, IGF-I levels increased (P < 0.01; 26.6 +/- 2.8 to 88.9 +/- 14.2 nmol/l) and insulin levels fell (P < 0.05; 0.096 +/- 0.018 to 0.043 +/- 0.009 nmol/l). During the insulin infusion, insulin levels increased (P < 0.01; 0.057 +/- 0.013 to 0.340 +/- 0.099 nmol/l), and there was no change in IGF-I. There was no significant change in leucine production rate (Ra; a measure of protein degradation) during the IGF-I infusion (2.23 +/- 0.17 to 2.13 +/- 0.2 mumol.kg-1.min-1), but there was an increase (P < 0.03) in nonoxidative leucine disposal rate (Rd; a measure of protein synthesis; 1.83 +/- 0.15 to 2.05 +/- 0.21 mumol.kg-1.min-1). In contrast, insulin reduced (P < 0.02) leucine Ra (1.81 +/- 0.24 to 1.47 +/- 0.24 mumol.kg-1.min-1) and had no effect on nonoxidative leucine Rd (1.44 +/- 0.25 to 1.41 +/- 0.22 mumol.kg-1.min-1). We conclude that IGF-I, under conditions of adequate substrate supply, directly increases protein synthesis in contrast to insulin, which exerts its anabolic action by reducing proteolysis.

scholarly journals Insulin-like Growth Factor I (IGF-I) Increases Whole Body Protein Synthesis in Contrast to Insulin Which Reduces Proteolysis

1994 ◽  
Vol 3 (Supple5) ◽  
pp. 240-240
Author(s):  
David L. Russell-Jones ◽  
Marlot A. Umpleby ◽  
Tom D. Hennessy ◽  
Peter H. Sonksen
Keyword(s):  
Protein Synthesis ◽  
Growth Factor ◽  
Whole Body ◽  
Insulin Like Growth Factor ◽  
Body Protein ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

scholarly journals Effect of long-term refeeding on protein metabolism in patients with cirrhosis of the liver

1997 ◽  
Vol 77 (2) ◽  
pp. 197-212 ◽  
Author(s):  
Jens Kondrup ◽  
Klaus Nielsen ◽  
Anders Juul
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Protein Degradation ◽  
Protein Metabolism ◽  
Cirrhosis Of The Liver ◽  
N Balance ◽  
Whole Body ◽  
Protein Requirement ◽  
Protein Utilization ◽  
Igf I

Patients with cirrhosis of the liver require an increased amount of protein to achieve N balance. However, the utilization of protein with increased protein intake, i.e. the slope from regression analysis of N balance v. intake, is highly efficient (Nielsen et al. 1995). In the present study, protein requirement and protein utilization were investigated further by measuring protein synthesis and degradation. In two separate studies, five or six patients with cirrhosis of the liver were refed on a balanced diet for an average of 2 or 4 weeks. Protein and energy intakes were doubled in both studies. Initial and final whole-body protein metabolism was measured in the fed state by primed continous [15N]glycine infusion. Refeeding caused a statistically significant increase of about 30% in protein synthesis in both studies while protein degradation was only slightly affected. The increase in protein synthesis was associated with significant increases in plasma concentrations of total amino acids (25%), leucine (58%), isoleucine (82%), valine (72%), proline (48%) and triiodothyronine (27%) while insulin, growth hormone, insulin-like growth factor (IGF)-I and IGF-binding protein-3 were not changed significantly. The results indicate that the efficient protein utilization is due to increased protein synthesis, rather than decreased protein degradation, and suggest that increases in plasma amino acids may be responsible for the increased protein synthesis. A comparison of the patients who had a normal protein requirement with the patients who had an increased protein requirement suggests that the increased protein requirement is due to a primary increase in protein degradation. It is speculated that this is due to low levels of IGF-I secondary to impaired liver function, since initial plasma concentration of IGF-I was about 25% of control values and remained low during refeeding.

Insulin-like growth factor I accelerates protein synthesis in skeletal muscle during sepsis

1995 ◽  
Vol 269 (5) ◽  
pp. E977-E981 ◽  
Author(s):  
C. V. Jurasinski ◽  
T. C. Vary
Keyword(s):  
Protein Synthesis ◽  
Growth Factor ◽  
Peptide Chain ◽  
Translational Efficiency ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin ◽  
Chain Initiation ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Sepsis causes an inhibition of protein synthesis in gastrocnemius that is resistant to the anabolic effects of insulin. The purpose of the present studies was to investigate the effect of recombinant human insulin-like growth factor I (IGF-I) on protein synthesis during a 30-min perfusion of the isolated rat hindlimb from septic rats. Inclusion of IGF-I (1 or 10 nM) in the perfusate stimulated protein synthesis in gastrocnemius of septic rats 2.5-fold and restored rates of protein synthesis to those observed in control rats. The stimulation of protein synthesis did not result from an increase in the RNA content but was correlated with a 2.5-fold increase in the translational efficiency. The enhanced translational efficiency was accompanied by a 33 and 55% decrease in the abundance of free 40S and 60S ribosomal subunits, respectively, indicating that IGF-I accelerated peptide-chain initiation relative to elongation/termination. These studies provide evidence that IGF-I can accelerate protein synthesis in gastrocnemius during chronic sepsis by reversing the sepsis-induced inhibition of peptide-chain initiation.

Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans

1991 ◽  
Vol 260 (3) ◽  
pp. E499-E504 ◽  
Author(s):  
D. A. Fryburg ◽  
R. A. Gelfand ◽  
E. J. Barrett
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Growth Hormone ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Igf I ◽  
Normal Humans

The short-term effects of growth hormone (GH) on skeletal muscle protein synthesis and degradation in normal humans are unknown. We studied seven postabsorptive healthy men (age 18-23 yr) who received GH (0.014 micrograms.kg-1.min-1) via intrabrachial artery infusion for 6 h. The effects of GH on forearm amino acid and glucose balances and on forearm amino acid kinetics [( 3H]Phe and [14C]Leu) were determined after 3 and 6 h of the GH infusion. Forearm deep vein GH rose to 35 +/- 6 ng/ml in response to GH, whereas systemic levels of GH, insulin, and insulin-like growth factor I (IGF-I) were unchanged. Forearm glucose uptake did not change during the study. After 6 h, GH suppressed forearm net release (3 vs. 6 h) of Phe (P less than 0.05), Leu (P less than 0.01), total branched-chain amino acids (P less than 0.025), and essential neutral amino acids (0.05 less than P less than 0.1). The effect on the net balance of Phe and Leu was due to an increase in the tissue uptake for Phe (71%, P less than 0.05) and Leu (37%, P less than 0.005) in the absence of any significant change in release of Phe or Leu from tissue. In the absence of any change in systemic GH, IGF-I, or insulin, these findings suggest that locally infused GH stimulates skeletal muscle protein synthesis. These findings have important physiological implications for both the role of daily GH pulses and the mechanisms through which GH can promote protein anabolism.

Effects of insulin-like growth factor-I, insulin, and leucine on protein turnover and ubiquitin ligase expression in rainbow trout primary myocytes

2010 ◽  
Vol 298 (2) ◽  
pp. R341-R350 ◽  
Author(s):  
Beth M. Cleveland ◽  
Gregory M. Weber
Keyword(s):  
Protein Synthesis ◽  
Rainbow Trout ◽  
Growth Factor ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Protein Turnover ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

The effects of insulin-like growth factor-I (IGF-I), insulin, and leucine on protein turnover and pathways that regulate proteolytic gene expression and protein polyubiquitination were investigated in primary cultures of 4-day-old rainbow trout myocytes. Supplementing media with 100 nM IGF-I increased protein synthesis by 13% ( P < 0.05) and decreased protein degradation by 14% ( P < 0.05). Treatment with 1 μM insulin increased protein synthesis by 13% ( P < 0.05) and decreased protein degradation by 17% ( P < 0.05). Supplementing media containing 0.6 mM leucine with an additional 2.5 mM leucine did not increase protein synthesis rates but reduced rates of protein degradation by 8% ( P < 0.05). IGF-I (1 nM–100 nM) and insulin (1 nM-1 μM) independently reduced the abundance of ubiquitin ligase mRNA in a dose-dependent manner, with maximal reductions of ∼70% for muscle atrophy F-box (Fbx) 32, 40% for Fbx25, and 25% for muscle RING finger-1 (MuRF1, P < 0.05). IGF-I and insulin stimulated phosphorylation of FOXO1 and FOXO4 ( P < 0.05), which was inhibited by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin, and decreased the abundance of polyubiquitinated proteins by 10–20% ( P < 0.05). Supplementing media with leucine reduced Fbx32 expression by 25% ( P < 0.05) but did not affect Fbx25 nor MuRF1 transcript abundance. Serum deprivation decreased rates of protein synthesis by 60% ( P < 0.05), increased protein degradation by 40% ( P < 0.05), and increased expression of all ubiquitin ligases. These data suggest that, similar to mammals, the inhibitory effects of IGF-I and insulin on proteolysis occur via P I3-kinase/protein kinase B signaling and are partially responsible for the ability of these compounds to promote protein accretion.

Effects of growth hormone and an antiserum to rat growth hormone on serum IGF-I and muscle protein synthesis and accretion in the rat

1993 ◽  
Vol 139 (3) ◽  
pp. 395-401 ◽  
Author(s):  
R. M. Palmer ◽  
D. J. Flint ◽  
J. C. MacRae ◽  
F. E. Fairhurst ◽  
L. A. Bruce ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Protein Synthesis ◽  
Protein Content ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Polyclonal Antiserum ◽  
Whole Body ◽  
Total Protein Content ◽  
Plantaris Muscle ◽  
Igf I

