Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that spontaneous physical exercise can delay onset of experimental anorexia and cachexia, and retard tumour growth; we now report the effects on insulin sensitivity, hormonal levels and skeletal muscle protein metabolism. Insulin sensitivity determined with a euglycaemic hyperinsulinaemic clamp revealed a normalised glucose disposal rate in tumour-bearing exercising (TBE) versus sedentary (TBS) animals (TBE 15.55 +/- 2.71 versus TBS 2.47 +/- 2.12 mg/kg/min; P < 0.05). Both TBE and TBS animals had decreased levels of corticosterone during the clamp. Serum levels of insulin during tumour progression were unaffected by exercise, but the insulin: glucagon ratio increased and the progressive decrease in rT3 was attenuated. The concentration of glucagon decreased in both tumour-bearing groups during the experiment, while TBE animals showed a relative reduction in corticosterone. Capacity for skeletal muscle protein synthesis, expressed as RNA: protein ratio, was normalised in TBE animals in two tumour protocols (TBE 5.9 +/- 0.6 versus TBS 4.7 +/- 0.3; TBE 2.9 +/- 0.4 versus TBS 1.8 +/- 0.2; P < 0.05, respectively). Incorporation rate of 14C-phenylalanine into skeletal muscle protein was increased in the TBE group in vitro and in vivo. In the postexercise period, protein degradation evaluated by tyrosine release in vitro was increased, but decreased over time. This study has confirmed a positive skeletal muscle protein balance in exercising tumour-bearing animals, partly explained by the increased insulin sensitivity. This conclusion was further supported by the less catabolic pattern indicated by hormonal levels.
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PMID:Insulin sensitivity, hormonal levels and skeletal muscle protein metabolism in tumour-bearing exercising rats. 753 77

Chronic liver disease is characterized by numerous metabolic alterations, predominantly catabolic, resulting in the clinical picture of malnutrition and even cachexia in some patients. The following review focuses on disturbances of glucose metabolism and of hormonal interactions that could contribute to the clinical picture of malnutrition seen in chronic liver disease. Body composition is altered in a characteristic manner with an increase in fat mass and a significant loss of muscle tissue. Furthermore, defective glucose storage due to reduced insulin sensitivity predominantly of muscle tissue has been observed. The pathogenesis of insulin resistance leading to an impaired glucose tolerance or a manifest diabetes mellitus is as yet unknown. A receptor/postreceptor dysfunction probably exists in chronic liver disease that might be explained by the following factors: 1. Altered membrane lipid composition and increased levels of free fatty acids; 2. long-lasting hyperinsulinemia; 3. increased plasma levels of insulin counteracting hormones such as growth hormone, glucagon, catecholamines and possibly cytokines; 4. a lack of liver-derived humoral factors with insulin-like activity, i.e. insulin-like growth factors I and II.
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PMID:Glucose metabolism and liver cirrhosis. 755 77

An increase in gluconeogenesis contributes to the cachexia seen in severe injury, sepsis, and malignancy by converting amino acids from skeletal muscle to glucose. Since tumor necrosis factor alpha (TNF alpha) may mediate this cachexia, we examined the effect of this cytokine on gluconeogenesis. Twenty-eight male Fischer rats were injected intraperitoneally with TNF alpha (250 micrograms/kg) or saline, and after 4 hours, isolated hepatocytes were obtained by in situ collagenase liver perfusion. Hepatocytes were incubated with alanine (10 mM), and rates of gluconeogenesis were determined. Plasma lactate, glucose, insulin, glucagon, cortisol, and amino acids were measured. TNF alpha administration resulted in a 50% increase in gluconeogenesis from alanine (P < 0.05) and a three-fold increase in plasma glucagon (P = 0.01). Total and glucogenic plasma amino acids decreased with TNF alpha injection (P < 0.05). In vivo TNF alpha causes an increase in hepatic gluconeogenesis associated with increased plasma glucagon.
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PMID:Tumor necrosis factor alpha stimulates gluconeogenesis from alanine in vivo. 763 Jan 67

