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)

The ability of 10 muM epinephrine or isoproterenol to stimulate cyclic AMP accumulation was decreased in hepatocytes isolated from hyperthyroid (triiodothyronine treated) as compared to euthyroid rats. In the presence of methylisobutylxanthine, epinephrine or isoproterenol-stimulated cyclic AMP accumulation was approximately 65% lower in hyperthyroid as compared with euthyroid rat hepatocytes. The ability of glucagon to stimulate a cyclic AMP response was also decreased in the hyperthyroid state, when assayed in either the absence or presence of a methyl xanthine. The character of the catecholamine-stimulated cyclic AMP response was beta adrenergic in both the hyperand euthyroid states. No evidence for an alpha(2) adrenergic mediated component of catecholamine action on cyclic AMP levels was noted. Cyclic AMP phosphodiesterase activity of hepatocyte homogenates was not altered in the hyperthyroid state. Hormone-stimulated, guanine nucleotide- and fluoride-activatable adenylate cyclase activity was reduced in subcellular fractions obtained from hyperthyroid as compared with euthyroid rat hepatocytes. Beta adrenergic receptor binding was reduced approximately 35% and glucagon receptor binding reduced approximately 50% in the hyperthyroid as compared with euthyroid rat hepatocyte membrane fractions. The status of the regulatory components of adenylate cyclase were examined by in vitro treatment of subcellular fractions with cholera toxin. The ability of cholera toxin to modulate adenylate cyclase was not altered by hyperthyroidism. Cholera toxin catalyzed AD[(32)P]ribosylation of hyperthyroid and euthyroid rat hepatocyte proteins separated electrophoretically displayed nearly identical autoradiograms. Studies of the reconstitution of adenylate cyclase activity of S49 mouse lymphoma cyc(-) mutant membranes by detergent extracts from rat hepatocyte membranes, indicated that hyperthyroidism was associated with a reduced capacity of regulatory components to confer fluoride, but not guanine nucleotide activatability to catalytic cyclase. Thyroid hormones regulate the hormone-sensitive adenylate cyclase system of rat hepatocytes at several distinct loci of the system.
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PMID:3,3',5-triiodothyronine administration in vivo modulates the hormone-sensitive adenylate cyclase system of rat hepatocytes. 627 41

Experiments were performed to determine whether the TSH receptor-adenylate cyclase (AC) system in benign and malignant thyroid neoplasms differs from the TSH receptor-AC system in normal thyroid tissue removed from the same patients. TSH binding and AC assays were performed using the same in vitro conditions. TSH binding was rapid, reversible, saturable, and hormone specific in particulate fractions from both normal and neoplastic thyroid tissue. A positive correlation existed between the equilibrium constants for [125I]bovine ([125I]bTSH) TSH binding and the concentration of TSH required to activate AC, suggesting that binding sites were coupled to AC in neoplastic thyroid tissue. Mean values for dissociation constants (Kd1 and Kd2), capacity (site 2), as determined by Scatchard analysis, and nonspecific binding (NSB) for the TSH receptors were lower in neoplastic thyroid. Some normal thyroid tissue appeared to lack a high affinity site, and some tumors lacked a low affinity binding site. Hormone specificities (bTSH, human (h) TSH, hLH, hFSH, hGH, hACTH, and glucagon) in normal thyroid and neoplastic tissue were virtually identical. hFSH, hACTH, hGH, and glucagon failed to inhibit [125I]bTSH binding or stimulate AC in either normal or neoplastic thyroid tissue, whereas hLH inhibited [125I]bTSH binding and stimulated AC, but required 10- to 100-fold higher concentrations than hTSH or bTSH. The specific binding and NSB of [125I]bTSH in both normal and neoplastic thyroid tissue was highest at pH 7.0 and lowest at pH 8.3. In contrast to bTSH binding, TSH stimulation of AC was lowest at pH 7.0 in both normal and neoplastic tissues and highest at pH levels of 7.5-8.0. TSH binding and TSH stimulation of AC activity were highest in the absence of NaCl and decreased progressively as the salt concentration was increased in both normal and neoplastic thyroid tissues. Increasing the sucrose concentration and, thus, the osmolarity of the system had a minimal effect on the binding of [125I]bTSH. Preincubation with ammonium sulfate did not significantly influence binding. Basal AC activity and the AC response to TSH were greater in neoplastic thyroid than in normal tissues. These studies demonstrate that changes in salt concentration and pH affect the TSH receptor-cyclase system in a comparable fashion in normal and neoplastic thyroid tissues. The discriminatory properties of the TSH receptor are also maintained in thyroid neoplasms. Thyroid tumors, however, have a higher affinity for TSH and display a greater AC response to TSH than normal thyroid tissue.
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PMID:Characterization of the thyrotropin receptor-adenylate cyclase system in neoplastic human thyroid tissue. 630 32

