Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of growth hormone (GH) as an anabolic agent is limited by its tendency to cause hyperglycemia and by its inability to reverse nitrogen wasting in some catabolic conditions. In a previous study comparing the anabolic actions of GH and IGF-I (insulin-like growth factor I), we observed that intravenous infusions of IGF-I (12 micrograms/kg ideal body wt [IBW]/h) attenuated nitrogen wasting to a degree comparable to GH given subcutaneously at a standard dose of 0.05 mg/kg IBW per d. IGF-I, however, had a tendency to cause hypoglycemia. In the present study, we treated seven calorically restricted (20 kcal/kg IBW per d) normal volunteers with a combination of GH and IGF-I (using the same doses as in the previous study) and compared its effects on anabolism and carbohydrate metabolism to treatment with IGF-I alone. The GH/IGF-I combination caused significantly greater nitrogen retention (262 +/- 43 mmol/d, mean +/- SD) compared to IGF-I alone (108 +/- 29 mmol/d; P < 0.001). GH/IGF-I treatment resulted in substantial urinary potassium conservation (34 +/- 3 mmol/d, mean +/- SE; P < 0.001), suggesting that most protein accretion occurred in muscle and connective tissue. GH attenuated the hypoglycemia induced by IGF-I as indicated by fewer hypoglycemic episodes and higher capillary blood glucose concentrations on GH/IGF-I (4.3 +/- 1.0 mmol/liter, mean +/- SD) compared to IGF-I alone (3.8 +/- 0.8 mmol/liter; P < 0.001). IGF-I caused a marked decline in C-peptide (1,165 +/- 341 pmol/liter; mean +/- SD) compared to the GH/IGF-I combination (2,280 +/- 612 pmol/liter; P < 0.001), suggesting maintenance of normal carbohydrate metabolism with the latter regimen. GH/IGF-I produced higher serum IGF-I concentrations (1,854 +/- 708 micrograms/liter; mean +/- SD) compared to IGF-I only treatment (1,092 +/- 503 micrograms/liter; P < 0.001). This observation was associated with increased concentrations of IGF binding protein 3 and acid-labile subunit on GH/IGF-I treatment and decreased concentrations on IGF-I alone. These results suggest that the combination of GH and IGF-I treatment is substantially more anabolic than either IGF-I or GH alone. GH/IGF-I treatment also attenuates the hypoglycemia caused by IGF-I alone. GH/IGF-I treatment could have important applications in diseases associated with catabolism.
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PMID:Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. 767 7

In summary, corticosteroids suppress linear growth. The growth suppression is mediated by perturbations in growth factors as evidenced by: (1) abnormal spontaneous GH secretion and a blunted response to provocative stimuli and (2) decreased local production of IGF-I. Corticosteroids suppress GH responses by altering somatostatin tone. In addition, corticosteroids are anti-anabolic with resultant protein wasting. Exogenous administration of rhGH is effective in reversing all the clinical catabolic effects of corticosteroids. The duel factors of corticosteroids and uremia which are growth suppressive can be overcome by exogenous rhGH administration.
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PMID:Corticosteroids and growth. 790 67

This review focuses on the effects of hormones on protein kinetics in humans. Most of the recent knowledge on the regulation of protein metabolism in humans has been obtained by tracing protein kinetics in vivo, using labelled isotopes of essential or non-essential amino acids. This technique allows the rates of the whole-body protein synthesis and breakdown to be estimated together with amino acid oxidation and the fractional synthetic rates of mixed muscle proteins or of single plasma proteins. Changes induced within these parameters by hormonal administration or endocrine diseases are also discussed. Hormones, on the basis of their net effect on protein balance (protein synthesis minus protein breakdown), are divided into two categories: those provided with an anabolic action and those with a prevalent catabolic action. The effects on protein metabolism of the following hormones are reviewed: insulin, growth hormone, IGF-I, adrenaline, androgens, estrogens, progesterone, glucagon, glucocorticosteroids, thyroid hormones. The review concludes with a report on the effects of multiple hormonal infusions on whole-body protein kinetics and a discussion on the potential role played by the concomitant increase of several hormones in the pathogenesis of protein wasting that complicates stress diseases.
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PMID:Hormonal regulation of human protein metabolism. 876 67

