3-methylhistidine Excretion Research Articles

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

The modifying influence of anaesthesia on postoperative protein catabolism

We studied two groups of six patients scheduled for gastrointestinal surgery; they were allocated randomly to receive high- or low-dose fentanyl anaesthesia. The confounding effect of protein balance, before the trauma of surgery, on postoperative nitrogen excretion was controlled by standardized protein intake before operation, supplemented by adequate calories. The high-dose group had significantly lower stress levels during surgery, assessed by arterial blood concentrations of cortisone, adrenaline and glucose. After operation, protein catabolism was measured for 7 days. The high-dose group had significantly lower postoperative excretion of ammonia and slightly lower excretion of urea and 3-methylhistidine. Low-stress anaesthesia may thus diminish postoperative catabolism, which could be important in frail patients by reducing mortality, ICU resources, or both.

Relationship between fat-free mass and urinary excretion of creatinine and 3-methylhistidine in adult humans

The urinary excretion of endogenous creatinine (CRTN) and 3-methylhistidine (3-MH) has been proposed as a predictor of fat-free mass (FFM) in healthy subjects. In this study, we report the relationship between FFM, estimated by densitometry plus deuterium dilution, and daily urinary excretion of CRTN and 3-MH in a sample of 20 healthy adult subjects of both sexes. 3-MH and CRTN were measured in 2 days of urine collection, which followed 4 days of meat-free diet. Meat-free diet was maintained throughout the period of urine collection. The mean of 2 days of excretion of 3-MH was 237.7 +/- 87.3 (SD) and 138.9 +/- 31.2 mumol/day in men and women, respectively. The mean CRTN excretion was 1.51 +/- 0.22 and 0.98 +/- 0.15 g/day in men and women, respectively. CRTN excretion was found well associated with FFM (R2 = 0.89; P < 0.0001), whereas 3-MH was lightly associated with FFM (R2 = 0.33; P < 0.01). Residuals from the regression of 3-MH vs. FFM were found to be correlated with CRTN excretion and FFM (R2 = 0.57 and 0.67, respectively), suggesting that muscularity and the absolute amount of lean mass are relevant for the error in predicting FFM from 3-MH excretion. Data confirm that urinary CRTN excretion can be an expedient indirect method for evaluating body composition in healthy adult subjects. Data also suggest that the relationship between 3-MH and FFM is complex, limiting the possibility of predicting body composition from the excretion of this metabolite.

The effects of different intravenous feeding regimens on the rates of synthesis of α1-antitrypsin after surgery

The effects of two nutritional regimens on the synthesis of alpha-1 antitrypsin were investigated postoperatively in gynaecological cancer patients. Total parenteral nutrition (TPN) or a hypocaloric amino acid mixture was administered on the day of surgery and continued for 3 days. The rate of synthesis of alpha-1 antitrypsin was estimated by a computer model from serial plasma concentrations of this protein and a reference protein, albumin. The hypocaloric amino acid mixture resulted in a more negative nitrogen balance than that produced during administration of TPN containing the same amount of nitrogen but more non-protein energy. Urinary excretion of 3-methylhistidine was significantly greater (p = 0.017) in the hypocaloric amino acid group (350 ± 40 μmol/day; mean ± SE) on the third postoperative day, as compared to the TPN group (240 ± 20 μmol/day). In spite of this the synthesis of alpha-1 antitrypsin was apparently greater in the hypocaloric amino acid than in the TPN group. The accumulated plasma appearance rate of alpha-1 antitrypsin was significantly higher (p = 0.0465) in HAA group, at 70 h it was 490 ± 40 compared to 400 ± 20 times the pre-operative synthesis in the TPN group.

Glutamine-supplemented parenteral nutrition improves gut mucosa integrity and function in endotoxemic rats.

