Body Protein Metabolism Research Articles

Metabolic actions of growth hormone in man.

GH continues to be produced after the cessation of childhood growth and is the most abundant pituitary hormone in the adult pituitary. There is strong evidence that GH continues to exert significant biological effects on body metabolism in adult humans. The actions of GH may be direct or indirectly mediated by IGF-1. The direct actions of GH impart major effects on glucose, lipid and sodium homeostasis. GH administration causes hyperinsulinaemia and impairs the ability of insulin to suppress hepatic glucose production and to stimulate glucose uptake and oxidation. GH enhances fat utilisation by stimulating lipolysis and fat oxidation. The significance of these effects is reflected in the finding of increased adiposity in GH deficiency (GHD) and reduced fat mass in acromegaly. GH causes sodium retention which occurs in part through activation of the renin-angiotensin system. Extracellular water volume is diminished in GHD and increased in relation to the extent of GH excess in acromegaly. Lean body mass is reduced in GHD and restored by GH treatment. The anabolic actions of GH are mediated by IGF-1. Studies of whole body protein metabolism show that this occurs through the stimulation of protein synthesis, reduction in protein oxidation but not inhibition of protein breakdown. GH plays an important role in the regulation of substrate metabolism and body composition in man.

Resting metabolic rate and protein turnover in apparently healthy elderly Gambian men

Body composition, resting energy expenditure (REE), and whole body protein metabolism were studied in 26 young and 28 elderly Gambian men matched for body mass index during the dry season in a rural village in The Gambia. REE was measured by indirect calorimetry (hood system) in the fasting state and after five successive meals. Rates of whole body nitrogen flux, protein synthesis, and protein breakdown were determined in the fed state from the level of isotopic enrichment of urinary ammonia over a period of 12 h after a single oral dose of [15N]glycine. Expressed in absolute value, REE was significantly lower in the elderly compared with the young group (3.21 +/- 0.07 vs. 4.04 +/- 0.07 kJ/min, P < 0.001) and when adjusted to body weight (3.29 +/- 0.05 vs. 3.96 +/- 0.05 kJ/min, P < 0.0001) and fat-free mass (FFM; 3.38 +/- 0.01 vs. 3.87 +/- 0.01 kJ/min, P < 0.0001). The rate of protein synthesis averaged 207 +/- 13 g protein/day in the elderly and 230 +/- 13 g protein/day in the young group, whereas protein breakdown averaged 184 +/- 13 g protein/day in the elderly and 203 +/- 13 g protein/day in the young group (nonsignificant). When values were adjusted for body weight or FFM, they did not reveal any difference between the two groups. It is concluded that the reduced REE adjusted for body composition observed in elderly Gambian men is not explained by a decrease in protein turnover.

The effects of a new amino-acid dipeptide solution on nitrogen balance and humoral growth factors in the postoperative state in man

27 patients admitted for elective abdominal surgery were allocated to receive postoperative total parenteral nutrition supplemented with glutamine (glycyl-glutamine) and tyrosine (glycyl-tyrosine) containing dipeptides (DP-Gln 20; 0.16 g glutamine/kg BW/24 h) or isonitrogenous Vamin 18 for 5 days. The aim was to evaluate safety and effects on short-life plasma proteins, nitrogen balance, 3-methylhistidine excretion and alimentary growth factors in plasma. No differences in transthyretin or retinol binding protein levels, nitrogen balance or 3-methylhistidine excretion were found in patients receiving DP-Gln 20 compared to Vamin 18. There were higher plasma levels of peptide YY in the dipeptide group 5 days after surgery (p < 0.05). A correlation between insulin levels and nitrogen balance was found only in DP-Gln 20 treated patients day 6 (r = 0.91, p < 0.01). DP-Gln 20 is a glutamine dipeptide (Gly-Gln) containing amino acid solution which is considered safe in the postoperative state in man. No beneficial effects on whole body protein metabolism were found by adding DP-Gln 20 to total parenteral nutrition.

Rates of albumin and fibrinogen synthesis and whole body protein and carbohydrate metabolism return to normal within two weeks after liver transplantation

Rates of albumin and fibrinogen synthesis and whole body protein and carbohydrate metabolism return to normal within two weeks after liver transplantation

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.