The case of a female patient with fasting hypoglycaemia before the development of Type 1 (insulin-dependent) diabetes mellitus is reported. She presented with primary hypothyroidism, partial hypopituitarism, adrenal insufficiency and glucagon deficiency. Thyroid microsomal and gastric parietal cell antibodies were detected as well as HLA-B8, whereas islet cell antibodies were not demonstrable, even 2 years after the onset of diabetes. Plasma chromatography revealed true pancreatic glucagon (IRG3500) close to undetectable in basal samples with a questionable increase from 3 to 18 pg/ml during insulin-induced hypoglycaemia. After an overnight fast, moderate hyperaminoacidaemia was found with elevations of alanine, glycine, serine, arginine and ornithine as seen in pancreatectomized patients. It is suggested that the deficient glucagon secretion in this patient might, at least in part, have been the cause of fasting hypoglycaemia and the failure of glucose recovery following insulin-induced hypoglycaemia. Possible, the A cell deficiency was part of the polyglandular failure syndrome in this patient.
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PMID:Glucagon deficiency associated with hypoglycaemia and the absence of islet cell antibodies in the polyglandular failure syndrome before the onset of insulin-dependent diabetes mellitus: a case report. 635 16

The role of glucocorticosteroid and thyroid hormone and of glucagon and insulin in the pre- and postnatal developmental formation of carbamoyl-phosphate synthase, ornithine transcarbamoylase, arginase, glutamate dehydrogenase, tyrosine aminotransferase, glucose-6-phosphatase, hexokinase and glucokinase activities in rat liver was investigated. Glucocorticosteroids and a low insulin/glucagon ratio always stimulate formation of carbamoyl-phosphate synthase, ornithine transcarbamoylase, arginase, glutamate dehydrogenase, tyrosine aminotransferase and glucose-6-phosphatase, while glucocorticosteroids and a high insulin/glucagon ratio stimulate formation of glucokinase. Thyroid hormone stimulates the formation of carbamoyl-phosphate synthase, arginase and tyrosine aminotransferase only before birth, whereas it stimulates the formation of glutamate dehydrogenase and glucose-6-phosphatase both before and after birth. Ornithine transcarbamoylase activity is depressed after thyroid-hormone treatment before and after birth. DNA content is always decreased by glucocorticosteroids and increased by thyroid hormone. The effect of these hormones on hexokinase is complex, probably due to different responses of the constitutive isozymes. With the exception of the effects of thyroid hormone on carbamoyl-phosphate synthase, arginase and tyrosine aminotransferase before birth, which may be indirect, the responses of enzyme activities and DNA content to treatment with glucocorticosteroid hormones, glucagon, insulin and thyroid hormone are qualitatively the same in fetuses, neonates, sucklings, weanlings and adults. Thus, the developmental profiles of the enzyme clusters reflect the changing levels of the relevant hormones. The enzymes that are stimulated by glucocorticosteroids and the insulin/glucagon ratio show increases in enzyme activity perinatally and around weaning, and relatively low activities in between, while those enzymes that are additionally stimulated by thyroid hormone differ in exhibiting relatively high activities between birth and weaning.
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PMID:Multihormonal control of enzyme clusters in rat liver ontogenesis. II. Role of glucocorticosteroid and thyroid hormone and of glucagon and insulin. 702 60

The endocrine response to stress is complex. Elevations in the serum concentrations of the "classic" stress hormones, epinephrine and cortisol, occur following many kinds of physiologic challenge and are accompanied by elevations in corticotropin, GH, and glucagon levels. These changes are probably responsible for the hyperglycemia and hypercatabolism common to most critical illness. If volume depletion is present, vasopressin, renin, and aldosterone secretion are also likely to be stimulated. These hormones, if present in excess, may produce fluid retention and hyponatremia. In some critically ill patients, there is a dissociation of renin and aldosterone production called hyperreninemic hypoaldosteronism, but the clinical importance of this syndrome is poorly understood. Thyroid hormone metabolism is commonly affected by critical illness, which results in characteristic abnormalities of thyroid function testing known as the euthyroid sick syndrome. The reproductive axis is exquisitely sensitive to physiologic stress; hypogonadotropic hypogonadism is a common finding in critical illness. The ongoing challenge to the clinician is to determine whether seemingly abnormal hormone measurements in critically ill patients reflect an appropriate homeostatic response to severe illness or, instead, whether they denote an independent metabolic disorder that might actually cause or contribute to the patient's unstable condition. In view of the exceedingly complex (and poorly understood) interactions involved in the human response to a severe illness, a thoughtful approach to the whole patient is essential and far preferable to indiscriminate hormone testing. Such testing, at best, may be uninterpretable in light of the clinical circumstances or, at worst, may lead to therapeutic misadventures.
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PMID:The endocrine response to critical illness. 780 93