ABSTRACT Rats were injected twice daily for up to 10 days with GH or with a polyclonal antiserum to rat GH, commencing at 21–22 days of age. Administration of bovine or human GH (1 mg/day) improved whole body growth rates by 22% and 29% respectively. Plantaris muscle mass was also increased, by 7 and 14% respectively. Anti-GH injected twice daily resulted in a 7% decrease in body weight at 4 days and a 10% reduction by 10 days. Similar decreases were observed in the total protein content of plantaris and soleus muscles. The decrease in the fractional rate of protein synthesis was proportionately greater than the decline in protein content in plantaris muscle whereas in the soleus no change in the rate of protein synthesis was observed, suggesting that the effect on this muscle was due to an increase in the rate of protein degradation. Serum total IGF-I was unchanged by treatment with either GH or anti-GH while the amount of hepatic IGF-I mRNA was also unaffected by anti-GH injection. These data are consistent with a direct effect of GH or an effect mediated by an autocrine/paracrine mechanism of action on muscle but do not support a role for serum total IGF-I as an endocrine mediator of GH action. Journal of Endocrinology (1993) 139, 395–401

Passive immunization against circulating insulin-like growth factor-I (IGF-I) increases protein catabolism in lambs: evidence for a physiological role for circulating IGF-I

1992 ◽  
Vol 135 (2) ◽  
pp. 279-284 ◽  
Author(s):  
J. B. Koea ◽  
B. W. Gallaher ◽  
B. H. Breier ◽  
R. G. Douglas ◽  
S. Hodgkinson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Turnover ◽  
Passive Immunization ◽  
Physiological Role ◽  
Whole Body ◽  
Insulin Like Growth Factor ◽  
Protein Catabolism ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

ABSTRACT Primed constant infusions of [14C]urea were used to determine the acute effect of passive immunization against circulating free and protein-bound insulin-like growth factor-I (IGF-I) on the rate of net protein catabolism (NPC) in castrated male lambs fasted for 48 h. Following an intravenous bolus of 50 ml IGF-I antiserum, the rate of NPC increased to a peak 30 min after injection of 1·69 ± 0·16 g/kg per day from a baseline value of 1·45±0·22 g/kg per day (P<0·05, n = 4). In three animals given 50 ml equivalents of the purified immunoglobulin fraction, NPC increased from 1·31 ±0·20 to 1·59±0·16 g/kg per day (P<0·05). A similar trend was observed in animals given 25 ml antiserum (n = 4). The rate of NPC did not increase following a bolus of non-immune serum in control animals and the rate of NPC in the treated lambs returned to control levels within 60 min of antibody injection. Plasma insulin and glucose concentrations in both the treated and control groups were unchanged throughout the study. These data suggest that circulating IGF-I has a physiological role in regulating whole body protein turnover during starvation and possibly other catabolic states. The effect of immunoneutralization of circulating IGF-I is transient and this suggests that while IGF-I has an endocrine role in the regulation of protein turnover, other regulatory mechanisms are involved. Journal of Endocrinology (1992) 135, 279–284

IGF-I and insulin regulate eIF4F formation by different mechanisms in muscle and liver in the ovine fetus

2002 ◽  
Vol 283 (3) ◽  
pp. E593-E603 ◽  
Author(s):  
Weihua Shen ◽  
Daniel Mallon ◽  
David W. Boyle ◽  
Edward A. Liechty
Keyword(s):  
Insulin Infusion ◽  
Protein Kinase B ◽  
Initiation Factor ◽  
Regulatory Mechanisms ◽  
S6 Kinase ◽  
Akt Phosphorylation ◽  
Factor I ◽  
Igf I ◽  
Ovine Fetus ◽  
Kinase Pathway

The mechanisms by which insulin-like growth factor I (IGF-I) and insulin regulate eukaryotic initiation factor (eIF)4F formation were examined in the ovine fetus. Insulin infusion increased phosphorylation of eIF4E-binding protein (4E-BP1) in muscle and liver. IGF-I infusion did not alter 4E-BP1 phosphorylation in liver. In muscle, IGF-I increased 4E-BP1 phosphorylation by 27%; the percentage in the γ-form in the IGF-I group was significantly lower than that in the insulin group. In liver, only IGF-I increased eIF4G. Both IGF-I and insulin increased eIF4E · eIF4G binding in muscle, but only insulin decreased the amount of 4E-BP1 associated with eIF4E. In liver, only IGF-I increased eIF4E · eIF4G binding. Insulin increased the phosphorylation of p70 S6 kinase (p70S6k) in both muscle and liver and protein kinase B (PKB/Akt) in muscle, two indicative signal proteins in the phosphatidylinositol (PI) 3-kinase pathway. IGF-I increased PKB/Akt phosphorylation in muscle but had no effect on p70S6k phosphorylation in muscle or liver. We conclude that insulin and IGF-I modulate eIF4F formation; however, the two hormones have different regulatory mechanisms. Insulin increases phosphorylation of 4E-BP1 and eIF4E · eIF4G binding in muscle, whereas IGF-I regulates eIF4F formation by increasing total eIF4G. Insulin, but not IGF-I, decreased 4E-BP1 content associated with eIF4E. Insulin regulates translation initiation via the PI 3-kinase-p70S6kpathway, whereas IGF-I does so mainly via mechanisms independent of the PI 3-kinase-p70S6k pathway.

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