Effect of prednisone on protein metabolism in Duchenne dystrophy

Prednisone improves strength in Duchenne dystrophy and changes the natural history of the disease. We studied the in vivo effects of prednisone (0.75 mg.kg-1.day-1) on muscle and whole body protein metabolism in six patients with Duchenne dystrophy and three patients with Becker dystrophy. Patients were admitted to the Clinical Research Center for study and consumed a constant flesh-free diet. Strength was measured by manual and quantitative muscle testing. Fractional muscle protein breakdown was estimated by the ratio of 3-methylhistidine to creatinine excretion determined in three consecutive 24-h urine collections. Whole body protein kinetics were studied in the postabsorptive state using a primed continuous infusion of L-[1-13C]leucine. Fractional muscle protein synthesis was determined from tracer incorporation into noncollagen muscle protein obtained by needle biopsy. After 6-8 wk of prednisone treatment, average muscle strength increased by 15% (P < 0.04), and 24-h creatinine excretion (an index of muscle mass) increased by 21% (P = 0.002). 3-Methylhistidine excretion decreased by 10%, but the change was not statistically significant. The ratio of 3-methylhistidine to creatinine excretion decreased by 26% (P < 0.04). Fractional muscle protein synthesis and whole body protein synthesis and breakdown did not change significantly. We conclude that the beneficial effect of prednisone on strength in Duchenne dystrophy appears to be associated with an increase in muscle mass, which may be mediated by inhibition of muscle proteolysis rather than stimulation of muscle protein synthesis.

Insulin, Cortisol and Thyroid Hormones Modulate Maternal Protein Status and Milk Production and Composition in Humans

AbstractThe partitioning of dietary and endogenous nutrients during lactation is not well understood. To examine associations between plasma hormone and substrate profiles and indices of either maternal body protein metabolism or lactational performance, we measured plasma insulin, cortisol, prolactin, thyroxine, triiodothyronine, individual amino acid, blood urea nitrogen, and prealbumin concentrations in lactating and nulliparous women in the postabsorptive state. We related these measurements to the subjects' nitrogen balance, urinary 3-methylhistidine excretion, [1-13C]leucine metabolism and milk production. Insulin concentrations showed significant positive relationships with nitrogen balance and prealbumin concentrations; cortisol levels showed a significant negative relationship with nitrogen balance and a significant positive relationship with leucine incorporation into protein. Thyroid hormone concentrations showed significant positive relationships with urinary 3-methylhistidine excretion, leucine incorporation into protein, and milk production. Proline concentrations were associated positively with nitrogen balance and negatively with leucine incorporation into protein, whereas glutamate-glutamine concentrations showed positive associations with leucine oxidation and milk nitrogen concentrations. We propose that insulin and cortisol modulate the channeling of nutrients between anabolic and anti-anabolic aspects of maternal body protein metabolism, whereas thyroid hormones and cortisol modulate nutrient partitioning toward milk production and visceral protein synthesis. We suggest that some nonessential amino acids (proline, glutamate-glutamine) may become limiting during lactation because of their unique contributions to milk protein synthesis

Lymphocyte Protein Synthesis In Vivo: a Measure of Activation

1. The 'flooding' dose technique was used to measure rates of lymphocyte protein synthesis after infusion of [1-13C]leucine (20 atoms % enrichment, 4 g/70 kg body weight). Lymphocyte protein synthesis was measured in healthy subjects and in patients with metastatic colorectal cancer before and during infusion of recombinant interleukin-2. Rates of protein synthesis were compared with thymidine uptake in vitro and phenotypic analysis of lymphocytes. 2. The median rate of lymphocyte protein synthesis in four healthy subjects was 9% (range 7.2-11.4%/day) and in seven patients with colorectal cancer was 6.4% (range 4.2-8.2%/day). After recombinant interleukin-2 treatment the median rate of lymphocyte protein synthesis was 27.8% (range 25.2-33.7%/day). 3. The increased rates of lymphocyte protein synthesis in vivo, after recombinant interleukin-2 infusion, corresponded with increased rates of thymidine uptake and changes in the phenotypic expression of lymphocytes, but these were less consistent than the measured rates of protein synthesis. 4. It is concluded that lymphocyte activation is accompanied by a marked increase in lymphocytic protein synthesis which may have important implications for whole body protein metabolism. Furthermore, measurement of lymphocyte protein synthesis may provide a determination of lymphocyte activation in vivo.