Over the last several years, the authors have studied the relationship of insulin-like growth factors (IGFs) and the insulin-like growth factor binding proteins (IGFBPs) in the circulation in a number of clinical settings. Patterns have emerged that seem to be characteristic of various conditions. In aging, there are marked decreases in IGF-I and -II, normal levels of IGFBP-3, and marked increases in IGFBP-1 in serum. Using ligand blotting and an IGFBP-3 proteolysis assay, BP-3 is intact. Based on native gel electrophoresis, IGFBP-1 is in its most highly phosphorylated state in those elders who have high IGFBP-1 levels. This pattern is slightly different in catabolic conditions such as AIDS (wasting in adults; failure to thrive in children), uncontrolled diabetes mellitus, trauma, and severe burns. In these conditions, serum levels of IGF-I and -II are markedly diminished, IGFBP-3 levels are also decreased, and IGFBP-1 levels are markedly increased. In addition, there is increased proteolysis of IGFBP-3 (AIDS failure to thrive, uncontrolled diabetes mellitus) and disruption of the ternary complex with decreased levels of ALS (AIDS wasting and burns). IGFBP-1 is in its most highly phosphorylated state in all catabolic conditions studied. Thus, the alterations in the circulating levels of IGFs and the changes in the physical state of the IGFBPs may lead to decreased anabolic activity and be a part of the mechanism of increased catabolism and wasting.
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PMID:IGFBP-3. Functional and structural implications in aging and wasting syndromes. 944 38

Prolonged critical illness is characterized by feeding-resistant wasting of protein, whereas reesterification, instead of oxidation of fatty acids, allows fat stores to accrue and associate with a low-activity status of the somatotropic and thyrotropic axis, which seems to be partly of hypothalamic origin. To further unravel this paradoxical metabolic condition, and in search of potential therapeutic strategies, we measured serum concentrations of leptin; studied the relationship with body mass index, insulin, cortisol, thyroid hormones, and somatomedins; and documented the effects of hypothalamic releasing factors, in particular, GH-secretagogues and TRH. Twenty adults, critically ill for several weeks and supported with normocaloric, continuously administered parenteral and/or enteral feeding, were studied for 45 h. They had been randomized to receive one of three combinations of peptide infusions, in random order: TRH (one day) and placebo (other day); TRH + GH-releasing peptide (GHRP)-2 and GHRP-2; TRH + GHRH + GHRP-2 and GHRH + GHRP-2. Peptide infusions were started after a 1-microgram/kg bolus at 0900 h and infused (1 microgram/kg.h) until 0600 h the next morning. Serum concentrations of leptin, insulin, cortisol, T4, T3, insulin-like growth factor (IGF)-I, IGF-binding protein-3 and the acid-labile subunit (ALS) were measured at 0900 h, 2100 h, and 0600 h on each of the 2 study days. Baseline leptin levels (mean +/- SEM: 12.4 +/- 2.1 micrograms/L) were independent of body mass index (25 +/- 1 kg/m2), insulin (18.6 +/- 2.9 microIU/mL), cortisol (504 +/- 43 mmol/L), and thyroid hormones (T4: 63 +/- 5 nmol/L, T3: 0.72 +/- 0.08 nmol/L) but correlated positively with circulating levels of IGF-I [86 +/- 6 micrograms/L, determination coefficient (R2) = 0.25] and ALS (7.2 +/- 0.6 mg/L, R2 = 0.32). Infusion of placebo or TRH had no effect on leptin. In contrast, GH-secretagogues elevated leptin levels within 12 h. Infusion of GHRP-2 alone induced a maximal leptin increase of +87% after 24 h, whereas GHRH + GHRP-2 elevated leptin by up to +157% after 24 h. The increase in leptin within 12 h was related (R2 = 0.58) to the substantial rise in insulin. After 45 h, and having reached a plateau, leptin was related to the increased IGF-I (R2 = 0.37). In conclusion, circulating leptin levels during protracted critical illness were linked to the activity state of the GH/IGF-I axis. Stimulating the GH/IGF-I axis with GH-secretagogues increased leptin levels within 12 h. Because leptin may stimulate oxidation of fatty acids, and because GH, IGF-I, and insulin have a protein-sparing effect, GH-secretagogue administration may be expected to result in increased utilization of fat as preferential substrate and to restore protein content in vital tissues and, consequently, has potential as a strategy to reverse the paradoxical metabolic condition of protracted critical illness.
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PMID:Leptin levels in protracted critical illness: effects of growth hormone-secretagogues and thyrotropin-releasing hormone. 974 4

