Recombinant human insulin-like growth factor-I enhances whole body protein anabolism and significantly diminishes the protein catabolic effects of prednisone in humans without a diabetogenic effect.

To investigate whether recombinant human insulin-like growth factor-I (rhIGF-I) could serve as a protein-sparing nondiabetogenic agent, 21 healthy volunteers (mean age, 25 +/- 1 yr) were studied in 3 similar clinical models: rhIGF-I alone, rhIGF-I and prednisone, and prednisone alone. In study A, 6 subjects received infusions of [14C]leucine and [2H2]glucose before and after 5-7 days of rhIGF-I (100 micrograms/kg, sc, twice daily, followed by 16 h of a 10 micrograms/kg.h continuous sc infusion). The rate of appearance (Ra) of leucine, an estimate of whole body proteolysis, did not change significantly, whereas leucine oxidation decreased (-31 +/- 4%; P = 0.001), hence the nonoxidative leucine disposal (NOLD) increased significantly (P = 0.04). These effects are similar to those reported with high dose hGH. Plasma glucose concentrations did not change despite a significant reduction in circulating insulin concentrations (-58 +/- 11%; P = 0.01) and an increase in the glucose Ra (+12 +/- 5%; P = 0.04). After rhIGF-I treatment, plasma IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-2 all increased significantly, whereas IGFBP-3 did not change. In study B, seven subjects received rhIGF-I combined with oral prednisone (0.8 mg/kg.day) for 5 days. Group C (n = 8) received only prednisone. In group B, both the leucine Ra and oxidation increased (Ra, +7 +/- 3%; oxidation, +45 +/- 13%), but this increase was significantly less than that seen in group C (Ra, +25 +/- 5%; oxidation, 117 +/- 17%; P < 0.005 vs. group B). Group B showed no significant changes in postabsorptive glucose concentrations despite marked reductions in circulating insulin levels, in contrast to the increase in insulin and glucose concentrations observed in group C. In conclusion, 100 micrograms/g rhIGF-I, given twice daily, 1) has GH-like effects on whole body protein metabolism, 2) markedly diminishes the protein catabolic effect of glucocorticosteroids, and 3) is nondiabetogenic in prednisone-treated humans. This agent offers promise in the treatment of protein catabolic states.

[1]  J. Christiansen,et al.  Insulin-like growth factor I stimulates lipid oxidation, reduces protein oxidation, and enhances insulin sensitivity in humans. , 1993, The Journal of clinical investigation.

[2]  U. Keller,et al.  Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in humans. , 1993, The Journal of clinical investigation.

[3]  S. E. Knowles,et al.  Anabolic effects of insulin-like growth factor-I (IGF-I) and an IGF-I variant in normal female rats. , 1993, The Journal of endocrinology.

[4]  R. Baxter,et al.  Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. , 1993, The Journal of clinical investigation.

[5]  J. H. Shaw,et al.  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, The Journal of endocrinology.

[6]  F. A. Kenney,et al.  Heated dorsal hand vein sampling for metabolic studies: a reappraisal. , 1992, The American journal of physiology.

[7]  U. Keller,et al.  Effect of increasing doses of recombinant human insulin-like growth factor-I on glucose, lipid, and leucine metabolism in man. , 1992, The Journal of clinical endocrinology and metabolism.

[8]  F. Horber,et al.  Low dose recombinant human insulin-like growth factor-I fails to affect protein anabolism but inhibits islet cell secretion in humans. , 1992, The Journal of clinical endocrinology and metabolism.

[9]  A. Suikkari,et al.  Growth hormone and insulin-like growth factor regulate insulin-like growth factor-binding protein-1 in Laron type dwarfism, growth hormone deficiency and constitutional short stature. , 1992, Acta endocrinologica.

[10]  P. Wilton.  Treatment with recombinant human insulin-like growth factor I of children with growth hormone receptor deficiency (Laron syndrome). Kabi Pharmacia Study Group on Insulin-like Growth Factor I Treatment in Growth Hormone Insensitivity Syndromes. , 1992, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[11]  J. H. Shaw,et al.  Synergistic effect of insulin-like growth factor-I administration on the protein-sparing effects of total parenteral nutrition in fasted lambs. , 1992, Endocrinology.