Acute growth hormone effects on amino acid and lipid metabolism.

The anabolic actions of GH are well known, although specific tissue responses and the mechanism of nitrogen conservation are less well understood. This study was designed to examine the acute metabolic effects of GH on whole body and regional protein metabolism, using an experimental protocol which controlled for confounding perturbations in other hormones by a simultaneous infusion of somatostatin. Control subjects received replacement doses of insulin, glucagon, and GH for the entire 7-h study period, whereas GH subjects received an identical protocol, except for an increased dose of GH sufficient to increase serum concentrations into the high-physiological range (12-20 ng/mL) for the final 3.5 h of the study (P < 0.001). Thirteen young, healthy male subjects were studied in the postabsorptive period; five served as control subjects and eight as treatment (GH) subjects. Each received continuous iv infusions of somatostatin, L-[13-C]leucine, and L-[2H5]phenylalanine throughout the study. Femoral arterial and venous sampling allowed for simultaneous measurements across the leg and in the whole body. C-Peptide levels were suppressed throughout the infusion; insulin, glucagon, insulin-like growth factor I, cortisol, epinephrine, norepinephrine, and glucose concentrations were not different between groups. Glycerol concentrations increased 3-fold in GH subjects during the final 3.5-h period (P = 0.04). Concentrations of several amino acids declined through the study, but no differences were observed between treatment groups. Leucine oxidation was reduced in GH compared to control subjects (P = 0.04). No changes in CO2 production or whole body leucine or phenylalanine flux were observed, whereas nonoxidative disposal of leucine was marginally higher in GH compared to control subjects (P = 0.07). By contrast, rates of appearance and disappearance of both leucine and phenylalanine across the leg all were relatively lower in GH compared to control subjects; leucine balance across the leg was reduced by GH (P = 0.03), whereas phenylalanine balance was not influenced by GH. Our data thus demonstrate an acute stimulatory effect of GH on lipolysis, a decrease in leucine oxidation, and no stimulation of muscle protein synthesis in spite of enhanced protein synthesis in nonmuscle tissue.

Effect of lanreotide, a somatostatin analogue, on urea synthesis in normal man

The aim was to investigate the effect of lanreotide (Angiopeptin) on urea synthesis. Lanreotide is a somatostatin analogue used in therapy trials of certain cancers. Cancer patients are often protein catabolic, thus the effect of lanreotide on whole body protein metabolism is of importance. We investigated the effect of lanreotide by measuring urea nitrogen synthesis rate (UNSR) and blood α-amino nitrogen levels before, during and after a 30 min iv infusion of 25 g of an electrolyte-free amino acid solution. 6 healthy male subjects were studied following, i) placebo (saline), ii) lanreotide 5 μg/kg, and iii) lanreotide 80 μg/kg. Lanreotide decreased urea nitrogen synthesis rate (mmol/h) during amino acid infusion significantly compared to saline, independent of dose of lanreotide (max ± SE of urea nitrogen synthesis rate measurements in each study: 117 ± 8 mmol/h (saline), 85 ± 10 mmol/h (high dose) and 85 ± 12 mmol/h (low dose)). This occurred in spite of significantly higher plasma α-amino nitrogen following lanreotide (peak ± SE of α-amino nitrogen level in each study: 3.7 ± 0.1 mmol/l placebo versus 4.8 ± 0.2 mmol/l low dose and 4.7 ± 0.4 mmol/l high dose (p < 0.01). We conclude that a single dose of lanreotide decreases whole body urea nitrogen synthesis rate thereby conserving body protein. The results indicate that long term lanreotide therapy may not lead to further protein catabolism in cancer patients.