High doses of lipopolysaccharide (LPS) induce transient hyperglycemia, then chronic hypoglycemia and increased insulin resistance. In addition, appetite is reduced, while body temperature and concentrations of cortisol and tumor necrosis factor alpha (TNFalpha) are elevated. Furthermore, concentrations of GH and IGF-I are reduced in cattle. The objectives of this study were to determine whether a gonadal steroid implant (20 mg estrogen and 200 mg progesterone) given to endotoxemic steers would: (1) reduce hyperglycemia, reduce hypoglycemia, reduce insulin resistance, (2) reduce changes in concentrations of GH and IGF-I, (3) reduce inappetence and reduce concentrations of blood urea nitrogen (BUN) and non-esterified fatty acids (NEFA), and (4) reduce fever and concentrations of TNFalpha and cortisol. Holstein steers were assigned within a 2x2 factorial arrangement of treatments as follows (n=5 per group): C/C, no steroid and vehicle; S/C, steroid and vehicle; C/E, no steroid and LPS (1 microg/kg body weight (BW), i.v.); S/E, steroid and endotoxin. Steroid implants were given at 20 weeks of age (day 0) and serial blood samples (15 min) were collected on day 14 for 8 h, with vehicle or LPS injected after 2 h. Intravenous glucose tolerance tests (100 mg/kg BW) were carried out at 6 h and 24 h. Hyperglycemia was 67% lower (P<0.05) in S/E- compared with C/E-treated steers between 30 and 150 min after i.v. injection of LPS. Hypoglycemia developed after 4 h and insulin resistance was greater in S/E- compared with C/E-treated steers (P<0. 05) at 6 and 24 h. Concentrations of IGF-I were restored earlier in steroid-treated steers than in controls. Concentrations of GH were not affected by steroids, but increased 1 h after injection of LPS, then were reduced for 2 h. Appetite was greater (P<0.05) in S/E- (2.1% BW) compared with C/E-treated steers (1.1% BW) (pooled s.e.m.=0.3). Concentrations of NEFA increased after injecting LPS, but concentrations were lower (P<0.05) in S/E- compared with C/E-treated steers. LPS did not affect concentrations of BUN, but concentrations were lower in steroid-treated steers. Steroids did not affect body temperature or concentrations of TNFalpha and cortisol. In summary, gonadal steroids reduce hyperglycemia, reduce inappetence and tissue wasting, but increase insulin resistance. Furthermore, concentrations of IGF-I are restored earlier in steroid-treated than in non-steroid-treated steers injected with LPS. It is concluded that gonadal steroids reduce severity of some endocrine and metabolic parameters associated with endotoxemia. However, it is unlikely that gonadal steroids acted via anti-inflammatory and immunosuppressive actions of glucocorticoids or through reducing concentrations of cytokines.
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PMID:Estradiol/progesterone implants increase food intake, reduce hyperglycemia and increase insulin resistance in endotoxic steers. 983 64