Cancer and its therapies frequently produce anorexia and cachexia. In this study, the acute (3 days) and chronic (4 wks) nutrition-related effects of cancer therapy with recombinant human tumor necrosis factor (rHuTNF) were investigated and described. Nutritional status, as measured by body weight and body composition (body fat and lean-to-fat ratio) with use of bioelectrical impedance, did not appear to deteriorate. None of the serum lipids changed significantly, but triglycerides did rise modestly over four weeks of therapy. Glucose and the peptide hormones (insulin, C-peptide, glucagon, and pancreatic polypeptide) thought to affect appetite did not change with rHuTNF therapy. Therefore, although TNF is thought to contribute to wasting in animal models, it had no negative effect on nutritional status in our small sample. The lack of adverse effect noted in this study is possibly due to the low dose level of rHuTNF or to adaptation.
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PMID:Lack of significant changes in nutrition-related parameters with tumor necrosis factor treatment of cancer. 834 74

We previously established pluripotent transformed rat islet cell lines, MSL-cells, of which certain clones have been used to study processes of islet beta-cell maturation, including the transcriptional activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in NEDH rats resulted in stable hypoglycemic insulinoma tumor lines, such as MSL-G2-IN. Occasionally, hypoglycemia as well as severe weight loss were observed in the early tumor passages of MSL-G and the subclone, NHI-5B, which carry the transfected neomycin and human insulin genes as unique clonal markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (< 0.3% of total body weight), and the observed weight loss parallels that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene expression in both of the anorectic tumors, whereas insulin and islet amyloid polypeptide gene expression were confined to the insulinoma. Both tumor phenotypes produced cholecystokinin and gastrin in variable small amounts, making it unlikely that these hormones contribute to the anorectic phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to the administration of cholecystokinin, neither glucagon, Glp-1 (7-36)amide, nor their combination, affected feeding behavior in fasted mice, suggesting the presence of a hitherto unidentified anorectic substance released from the glucagonoma. We conclude 1) that glucagonomas and insulinomas can be derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to that reported in animals carrying tumor necrosis factor-producing experimental tumors.
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PMID:The dissociation of tumor-induced weight loss from hypoglycemia in a transplantable pluripotent rat islet tumor results in the segregation of stable alpha- and beta-cell tumor phenotypes. 840 49

Early and severe loss of body weight associated with pronounced tissue changes developed in rats transplanted with a fast-growing ascites hepatoma (Yoshida AH-130). The protein content showed an early and marked fall in the skeletal muscle, while in the liver it transiently increased 4 days after implantation then declined to values lower than in control animals. Protein loss in gastrocnemius muscle and liver resulted mainly from enhancement of protein catabolism (Tessitore L. et al., Biochem. J., 241: 153-158, 1987). In contrast to the tumour-bearing rats, in the pair-fed animals the initial body weight was maintained, while the protein mass decreased sharply in the liver and moderately in the gastrocnemius muscle. In host animals total plasma protein decreased during the period of tumour growth, while both triglycerides and total cholesterol markedly increased. Glucose remained unchanged even when overt cachexia had developed. The total free amino acid concentration in the plasma of tumour-bearing rats decreased slightly by day 4 and returned to values close to those of controls in the late stages of tumour growth. By contrast, in the pair-fed controls the plasma levels of triglycerides and particularly of total free amino acids and glucose decreased over the whole experimental period, whereas total protein and cholesterol were unchanged. Marked perturbations in the hormonal homeostasis developed early after tumour transplantation. The plasma levels of glucagon, corticosterone and catecholamines rose sharply, while those of insulin and thyroid hormones decreased. Furthermore, high plasma concentrations of prostaglandin E2 (PGE2) and tumour necrosis factor (TNF) were observed over the whole experimental period. IL-1-like activity, TNF and PGE2 were released in vitro from AH-130 cells. These data suggest that the systemic effects of AH-130 tumour on the host rat reflected the interplay of a complex network of factors, including classical hormones and cytokines, all of which likely concur in enhancing tissue protein catabolism.
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PMID:Humoral mediation for cachexia in tumour-bearing rats. 842 75

During the past 20 years, efforts have been made to elucidate the metabolic changes observed in patients with cancer by using stable and radioactive isotopic tracers. These metabolic changes in patients with cancer may be similar to those in other stress conditions, in which glucose production and utilization, lipolysis and free fatty acid flux, and net protein catabolism are increased. Stress hormones, such as glucagon and catecholamines, and certain cytokines may be responsible for these metabolic changes. Although it has been shown that cachexia in patients with cancer signals a poor prognosis, efforts to improve the clinical outcomes with nutritional support have been disappointing. The failure of cancer patients to respond to nutritional support may be related to an alteration in the intermediate metabolism. Therefore, further research evaluating the metabolic abnormalities associated with cancer may lead to more effective nutritional therapies.
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PMID:Metabolic alteration in patients with cancer: nutritional implications. 954 4