Dietary intake of adolescents with Crohn's disease

The adolescent years are characterized by a dramatic increase in height and the development of secondary sexual characteristics. Severe impairment of linear growth, retarded skeletal maturation, and delayed sexual development occur in an estimated 5% to 10% of pediatric patients with ulcerative colitis and 25% of pediatric patients with Crohn's disease ( 1. Kelts DG Grand RJ Shen G Watkins JB Werlin SL Boehme C Nutritional basis of growth failure in children and adolescent with Crohn's disease. Gastroenterology. 1979; 76: 720-727 Google Scholar , 2. Kirschner BS Sutton MM Somatomedin C levels in growth impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology. 1986; 91: 830-836 Google Scholar , 3. Motil KJ Grand RJ Matthews DE Bier DM Maletskos CJ Young VR Whole body leucine metabolism in adolescents with Crohn's disease and growth failure during nutritional supplementation. Gastroenterology. 1982; 82: 1359-1368 Google Scholar , 4. Motil KJ Grand RJ Maletskos CJ Young VR The effect of disease, drug and diet on whole body protein metabolism in adolescents with Crohn's disease and growth failure. J Pediatr. 1982; 101: 345-351 Google Scholar , 5. Belli DC Seidman E Bouthillier L Weber AM Roy CC Pletinex M Beaulieu M Morin CL Chronic intermittent elemental diet improves growth failure in children with Crohn's disease. Gastroenterology. 1988; 94: 603-610 Google Scholar ). Although the pathogenesis is influenced by age at onset, duration of disease, disease activity, and medication, chronic undernutrition is considered a major cause of growth failure in children with Crohn's disease ( 6. Kleinman RE Balisteri WF Heyman MB Kirschner BS Lake AM Motil KJ Seidman E Udall JN Nutritional support for pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1989; 8: 8-12 Google Scholar , 7. Seidman E LeLeiko N Ament M Berman W Caplan D Evans J Kocoshis S Lake A Motil K Sutphen J Thomas D Nutritional issues in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1991; 12: 424-438 Google Scholar ). The nutritional basis of growth failure is thought to be multifactorial; some of the factors are decreased dietary intake, increased intestinal losses, and malabsorption.

Effect of NIDDM on the kinetics of whole-body protein metabolism.

We postulated that dietary protein utilization and body protein metabolism are altered in hyperglycemic individuals with non-insulin-dependent diabetes mellitus (NIDDM). This was tested by estimating the kinetics of protein metabolism in obese NIDDM patients in the hyperglycemic state of isoenergetic feeding and in the normoglycemic state induced by the prolonged use of a very-low-energy diet (VLED) and comparing them with results in obese nondiabetic subjects studied previously. Seven obese subjects with NIDDM (one male, six females, body mass index = 35.8 +/- 2.0 kg/m2) were given a 1.7 MJ (410 kcal) all protein (93 g/day) diet derived from hydrolyzed collagen and supplemented with tryptophan and methionine, which provides 16% of its amino acids as essential, a multivitamin and mineral supplement, and 16 mmol KCl for 42 days. During the seven-day isoenergetic diet and at weeks 4 and 6 of the VLED, amino nitrogen (N) flux rate was calculated from the urine [15N]urea enrichment by using the 60-h oral [15N]glycine method to obtain the integrated feeding-fasting metabolism. Rates of synthesis (S) and breakdown (B) were calculated from N flux. At day 7 of the isoenergetic diet, whole-body N flux, S, B, and resting metabolic rate (RMR) were 12-24% greater (P < 0.05) in the NIDDM subjects than observed in nondiabetic obese subjects. Mean plasma glucose decreased (P < 0.05) from the isoenergetic period (14.9 +/- 2.4 mM) to 7.2 +/- 1.2 mM at week 4 and 6.5 +/- 1.1 mM at week 6 of the VLED. RMR declined progressively by 25% at week 5 of the VLED. Corresponding significant (P < 0.05) decreases from isoenergetic feeding to weeks 4 and 6 of the VLED occurred in whole-body N flux (from 51 +/- 2 to 42 +/- 1 g N/day), in S (from 38 +/- 3 to 24 +/- 1 g N/day), and in B (from 39 +/- 3 to 26 +/- 1 g N/day) resulting in net losses (S-B). S-B was significantly more negative (P < 0.05) in NIDDM than in the nondiabetic obese subjects at week 4 (-1.5 +/- 0.5 vs. 0.9 +/- 0.3 g N/day) but not at week 6 (-1.3 +/- 0.4 vs. -0.9 +/- 4 g N/day). During the VLED, N balance became less negative with time but never reached equilibrium in NIDDM. Thus, abnormal protein metabolism is present in NIDDM in the isoenergetic fed state with moderate hyperglycemia and persists during a VLED that restores glycemia to near normal.

Effects of endotoxin on leucine and glucose kinetics in man: contribution of prostaglandin E2 assessed by a cyclooxygenase inhibitor.