Protracted critical illness is marked by protein wasting resistant to feeding, by accumulation of fat stores, and by suppressed pulsatile release of GH and TSH. We previously showed that the latter can be reactivated by brief infusion of GH-releasing peptide (GHRP-2) and TRH. Here, we studied combined GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation of the metabolic effectiveness of this novel trophic endocrine strategy. Fourteen patients (mean +/- SD age, 68 +/- 11 yr), critically ill for 40 +/- 28 days, were compared to a matched group of community-living control subjects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1 + 1 microg/kg x h) infusion in random order. At baseline, impaired anabolism, as indicated by biochemical markers (osteocalcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH secretion, as determined by deconvolution analysis, and low GH-dependent insulin-like growth factor and binding protein (IGFBP) levels]. Biochemical markers of accelerated catabolism (increased protein degradation and bone resorption) were related to tertiary hypothyroidism and the serum concentration of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independent of elevated serum cortisol. After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increased 19% vs. -6% with placebo, and leptin had rose 32% vs. -15% with placebo. These anabolic effects were linked to increased IGF-I and GH-dependent IGFBP, which reached near-normal levels from day 2 onward. In addition, protein degradation was reduced, as indicated by a drop in the urea/creatinine ratio, an effect that was related to the correction of tertiary hypothyroidism, with near-normal thyroid hormone levels reached and maintained from day 2 onward. Concomitantly, a spontaneous tendency of IGFBP-1 to rise and of insulin to decrease was reversed. Cortisol concentrations were not detectably altered. In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical illness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting serum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plus TRH agonism in this particular wasting condition.
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PMID:Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. 1019 72

An unexplained hallmark of prolonged critical illness is the fact that food does not prevent or reverse protein wasting, while fat is paradoxically accrued. This 'wasting syndrome' often persists after the underlying disease has been resolved and thus perpetuates intensive care dependency. Although the crucial role of an intact hypothalamus-pituitary axis for homeostasis during stress is well recognized, the differences between the neuroendocrine changes observed in acute and prolonged critical illness were only recently described. Novel insights in this area are reviewed here. The initial endocrine stress response consists primarily of a peripheral inactivation of anabolic pathways while pituitary activity is essentially amplified or maintained. These responses presumably provide the metabolic substrates and host defense required for survival and to delay anabolism, and thus should be considered as adaptive and beneficial. Persistence of this acute stress response throughout the course of critical illness was hitherto assumed. This assumption has now been invalidated, since a uniformly reduced pulsatile secretion of ACTH, TSH, LH, prolactin (PRL) and GH has been observed in protracted critical illness, causing diminished stimulation of several target organs. Impaired pulsatile secretion of anterior pituitary hormones in the chronic phase of critical illness seems to have a hypothalamic rather than a pituitary origin, as administration of relevant releasing factors evoked immediate and pronounced pituitary hormone release. A reduced availability of TRH, one of the endogenous ligands of the GH-releasing peptide (GHRP) receptor (such as the recently discovered ghrelin) and, in very long-stay critically ill men, also of GHRH, appear to be involved. This hypothesis was further explored by investigating the effects of continuous i.v. infusion of GHRH, GHRP, TRH and their combinations for several days. Pulsatile secretion of GH, TSH and PRL was re-amplified by relevant combinations of releasing factors which also substantially increased circulating levels of IGF-I, GH-dependent binding proteins, thyroxine and tri-iodothyronine (T3) while avoiding a rise in reverse T3. Active feedback-inhibition loops prevented overstimulation of target organs and metabolic improvement was noted with the combined infusion of GHRP and TRH. Whether this novel endocrine strategy will also enhance clinical recovery from critical illness remains to be explored.
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PMID:Novel insights into the neuroendocrinology of critical illness. 1087 25