The effects of glutamine-supplemented parenteral nutrition on protein metabolism, small intestinal mucosal metabolism, morphology, and barrier function were studied in endotoxin-treated rats. Forty-six male Wistar rats were randomized to two groups of 23 animals each and received total parenteral nutrition solutions supplemented with either glutamine (GLN group) or glycine (GLY group) at 2% wt/vol. Endotoxemia was induced by continuous intravenous infusion of endotoxin at a dose of 2 mg/kg per day throughout the 4-day study period. The GLN group had a less-negative cumulative nitrogen balance (-14.0 +/- 132.8 mg of nitrogen in the GLN group and -86.8 +/- 161.7 mg of nitrogen in the GLY group, p < .05) and less cumulative excretion of urinary 3-methylhistidine (2910 +/- 593 nmol) than the GLY group (4447 +/- 933 nmol, p < .01). Jejunal mucosal glutaminase activity and the arterio-portal venous blood glutamine concentration differences were significantly higher in the GLN group compared with the GLY group (15.6 +/- 2.3 vs 11.1 +/- 1.9 mumol/g per minute, p < .05, and 181 +/- 52 vs 147 +/- 36 nmol/mL, p < .05, respectively). The morphology of the jejunal mucosa in the GLN group was significant for having greater mucosal weight (23.4 +/- 3.1 vs 17.6 +/- 2.5 mg/cm), villus height (445 +/- 75 vs 357 +/- 57 microns), crypt depth (197 +/- 34 vs 161 +/- 28 microns), and wall thickness (751 +/- 77 vs 648 +/- 102 microns) than the GLY group (p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrogen metabolism at chronic low energy intakes

The response of animals adapted to moderate or severe energy restriction to supplements of free amino acids or protein is unknown. Lysine supplementation was examined because it is an amino acid frequently limiting in cereal-based diets. Male rats weighing 115 g were assigned to one of seven diet groups. Animals were fed either a gluten-based diet or the gluten diet supplemented with adequate levels of lysine for 8 weeks. These diets were fed ad libitum or at 40% or 75% restricted levels. An additional group was fed a high gluten diet at the same energy level as the 75% restricted rats. Body weight, muscle weights, and adipose tissue were reduced relative to the level of restriction. Restricted groups adapted to the energy restrictions and exhibited either slow growth or stable body weight after 4 weeks on the respective treatments. Lysine supplementation increased muscle mass and improved nitrogen balance in the ad libitum and 40% restricted groups, but had no effect on the 75% restricted group. Excretion of 3-methylhistidine (3MH) was higher in the energy restricted animals after 7 weeks on the respective diets, and lysine supplements further increased 3MH losses. Plasma lysine levels were reduced by the food restrictions and unaffected by lysine supplements in the restricted animals. These findings indicate that the efficacy of lysine supplementation depends on the absolute level of energy intake, and a lysine supplemented diet may be detrimental to skeletal muscle mass at very low energy intakes. The data also showed that rats adapt to a 75% food restriction by achieving and maintaining nitrogen balance despite the increase in myofibrillar protein breakdown.

Acute effects of resistance exercise on muscle protein synthesis rate in young and elderly men and women.

Muscle mass and function are improved in the elderly during resistance exercise training. These improvements must result from alterations in the rates of muscle protein synthesis and breakdown. We determined the rate of quadriceps muscle protein synthesis using the in vivo rate of incorporation of intravenously infused [13C]leucine into mixed-muscle protein in both young (24 yr) and elderly (63-66 yr) men and women before and at the end of 2 wk of resistance exercise training. Before training, the fractional rate of muscle protein synthesis was lower in the elderly than in the young (0.030 +/- 0.003 vs. 0.049 +/- 0.004%/h; P = 0.004) but increased (P < 0.03) to a comparable rate of muscle protein synthesis in both young (0.075 +/- 0.009%/h) and elderly subjects (0.076 +/- 0.011%/h) after 2 wk of exercise. In the elderly, muscle mass, 24-h urinary 3-methylhistidine and creatinine excretion, and whole body protein breakdown rate determined during the [13C]leucine infusion were not changed after 2 wk of exercise. These findings demonstrate that, during the initial phase of a resistance exercise training program, a marked increase in quadriceps muscle protein synthesis rate occurs in elderly and young adults without an increase in the rate of whole body protein breakdown. In the elderly, this was not accompanied by an increase in urinary 3-methylhistidine excretion, an index of myofibrillar protein breakdown.