The effects of endotoxin (E) administration on whole body protein and glucose metabolism were studied in normal volunteers. Injection of 4 ng/kg Escherichia coli E iv resulted in a relative increase in leucine flux (1-13C-leucine infusion technique) compared to controls [+0.12 +/- 0.10 vs. -0.45 +/- 0.23 mumol/kg.min after 360 min, P = 0.028, analysis of variance (ANOVA)], indicating increased proteolysis. Nonoxidative leucine flux was higher after E than after saline administration (0.08 +/- 0.11 vs. -0.47 +/- 0.18 mumol/kg.min, P = 0.007, ANOVA), suggesting increased amino acid incorporation into proteins. E caused a transient decrease of plasma glucose concentration (by 0.5 +/- 0.1 mmol/L after 150 min; P < 0.004 vs. saline controls) due to a relative increase in disappearance compared to appearance of glucose (6,6 D2-glucose infusion technique). These alterations were associated with increases in plasma concentrations of ACTH, beta-lipoprotein (beta-LPH), GH, cortisol, epinephrine, free fatty acid, beta-hydroxybutyrate, and decreases of plasma insulin. Pretreatment with ibuprofen, a cyclooxygenase inhibitor, blunted the effects of E on whole body leucine flux (P < 0.05 vs. E) and on nonoxidative leucine flux (P < 0.05 vs. E) but enhanced the E-induced decrease of plasma glucose concentration (P < 0.004 vs. E), due to a relative increase in glucose disappearance compared to appearance (P = 0.02). The increases in counterregulatory hormones (ACTH, beta-LPH, GH, cortisol, epinephrine) were also attenuated by ibuprofen. Thus, acute endotoxinemia results in a redistribution of whole body proteins due to an increase in both protein breakdown and amino acid incorporation into proteins and in decreased plasma glucose concentrations. The ibuprofen data suggested that these effects of E on leucine kinetics, but not on glucose metabolism, were prostaglandin E2-mediated.

EFFECTS OF SEX STEROIDS ON PROTEIN AND CALCIUM METABOLISM IN THE PREPUBERTAL HUMAN

Androgenic steroids participate in the acceleration of linear growth and increase in muscle mass during the transformation from the prepubertal to the pubertal man. To determine the acute changes in whole body protein and calcium (Ca) metabolism in the prepubertal human, we studied 6 healthy prepubertal boys (mean age:13±1 yrs) in the post absorptive state using a primed 4 hour infusion of [1-13C] leucine and the reciprocal pool model. Concomitantly, bone turnover was assessed by administering dual tracers of Ca, 42Ca 1v, 44Ca P.O., and measuring the Ca isotopic enrichments in blood & urine samples. Testosterone (T) enanthate (100 mg IM) was given 2 wks apart and patients studied again within 4 days of last injection. Mean [T] rose from 11±6 ng/dL to 843±125 and weight from 36.8±6.0 kg to 39.1±6.2 after T therapy. The rate of appearance of leucine (an indicator of proteolysis) was 1.66±.24 μMol/kg.min and increased to 1.98±.29 after T therapy, p=.08. Leucine oxidation decreased from 0.25±.04 μMol/kg.min to 0.13±.02, p=.017; thus the non oxidative leucine disappearance, which estimates protein synthesis, also Increased significantly from 1.41±.21 μMol/kg.min to 1.85±.27, p=.033. Kinetic studies on 2 subjects showed that all indicators of bone turnover (Vt), accretion (Vo+) and resorption (Vo−) showed an increase by approximately 30% after T therapy. These results demonstrate for the first time that short term acute administration of testosterone increases whole body estimates of protein turnover and anabolism and concomitantly increases Ca and bone turnover in the prepubertal human.