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is a 28-kDa plasma protein that binds to IGF-I and IGF-II with high affinity. IGFBP-1 is elevated in the blood as a result of sepsis, AIDS, excessive alcohol consumption, and diabetes and may, in part, be responsible for the wasting observed during these pathophysiological conditions. The liver is the principal site of IGFBP-1 synthesis, and we have previously shown that proinflammatory cytokines can directly stimulate IGFBP-1 secretion in a human hepatoma cell line (HepG2). The purpose of the present study was to investigate the role of the MAP kinase pathway in regulating IGFBP-1 synthesis by IL-1beta. We show that IL-1beta stimulates the phosphorylation of ERK-1 and -2 in a time- and dose-dependent manner. In addition, the MAP kinase-kinase MEK-1 and the ribosomal S6-kinase RSK-1 are also phosphorylated in response to IL-1beta. The transcription factor CREB, a potential substrate of both protein kinase A (PKA) and RSK-1, is phosphorylated in response to IL-1beta and cAMP in HepG2 cells. The ability of IL-1beta to stimulate the expression of IGFBP-1 and the phosphorylation of the above kinases was specifically inhibited by PD98059, a MEK-1 inhibitor. cAMP also stimulated IGFBP-1 synthesis, but PD98059 failed to block the cAMP effect. Conversely, a PKA inhibitor (H-89) inhibited the ability of cAMP, but not IL-1beta to stimulate IGFBP-1 synthesis. The effect of IL-1beta and cAMP on IGFBP-1 messenger RNA (mRNA) accumulation was additive. IL-1beta, cAMP, PD98059, and H-89 had similar effects on the accumulation of IGFBP-1 protein and mRNA. IL-1beta and cAMP did not change the half-life of IGFBP-1 mRNA, but PD98059 and SB202190, a p38 MAP kinase inhibitor, destabilized IGFBP-1 mRNA and blocked the phosphorylation of RSK-1 in response to IL-1beta. Our data demonstrate that the MAP kinase signal transduction pathway plays an important role in the regulation of IGFBP-1 synthesis by IL-1beta.
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PMID:Stimulation of insulin-like growth factor binding protein-1 synthesis by interleukin-1beta: requirement of the mitogen-activated protein kinase pathway. 1096 86

During life, all animals encounter situations that challenge their capability for optimal growth. In reacting to immune challenges in the form of disease, homeostatic mechanisms attempt to overcome disharmony of the body's internal environment, or simply put, stress. The overall impact of stress revolves around a dynamic relationship between the level of challenge imparted on physiological systems and the degree of host response that is mounted in the process of detecting and reacting to the stress. In growing animals, the majority of milder stress encounters are manifest in terms of energetic inefficiencies and periods of reduced anabolism. In contrast, severe stress is often characterized by frank catabolism and tissue wasting. In some instances a level of stress (that might be termed a "stress breakpoint") is reached at which time the host response itself contributes to the cascade of negative effectors that further cause illness. These "breakpoint" responses are characterized by more intense acute responses to stress or a much more protracted duration of the response than would be expected given the nature of the stress. Key to understanding how growth in the young animal responds to infectious stresses is the recognition that (a) when immune responses that normally maintain health go awry, the reporters and effectors of the immune system (cytokines and the nitric oxide cascade) can contribute to stress disease processes and (b) reactive nitrogen compounds derived from the nitric oxide, as well as super oxide anion can modify intracellular proteins and block otherwise normal biochemical processes that regulate cell function. A key example of this is the loss of regulation of IGF-I by GH. As animals react more severely to disease stress, IGF-I concentrations in plasma decline progressively. Recent data derived from (LPS) challenges performed on young calves suggest that the prolonged decline in IGF-I is associated with the development of hepatic cytotoxicity localized to regions of protein nitration as identified by immunohistochemistry. Identifying biochemical criteria for disease processes provides needed guidance for the further development of intervention strategies to limit the impact of disease on growth.
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PMID:Modulation of growth performance in disease: reactive nitrogen compounds and their impact on cell proteins. 1102 87


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