[12]  R. Horikawa,et al.  Effects of insulin-like growth factor I or human growth hormone in fasted rats. , 1992, Growth regulation.

[13]  S. E. Knowles,et al.  Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats. , 1992, The Biochemical journal.

[14]  D. Clemmons,et al.  Variables controlling the secretion of insulin-like growth factor binding protein-2 in normal human subjects. , 1991, The Journal of clinical endocrinology and metabolism.

[15]  J. H. Shaw,et al.  The effects of infusion of insulinlike growth factor (IGF) I, IGF-II, and insulin on glucose and protein metabolism in fasted lambs. , 1991, The Journal of clinical investigation.

[16]  L. Underwood,et al.  Effects of the infusion of insulin-like growth factor I in a child with growth hormone insensitivity syndrome (Laron dwarfism). , 1991, The New England journal of medicine.

[17]  F. Horber,et al.  Differential Effects of Prednisone and Growth Hormone on Fuel Metabolism and Insulin Antagonism in Humans , 1991, Diabetes.

[18]  D. Clemmons.  Insulinlike growth factor binding proteins , 1990, Trends in Endocrinology & Metabolism.

[19]  F. Horber,et al.  Human growth hormone prevents the protein catabolic side effects of prednisone in humans. , 1990, The Journal of clinical investigation.

[20]  F. Horber,et al.  Glucocorticosteroids increase leucine oxidation and impair leucine balance in humans. , 1989, The American journal of physiology.

[21]  F. Horber,et al.  Plasma reciprocal pool specific activity predicts that of intracellular free leucine for protein synthesis. , 1989, The American journal of physiology.

[22]  D. Clemmons,et al.  Radioimmunoassay of a 26,000-dalton plasma insulin-like growth factor-binding protein: control by nutritional variables. , 1988, The Journal of clinical endocrinology and metabolism.

[23]  D. Waters,et al.  Body composition response to exogenous GH during training in highly conditioned adults. , 1988, Journal of applied physiology.

[24]  D. Clemmons,et al.  Treatment of obese, diet-restricted subjects with growth hormone for 11 weeks: effects on anabolism, lipolysis, and body composition. , 1988, The Journal of clinical endocrinology and metabolism.

[25]  E. Froesch,et al.  Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. , 1987, The New England journal of medicine.

[26]  M. Haymond,et al.  Changes in leucine kinetics during meal absorption: effects of dietary leucine availability. , 1986, The American journal of physiology.

[27]  D. Matthews,et al.  Insulin-mediated reduction of whole body protein breakdown. Dose-response effects on leucine metabolism in postabsorptive men. , 1985, The Journal of clinical investigation.

[28]  B. Beaufrère,et al.  Use of reciprocal pool specific activities to model leucine metabolism in humans. , 1985, The American journal of physiology.

[29]  M. Haymond,et al.  Effects of ketosis on glucose flux in children and adults. , 1983, The American journal of physiology.

[30]  E. Schoenle,et al.  Insulin-like growth factor I stimulates growth in hypophysectomized rats , 1982, Nature.

[31]  D. Kipnis,et al.  Measurement of “True” Glucose Production Rates in Infancy and Childhood with 6,6-Dideuteroglucose , 1977, Diabetes.

[32]  K. Mashimo,et al.  A Simple Method for the Determination of Serum Free Insulin Levels in Insulin-treated Patients , 1973, Diabetes.

[33]  W. Tamborlane,et al.  Diverse effects of insulin-like growth factor I on glucose, lipid, and amino acid metabolism. , 1992, The American journal of physiology.

[34]  F. Horber,et al.  Determination of leucine and alpha-ketoisocaproic acid concentrations and specific activity in plasma and leucine specific activities in proteins using high-performance liquid chromatography. , 1989, Journal of chromatography.