Species Comparisons of Tissue Protein Metabolism: Effects of Age and Hormonal Action

Ontogenic responses in whole body and tissue protein metabolism are compared between ruminants and nonruminants. In sheep and cattle, the liver makes a smaller contribution to body protein mass and synthesis but is more responsive to age and nutrition than in the rodent. Protein synthesis increases within the gastrointestinal tract (to > 25% of total whole body protein synthesis) during the weaning phase in sheep and rats and in both species is sensitive to nutritional state. Protein synthesis in skin is also sensitive to intake but the sheep has a slower ontogenic decline compared with rats. Translational efficiency (g protein synthesis.d-1.g RNA-1) is unchanged for ovine muscle during the transition from the milk-fed to weaned state but is lower for the suckling rat. In contrast, in growing ruminants muscle translational efficiency decreases, whereas for the rat it is maintained. In young rodents, muscle protein synthesis is sensitive to nutrition and insulin, but the latter has little effect in sheep or indeed in nongrowing adult rats and humans. In ruminants the chronic response in muscle protein synthesis to intake may be exerted through the growth hormone and insulin-like growth factor 1 axis, although conclusive proof is lacking.

Effect of Human Growth Hormone and Insulin-Like Growth Factor I on Whole-Body Leucine and Estimates of Protein Metabolism

Recombinant human growth hormone (rhGH) administration to normal volunteers increases estimates of whole-body and forearm protein synthesis but has little effect on rates of proteolysis in both the postabsorptive state and during meal absorption. In contrast, insulin decreases estimates of whole-body and forearm proteolysis while decreasing or, in the presence of infused (or ingested) amino acids, sustaining estimates of protein synthesis. We have used high-dose prednisone as a controlled model for protein catabolism in normal volunteers and demonstrated that glucocorticosteroids increase estimates of whole-body proteolysis and the oxidation of leucine with little or no effect on estimates of whole-body protein synthesis. We have recently demonstrated that high-dose rhGH together with prednisone prevents the protein-catabolic effects observed with treatment with prednisone alone, while inducing insulin resistance and increased secretion of proinsulin. GH is thought to mediate its effects via the generation of insulin-like growth factor I (IGF-I). However, high rates of infusion of rhIGF-I induce hypoglycemia and decrease estimates of whole-body proteolysis and suppress the secretion of GH, insulin and glucagon, suggesting a predominant insulin-like effect on protein and glucose metabolism. When rhIGF-I is infused at a rate that achieves plasma IGF-I concentrations similar to those observed during rhGH treatment and yet avoids hypoglycemia, estimates of proteolysis and protein synthesis were not affected in the absence or presence of prednisone treatment. When rhGH and rhIGF-I are administered simultaneously, nitrogen balance is remarkably improved. Thus, the mechanism of action of both rhGH and/or rhIGF-I on body protein metabolism remains to be elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

Low dose recombinant human insulin-like growth factor-I fails to affect protein anabolism but inhibits islet cell secretion in humans.

The in vivo effects of recombinant human insulin-like growth factor-I (rhIGF-I) on whole body protein metabolism were studied to ascertain whether rhIGF-I has comparable effects as those reported with rhGH use in humans. The doses of rhIGF-I chosen achieved similar plasma IGF-I concentrations as those achieved after 7 days of rhGH injections. Eight normal volunteers were studied using [1-13C]- and [1-14C]leucine tracers, before, 4 h, and 28 h after a continuous infusion of rhIGF-I at 5 micrograms kg-1 h-1 (n = 6) and 10 micrograms kg-1 h-1 (n = 2). Two additional subjects were studied in a protein catabolic state after 7 days of high dose (0.8 mg kg-1 day-1) glucocorticosteroid administration. Plasma concentrations of rhIGF-I were similar using either 5 or 10 micrograms kg-1 h-1 and increased to values approximately 300% above baseline by 28 h of infusion. No decrease in the plasma glucose concentration was observed during the 28-h infusion; however, plasma insulin, C-peptide, and glucagon concentrations significantly decreased, whereas plasma free fatty acids were not affected. No changes were observed in the rate of proteolysis (as estimated by the rate of leucine appearance), the rate of leucine oxidation, or the rate of protein synthesis in the absence or presence of glucocorticosteroid treatment. Plasma concentrations of insulin-like growth factor binding protein-3 did not change during the rhIGF-I infusion whereas they increased 50% in subjects who received rhGH, and in whom rhGH caused a potent protein anabolic effect. These results suggest that rhIGF-I may have a somatostatin-like effect. In addition, we found that rhIGF-I infusion is insufficient to promote protein anabolism. This may be due to the failure of rhIGF-I alone to induce a pivotal GH-dependent cofactor(s) necessary for IGF-I to elicit an anabolic effect on protein metabolism in humans.

Leucine as a regulator of whole body and skeletal muscle protein metabolism in humans.