Apart from insulinomas, pancreatic tumors are rarely complicated by hypoglycemia and some may produce insulin-like growth factor II (IGF-II). To our knowledge, IGF-II-producing pancreatic tumors associated with hypoglycemia have not been reported previously. We describe what we believe to be the first case of "big" IGF-II-producing pancreatic acinar cell carcinoma. A 68-year-old man presented with a history of recurrent hypoglycemia. Abdominal computed tomography scan and magnetic resonance imaging showed a mass, approximately 5 cm in diameter, in the tail of the pancreas and two low-density areas in the liver. Low serum glucose was associated with low insulin levels and high levels of hormones (i.e., glucagon and IGF-II) that are functionally opposite to insulin. Although serum IGF-II level was within the normal range, most IGF-II was of the high molecular weight form, as determined by Western immunoblot analysis. Based on these findings, a diagnosis of hypoglycemia induced by IGF-II-producing pancreatic tumor was made. Surgery was not possible because of the patient's poor general condition. The patient ultimately died as a result of malignant cachexia. At autopsy, a yellowish-white tumor was found in the tail of the pancreas, and a histopathologic diagnosis of acinar cell carcinoma was made. Immunohistologically, the tumor cells contained IGF-II in an irregular staining pattern, suggesting that the hypoglycemia was caused by a pancreatic tumor producing "big" IGF-II.
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PMID:Acinar cell carcinoma of the pancreas associated with hypoglycemia: involvement of "big" insulin-like growth factor-II. 977 47

A large number of observations point towards cytokines, polypeptides released mainly by immune cells, as the molecules responsible for the metabolic derangements associated with cancer-bearing states. Indeed, these alterations lead to a pathological state known as cancer cachexia which is, unfortunately, one of the worst effects of malignancy, accounting for nearly a third of cancer deaths. It is characterized by weight loss together with anorexia, weakness, anemia, and asthenia. The complications associated with the appearance of the cachectic syndrome affect both the physiological and biochemical balance of the patient and have effects on the efficiency of the anticancer treatment, resulting in a considerably decreased survival time. At the metabolic level, cachexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores. The cachectic patient, in addition to having practically no adipose tissue, is basically subject to an important muscle wastage manifested as an excessive nitrogen loss. The metabolic changes are partially mediated by alterations in circulating hormone concentrations (insulin, glucagon, and glucocorticoids in particular) or in their effectiveness. The present study reviews the involvement of different cytokines in the metabolic and physiological alterations associated with tumor burden and cachexia. Among these cytokines, some can be considered as procachectic (such as tumor necrosis factor-alpha), while others having opposite effects can be named as anticachectic cytokines. It is the balance between these two cytokine types that finally seems to have a key role in cancer cachexia.
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PMID:The role of cytokines in cancer cachexia. 1023 51

Muscle atrophy and cachexia are associated with many human diseases. These catabolic states are often associated with the loss of glutathione (GSH), which is thought to contribute to the induction of oxidative stress within the muscle. Glutathione synthesis and secretary characteristics were studied in human skeletal muscle myoblasts and myotube-like cells derived from the myoblasts by growth factor restriction. Differentiation was associated with a shift in the sulfur amino acid precursor specificity for synthesis of GSH from cystine to cysteine, as well as loss in ability to use extracellular glutathione and activation of methionine use. The thiol drug N-acetylcysteine was also shown to be an effective precursor irrespective of the state of differentiation. Additionally, myoblasts and myotube cultures were shown to secrete GSH continually, but only the differentiated cells responded to stress hormones such as glucagon, vasopressin, and phenylephrine, by increased secretion of the tripeptide. The data suggest that the skeletal muscle cells may provide an important hormonally regulated extra-hepatic source of systemic GSH and also shed light on the mechanisms of accelerated turnover of GSH operating during strenuous muscle activity and trauma. The data may also provide biochemical rationales for the nutritional and/or pharmacological manipulation of GSH with sulfur amino acid precursors during the treatment of muscle-specific oxidative stress and atrophy.
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PMID:Differentiation-specific alterations to glutathione synthesis in and hormonally stimulated release from human skeletal muscle cells. 1182 Dec 57


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