Decreased plasma proteins, increased total plasma-free amino acids, and disturbed amino acid metabolism in the hereditary severe anemia of the Belgrade laboratory (b/b) rat.

The plasma amino acid pattern has been investigated in severely anemic Belgrade laboratory (b/b) rats. Nonanemic heterozygous (b/+) or normal homozygous (+/+) rats of the same age (six weeks) were used as controls. Decreased plasma proteins, increased total free amino acid, and urea concentrations in plasma associated with increased urea and 3-methylhistidine urinary excretion were found, indicating protein and amino acid metabolic alterations in anemic b/b rats. Plasma alanine, glutamine, tyrosine, and phenylalanine concentrations were increased. The significantly reduced molar ratio between valine+leucine+isoleucine and phenylalanine+tyrosine suggested severe disturbance in the hepatic energy-producing system and derangement of hepatic energy status. Partial or complete reversal of the anemia within 3 days by red blood cell transfusion or within 3 weeks by iron treatment resulted in normalization of tyrosine, alanine, glutamine, and total amino acid concentrations in plasma, as well as of molar ratio between valine+leucine+isoleucine and phenylalanine+tyrosine. This indicated a better oxygen supply to the liver and normalization of the hepatic energy status. These findings suggest that the metabolic disturbances in the b/b rat are the consequence of hypoxia due to the severe anemia.

Effect of Glucagon on Plasma Amino Acid and Glucose Levels in a Patient Who Had Undergone Total Pancreatectomy.

The plasma glucose and amino acid levels of a patient who had undergone total gastrectomy and total pancreatectomy 15 years previously were examined under 4 conditions determined by the method of exogenous glucagon injection. Glucagon was not injected in the first period, and 1mg of glucagon was injected twice a day in the second period. Twice a day 1mg of zinc glucagon was injected in the third period, and 2mg/day of glucagon by continuous subcutaneous glucagon infusion (CSGI) was given in the fourth period. The plasma pancreatic glucagon levels were within the normal range during CSGI. The effect of glucagon on plasma amino acid levels was greatest with CSGI. The effect became less in the order of zinc glucagon injection and twice-a-day injection of 1mg of glucagon. Furthermore, afternoon hyperglycemia and nocturnal hypoglycemia were suppressed with CSGI. Urinary nitrogen excretion was increased with glucagon injection. However, excretion of 3-methylhistidine did not show any significant increase. From these results we consider that exogenous glucagon injection has significant effects on the metabolism of glucose and amino acids after total pancreatectomy. We also conclude that both continuous subcutaneous glucagon infusion and zinc glucagon are useful in the postoperative management of total pancreatectomy.

Protein and amino acid metabolism in cancer cachexia: investigative techniques and therapeutic interventions.

Cancer cachexia is a complex syndrome characterized primarily by diminished nutrient intake and progressive tissue depletion that is manifest clinically as anorexia and host weight loss. The gradual loss of host protein stores is central to this process. This review outlines the techniques that have been used to evaluate human amino acid metabolism, their application in patients with cancer cachexia, and possible therapeutic interventions designed to overcome alterations in host protein and amino acid metabolism associated with malignant cachexia. The techniques of nitrogen balance and 3-methylhistidine excretion provide indirect estimates of overall nitrogen metabolism and skeletal muscle myofibrillar protein breakdown. Measurement of circulating amino acid concentrations, particularly when combined with assessment of arterial-venous differences and regional amino acid balance allows for investigation of interorgan amino acid metabolism. One of the most significant advances in in vivo amino acid metabolic research has been the development of labeled amino acid tracer studies to evaluate whole body and regional amino acid kinetics. The use of stable and unstable amino acid isotopes in these techniques is reviewed in detail. Virtually all of these techniques have now been employed in the evaluation of human cancer cachexia. The results of studies evaluating amino acid concentrations, regional amino acid balance, and 3-methylhistidine excretion are summarized. The use of regional and whole body kinetic studies in cancer cachexia are reviewed extensively. Most investigators have observed increased rates of whole body protein turnover, synthesis, and catabolism in both weight-stable and weight-losing cancer patients. Some studies have suggested a relationship between the extent of disease and the degree of aberration in amino acid kinetic parameters. Investigators have attempted to reverse some of these alterations by provision of substrate (nutritional support) or administration of specific pharmacologic or anabolic agents such as hydrazine sulfate, insulin, growth hormone, and beta-2 agonists. The role of total parenteral nutrition (TPN) in cancer and its effects on protein and amino acid kinetics and tumor growth are addressed. The possible benefits of specific amino acid nutritional formulations with increased branched chain amino acids, arginine, and glutamine are reviewed. Although many of these approaches appear promising, significant impact on clinically definable parameters remains to be demonstrated. A better understanding of the underlying protein catabolic mechanisms of cancer cachexia will likely lead to more effective therapies to reverse the protein calorie malnutrition associated with cancer cachexia.