Leucine has been proposed as an in vivo regulator of protein metabolism, although the evidence for this in humans remains inconclusive. To test this hypothesis, we infused either L-leucine (154 +/- 1 mumol.kg-1 x h-1) or saline intravenously in six healthy men in two separate studies. L-Leucine infusion increased plasma concentrations of leucine and alpha-ketoisocaproate from 112 +/- 6 and 38 +/- 3 mumol/l to 480 +/- 27 (P < 0.001) and 94 +/- 13 mumol/l (P < 0.001), respectively, without any significant change in circulating insulin or C peptide levels. Leucine infusion decreased plasma concentrations of several amino acids and decreased whole body valine flux and valine oxidation (using L-[1-13C]valine as a tracer) and phenylalanine flux (using [2H5]-phenylalanine as a tracer). According to arteriovenous differences across the leg, the net balance of phenylalanine, valine, and lysine shifted toward greater retention during leucine infusion, whereas alanine balance did not change. Valine release and phenylalanine release from the leg (estimated from the dilution of respective tracers) decreased, indicating inhibition of protein degradation by leucine infusion. We conclude that leucine decreases protein degradation in humans and that this decreased protein degradation during leucine infusion contributes to the decrease in plasma essential amino acids. This study suggests a potential role for leucine as a regulator of protein metabolism in humans.

Whole body protein metabolism and resting energy expenditure in pregnant Gambian women

Whole body protein metabolism and resting energy expenditure (REE) were measured at 11, 23, and 33 wk of pregnancy in nine pregnant (not malnourished) Gambian women and in eight matched nonpregnant nonlactating (NPNL) matched controls. Rates of whole body nitrogen flux, protein synthesis, and protein breakdown were determined in the fed state from the level of isotope enrichment of urinary urea and ammonia during a period of 9 h after a single oral dose of [15N]glycine. At regular intervals, REE was measured by indirect calorimetry (hood system). Based on the arithmetic end-product average of values obtained with urea and ammonia, a significant increase in whole body protein synthesis was observed during the second trimester (5.8 +/- 0.4 g.kg-1.day-1) relative to values obtained both for the NPNL controls (4.5 +/- 0.3 g.kg-1.day-1) and those during the first trimester (4.7 +/- 0.3 g.kg-1.day-1). There was a significant rise in REE during the third trimester both in the preprandial and postprandial states. No correlation was found between REE after meal ingestion and the rate of whole body protein synthesis.

Effect of hyperinsulinemia on ovine fetal leucine kinetics during prolonged maternal fasting.

The primary effect of insulin on whole body protein metabolism in postnatal life is to reduce proteolysis. To assess the role of insulin in the regulation of protein metabolism in prenatal life, leucine kinetics were determined in the ovine fetus at baseline and in response to hyperinsulinemia. These measurements were made in each fetus in two different maternal states: ad libitum maternal feeding and after a 5-day maternal fast. Maternal fasting resulted in significant increases in baseline fetal leucine rate of appearance (Ra; 51.9 +/- 16.7 vs. 37.3 +/- 3.6 mumol/min, P < 0.05) and leucine oxidation (30.1 +/- 8.9 vs. 8.8 +/- 2.2 mumol/min, P < 0.05). Hyperinsulinemia, which was associated with significant increases in fetal glucose utilization, did not affect total fetal leucine R(a) or leucine release from fetal proteolysis in either maternal state. Under well-fed maternal conditions, hyperinsulinemia produced no changes in the fetal oxidative or nonoxidative disposal of leucine. In contrast, during maternal fasting, hyperinsulinemia reduced fetal leucine oxidation (11.0 +/- 3.7 vs. 31.1 +/- 8.9 mumol/min, P < 0.05) and increased the nonoxidative disposal of leucine (35.4 +/- 4.0 vs. 19.0 +/- 6.1 mumol/min, P < 0.05). This resulted in a change in the fetal leucine accretion rate from negative to positive (-20.9 +/- 7.5 vs. 7.5 +/- 6.7 mumol/min, P < 0.05). These results suggest that, under conditions of restricted maternal substrate intake, fetal hyperinsulinemia and the attendant increase in fetal glucose utilization are associated with increased protein synthesis rather than decreased protein breakdown, thereby improving fetal leucine carcass accretion.