Decrease in urinary excretion of 3-methylhistidine by patients with Duchenne muscular dystrophy during glucocorticoid treatment.

Seven patients, aged 10-17 years, with Duchenne muscular dystrophy were treated orally with prednisolone (PSL) at a dose of 0.8-1.0 mg/kg per day for 8 weeks. During the treatment their muscle strength, serum creatine kinase (CK) activity, serum levels of myoglobin (Mb), and urinary excretion of 3-methylhistidine (3-MeH) and glycine (Gly) were measured serially. In all the patients, the motor function or muscle strength improved, and the serum CK activity and Mb level decreased during PSL treatment. Urinary excretion of 3-MeH, a unique constituent of muscle contractile proteins, decreased to 51-63% of the baseline value in weeks 6-9 after the start of PSL administration, and returned to the baseline level in week 12. The ratios of 3-MeH to creatinine and to Gly also decreased during the treatment. Urinary excretion of Gly, which is ubiquitous in all tissues including muscle, did not decrease during the treatment. These findings suggest that PSL inhibits proteolysis of muscle contractile protein.

Effects of Recombinant Human Growth Hormone in Patients With Severe Sepsis

The objective of this study was to evaluate the safety and the effect of recombinant exogenous growth hormone (GH) on nitrogen production in patients with severe sepsis. It was designed as a prospective, randomized, placebo-controlled trial, and performed in the medical intensive care unit of a university hospital. Twenty patients admitted with septic shock and receiving standard parenteral nutrition served as subjects. Treatment consisted of GH 0.1 mg/kg/day or placebo administered as continuous intravenous infusion on the second, third, and fourth days after admission. The study period was eight days. During GH administration, nitrogen production decreased significantly in the GH group and increased in controls (p < 0.01). Nitrogen balance became slightly positive in the GH group during treatment: 1.2 +/- 6.4 versus controls -3.7 +/- 3.8 g/day (day 3) (p < 0.05). Within 24 hours after cessation of treatment, differences between GH and controls disappeared. 3-Methylhistidine excretion as a measure of absolute muscle breakdown declined during the study period, but did not differ between groups. The levels of insulin, insulinlike growth factor 1, glycerol, free fatty acids, and beta-hydroxybutyrate increased during treatment. Despite continuous intravenous administration, GH levels gradually declined during the 3 treatment days, indicating increased metabolic clearance. Side effects other than insulin resistance were not observed. Growth hormone administration reduces nitrogen production and improves nitrogen balance in patients with severe sepsis. These effects are not sustained after cessation of treatment.

Antioxidant response to exercise-induced oxidative stress and protection by vitamin E.

There is an increased generation of free radicals and lipid peroxides associated with strenuous and exhaustive exercise. I In vitamin E-deficient animals, exercise increases susceptibility to free radical damage and results in premature exhaustion, greater fragility of lysosomal membranes, and marked depression of muscle mitochondrial respiratory control. The few human studies conducted to date indicate that vitamin E supplementation reduces oxidative stress and lipid peroxidation events following exercise and suggest that vitamin E requirements may increase with e ~ e r c i s e . ~ , ~ In order to investigate the potential for aprotective role of vitamin E supplementation against exercise-induced oxidative stress, 9 young (22-29 yr) and 12 older (55-74 yr) healthy men were studied following daily supplementation with 800 IU vitamin E or placebo for 48 days. Volunteers then engaged in a bout of eccentric exercise by running downhill on a treadmill at 75% of their maximum heart rate for 45 minutes. After 48 days, the concentration of plasma a-tocopherol increased6 (56% in young, 70% in older subjects) and y-tocopherol decreased (99% in young, 60% in older subjects). A protective effect of vitamin E was substantiated by measuring 24 h urinary thiobarbituric acid (TBA) adducts as an index of whole body response to oxidative stress. The protective effect of vitamin E extended up to 12 days postexercise, at which time muscle protein injury and remodeling was evident by urinary excretion of 3-methylhistidine.' Analysis of variance showed a significant (p < 0.01) effect of exercise on 24 h urinary TBA-adduct excretion. Both young and older placebo groups showed a marked increase in urinary TBA-adduct excretion that reached statistical significance by 12 d post-exercise (TABLE I ) . By contrast, vitamin E-supplemented groups showed no change in TBA-adduct excretion in 24 h urine samples. Significant decreases in both aand y-tocopherol concentration and a concomitant increase of lipid conjugated dienes (intermediate products of lipid peroxidation) were found in biopsies obtained from vastus lateralis muscle before and immediately after exercise. In addition, muscle levels of linoleic and arachidonic acids in supplemented men were higher (p < 0.05) post-exercise than in those receiving placebo. These alterations in whole body lipid peroxide status following a bout of eccentric exercise are consistent with the hypothesis that vitamin E provides protection against exercise-induced oxidative injury.

Relationship between a long-term treatment of 2-mercaptoethanol and protein metabolism in the ageing rat.

Female RLEF1/Lati rats were chronically treated with 2-mercaptoethanol in a dose of 13 micrograms.100 g bw-1.day-1 dissolved in drinking water. During a 48-h experiment 15N-labelled glycine was given orally in a dose of 5 mg 15N.kg bw-1 and urine samples were collected and analysed by an emission spectrometric isotope method. Protein synthesis and nitrogen excretion rate constants were calculated according to the three-pool model, and 3-methylhistidine excretion rates were also determined. 2-Mercaptoethanol appears to influence protein metabolism; however, the slower rates of protein synthesis proved to be apparent in almost all groups of treated rats. Protein synthesis and nitrogen excretion rate constants have exceptionally high values in 2-year-old rats, possibly explained by the occurrence of hypercompensation mechanisms in old age. These were reflected by the excretion rates of 3-methylhistidine which were reduced as a result of sulphhydryl group interactions in age-dependent cellular metabolic changes.

Influence of a meat-free diet on the urinary excretion of 3-methylhistidine and creatinine in chronic renal failure.

Urinary excretion of 3-methylhistidine has been proposed as an index of internal protein breakdown provided that the intake of exogenous 3-methylhistidine (meat) is excluded. To evaluate the potential use of 3-methylhistidine in the metabolic assessment of patients with advanced renal failure, we studied a group of 11 patients with markedly reduced renal function who were put on a meat-free diet (the protein intake was kept constant). Steady-state plasma concentration and urinary excretion of 3-methylhistidine were not achieved until 14 d after exclusion of meat from the diet. At that time the plasma concentration and urinary excretion of 3-methylhistidine had decreased by 43% and 60%, respectively. We conclude that the delay in reaching steady state makes the clinical use of urinary excretion of 3-methylhistidine in patients with advanced renal failure unpracticable as an index of protein breakdown. The exclusion of meat also resulted in a continuous decrease in the plasma level and urinary excretion of creatinine, with the result that plasma creatinine or its reciprocal become misleading for evaluation of changes in renal function until a new steady state has been reached.

The impact of leucine infusion on skeletal muscle amino acid and energy metabolism in severely traumatized patients

The response to trauma is associated with increased energy requirements and net protein breakdown. The branched chain aminoacids, especially leucine, are considered to act by serving as a fuel for muscle tissue and by stimulating synthesis of proteins and controlling protein breakdown. Such results have been obtained mainly from in vitro studies. The present study was designed to evaluate the pharmacological effect of leucine infusion on muscle energy/amino acid metabolism in man after severe multiple trauma. 16 patients were studied and randomly allocated into 2 groups. Group 1 was given fat and 20% glucose while group 2 received 6 g N in form of leucine dissolved in 10% glucose solution and fat. The patients received 40 kcal/kg/24 h over an 8 day period after trauma. Biochemical analyses, muscle biopsies (energy substrates, electrolytes, amino acids), nitrogen balance and 3-methyl histidine excretion in urine were evaluated. Biochemical data revealed a significant increase (p < 0.05) of serum urea in group 2 day 4 and 8 after trauma. Muscle intracellular electrolytes (K +, Mg 2+) and energy substrates (ATP, phosphocreatine) showed a similar decrease in both groups. The intracellular muscle amino acids displayed a pattern known to be related to trauma without differences between the groups. The cumulative nitrogen balance 8 days after the injury was −93.5 g N ± 10.1 (SEM) in group 1 and −73 g N ± 7.5 in group 2. The 3-methylhistidine excretion was markedly increased similar in both groups. The present study demonstrated no significant pharmacological effect of leucine administration on muscle metabolism, nitrogen balance or 3-methylhistidine excretion in severely traumatized patients. Conventional balanced amino acid solutions are probably optimal to meet the patients actual requirements.

Protein sparing during treatment of obesity: Ketogenic versus nonketogenic very low calorie diet

Although it is generally agreed that both ketogenic and nonketogenic very low calorie diets promote weight reduction, there is no consensus on a preference of one diet over the other in regard to protein sparing. In the present study, we compared the effects of isocaloric (600 kcal/d) and isonitrogenous (8 g nitrogen/d) ketogenic (low carbohydrate) and nonketogenic diets on parameters of protein and amino acid metabolism, in 16 morbidly obese women maintained on these diets for 4 weeks while confined to a metabolic ward. Cumulative urinary nitrogen excretion (g/4 wk) was significantly ( P < .01) greater (248 ± 6 v 207 ± 12, mean ± SEM, n = 8), and cumulative nitrogen balance significantly ( P < .02) more negative (−50.4 ± 4.4 v −18.8 ± 5.7), during treatment with the ketogenic than with the nonketogenic diet. Plasma leucine concentration (μmol/L) was significantly higher ( P < .05) during treatment with the ketogenic than with the nonketogenic diet at day 14 (210 ± 17 v 150 ± 8), but not at day 28 (174 ± 9 v 148 ±8). Whole-body rates of leucine oxidation (mmol/h) were significantly higher ( P < .05) during treatment with the ketogenic than with the nonketogenic diet at day 14 (1.29 ± 0.20 v 0.92 ±0.10) and at day 28 (1.00 ± 0.16 v 0.75 ± 0.10). Conversely, proteolysis, as measured by leucine turnover rate and urinary excretion of 3-methylhistidine, was not significantly different between the diets. We conclude that there is greater protein sparing by the nonketogenic than by the ketogenic very low calorie diet, and the mechanism appears to be greater protein synthesis.

Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats

The administration of insulin-like growth factor-I (IGF-I) via subcutaneously implanted osmotic pumps partially reversed a catabolic state produced by the co-administration of 20 micrograms of dexamethasone/day to 150 g male rats. Marked dose-dependent effects on body weight and nitrogen retention were produced, with the highest IGF-I dose, 695 micrograms/day, giving a 6 g increase in body weight over 7 days, compared with a 19 g loss in the dexamethasone-only group and an 18 g gain in pair-fed controls. Two IGF-I analogues that bind poorly to IGF-binding proteins, the truncated form, des(1-3)IGF-I, and a variant with an N-terminal extension as well as arginine at residue 3, LR3IGF-I, were approx. 2.5-fold more potent than IGF-I. The response with LR3IGF-I was particularly striking because this peptide binds 3-fold less well than IGF-I to the type 1 IGF receptor. The increased potencies of the IGF-I variants may relate to the substantially increased plasma levels of IGF-binding proteins, particularly IGFBP-3, produced by the combined treatment of dexamethasone with IGF-I or the variants. These binding proteins would be expected to decrease the transfer of IGF-I, but not that of the variants, from blood to tissue sites of action. Measurements of muscle protein synthesis at the end of the treatment period and muscle protein breakdown by 3-methylhistidine (3MH) excretion throughout the experiment indicated coordinate anabolic effects of the IGF peptides on both processes. Thus 3MH excretion was decreased at the highest IGF-I dose from 83.5 +/- 4.2 (S.E.M.) mumol/kg per 7 days to 65.1 +/- 2.2, compared with 54.9 +/- 1.2 in the pair-fed controls. Part of this response in 3MH excretion may have reflected a decrease in gut protein breakdown, because IGF-I and especially the IGF analogues increased the gut weight by up to 45%. Notwithstanding the effects on protein synthesis and breakdown, the fractional carcass weights remained low in the IGF-treated groups, although the increase in total carcass weight reflected nitrogen rather than fat gain. The dexamethasone-induced changes in liver, spleen and heart weight were restored towards normal by the IGF treatment. The experiment demonstrates the potential of IGF-I treatment of catabolic states and especially the value of modified forms of growth factors that bind weakly to IGF-binding proteins.

Nutritional and Metabolic Response to Acute Spinal‐Cord Injury

The metabolic response to complete spinal cord injury was prospectively studied in 10 patients with Frankel class A spinal cord injury. Weekly excretory and balance studies profile the changes in nitrogen, calcium, and 3-methylhistidine excretion in relation to body weight and metabolic rate. The initial resting energy expenditures were 10% below what was predicted, and body weight decreased by 10%. Nitrogen excretion paralleled the changes in body weight. Calcium excretion increased for 3 weeks and reached a plateau 150% above baseline. Our results chronicle the magnitude of metabolic response to spinal shock. Comparison with reported values shows this response exceeds that seen in immobilized patients. Nitrogen excretion rose to levels seen in highly stressed patients and must be considered in the management of patients with acute spinal-cord injury.

Protein and energy metabolism in patients with progressive muscular dystrophy.

Studies were made on whether body weight loss in patients with muscular dystrophy is due to reduced intake and/or abnormal expenditure of energy. For this, food intakes and various physiological variables were surveyed in totals of 310 patients with Duchenne muscular dystrophy (DMD) of 11 to 29 years old and 28 patients with limb-girdle muscular dystrophy (LGMD) of 30 to 47 years old. Energy and protein intakes, expressed on a unit body weight basis, in DMD patients were comparable to, or higher than the allowances for age-matched healthy controls, whereas those in LGMD patients were 92 and 94% respectively of these allowances. The basal metabolic rate (BMR), expressed as kcal/kg/day, of DMD patients of all ages was higher than that of controls, the difference increasing with age, and being about 20 to 30% higher than that of controls in older patients with DMD. The BMR of LGMD patients was nearly normal. The maintenance requirements of conventional dietary protein in DMD and LGMD patients were 1.26 and 0.84 g/kg/day, respectively. These values were about 68 and 12% higher than the normal adult value (0.75 g/kg/day), indicating decreased protein utilization and increased protein catabolism. Daily excretion of urinary 3-methylhistidine (3MH) per unit muscle mass (micrograms/mg creatinine) by MD patients was significantly higher than that by controls, indicating increased degradation of muscle protein. The BMR, maintenance protein requirement and 3MH excretion of DMD patients suggest that DMD is a hypercatabolic disease. Comparison of the energy and protein intakes with the allowances estimated in consideration of increased requirements showed deficiencies of energy and protein in DMD patients. Thus, we conclude that the underweight of the DMD patients resulted from nutrient deficiencies due to hypercatabolism, despite their considerably high intakes of energy and protein, expressed as per kg body weight. These deficiencies were confirmed by demonstrating decreased concentrations of free essential amino acids, particularly branched chain amino acids, in their serum. The values of variables of LGMD patients were intermediate between those of DMD patients and control subjects.