We previously demonstrated that hyperglucagonemia may be responsible for thyroid hormone alterations noted in some nonthyroidal illnesses. Since TSH secretion is also known to be altered in many subjects with several nonthyroidal illnesses, we assessed the influence of sustained hyperglucagonemia on TSH secretory pattern in 5 anesthetized dogs. Serum TSH concentrations were determined after a 16-h fast and again at intervals of 15 min during sustained hyperglucagonemia (515-645 pg/mL) induced by iv bolus administration of glucagon 0.1 mg followed by a continuous glucagon infusion 3 ng/kg/min for 3 h. TRH (200 micrograms) was administered iv at 60 min to assess the influence of sustained hyperglucagonemia on the hypothalamic pituitary thyrotroph axis during the study. A control study was also conducted using normal saline instead of glucagon, and both studies were performed in a randomized sequence. Basal TSH levels were not significantly different during both studies. However, serum TSH declined significantly during sustained hyperglucagonemia prior to TRH administration (delta TSH, pre-TRH, -0.86 +/- 0.24 vs 0.02 +/- 0.07 ng/mL for normal saline, p < 0.01). Furthermore, TSH response to iv TRH administration was significantly blunted during glucagon infusion alone as expressed by both the absolute rise (delta TSH, post-TRH, 1.1 +/- 0.5 vs 5.9 +/- 1.7 ng/ml for normal saline, p < 0.01) as well as an integrated response over a 2-h period (sigma TSH, post-TRH, 4.0 +/- 1.1 vs 11.7 +/- 3.5 ng/min/mL, p < 0.001). Therefore, this study demonstrates that sustained hyperglucagonemia inhibits basal TSH secretion as well as TSH response to iv TRH administration, a TSH secretory pattern similar to that noted at the peak of many nonthyroidal illnesses.
Thyroid 1995 Oct
PMID:Impaired TSH secretion during sustained hyperglucagonemia in anesthetized dogs. 856 78

While all the hormones described have regulatory effects on the rates of protein synthesis and breakdown there is a complex interaction between them in this control process. Insulin, GH and IGF-I play a dominant role in the day-to-day regulation of protein metabolism. In humans insulin appears to act primarily to inhibit proteolysis while GH stimulates protein synthesis. In the post-absorptive state IGF-I has acute insulin-like effects on proteolysis but in the fed state, or when substrate is provided for protein synthesis in the form of an amino acid infusion, IGF-I has been shown to stimulate protein synthesis. Growth hormone and testosterone have an important role during growth but continue to be required to maintain body protein during adulthood. Thyroid hormones are also required for normal growth and development. The hormones glucagon, glucocorticoids and adrenaline are all increased in catabolic states and may work in concert to increase protein breakdown in muscle tissue and to increase amino acid uptake in liver for gluconeogenesis. While increased glucocorticoids result in reduced muscle mass the effects of glucagon may be predominantly in the liver resulting in increased uptake of amino acids. In contrast to the catabolic effect of adrenaline on glucose and lipid metabolism, studies to date suggest that adrenaline may have an anti-catabolic effect on protein metabolism. Despite this adrenaline increases the production of the gluconeogenic amino acid alanine by muscle and its uptake by the splanchnic bed. There is considerable interest in the use of anabolic hormones, either alone or in combination, in the treatment of catabolic states. GH combined with insulin has been shown to improve whole-body and skeletal muscle kinetics while GH combined with IGF-I has a greater positive effect on protein metabolism in catabolic states than either hormone alone. If catabolic states are to be treated successfully a greater understanding of the role of the catabolic hormones in these states and the possible treatment of these states with anabolic hormones is required.
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PMID:The hormonal control of protein metabolism. 902 51

"Spot 14" (S14) was originally identified as a mRNA from rat liver that responded rapidly to thyroid hormone, and has now been shown to play a key role in the tissue-specific regulation of lipid metabolism. In addition to its responsiveness to thyroid hormone, S14 gene transcription is controlled by dietary substrates, such as glucose and polyunsaturated fatty acids, and by fuel-related hormones including insulin and glucagon. The S14 protein forms homodimers via a carboxyl-terminal "zipper" domain. The protein is located primarily in the cell nucleus, and its expression in liver is limited to the perivenous portion of the hepatic lobule, the site of fatty acid synthesis. S14 protein is critical for the induction of key enzymes involved in the switching of hepatic metabolism from the fasted to the fed state. S14 antisense oligonucleotides inhibit both the intracellular production of lipids and their export as very low-density lipoprotein (VLDL) particles. S14 acts at the level of transcription to regulate expression of genes encoding key metabolic enzymes, including those required for long-chain fatty acid synthesis. The human S14 gene is located at 11q13.5, a region that is amplified in a subset of aggressive breast cancers. S14 mRNA is expressed in most breast cancer-derived cell lines, and the protein is found in the nuclei of two thirds of human breast cancer specimens, but not in normal nonlactating mammary glands. S14 expression in breast tumors is highly concordant with overabundance of a key lipogenic enzyme. This indicates the association of S14 with enhanced tumor lipogenesis, an established marker of poor prognosis. In addition to the utility of S14 as a model system for elucidation of the mechanism of thyroid hormone action, studies of its regulation and function have provided insights into tissue-specific metabolic control by hormones and dietary substrates in both normal and neoplastic tissues.
Thyroid 1998 Sep
PMID:"Spot 14" protein: a metabolic integrator in normal and neoplastic cells. 977 55

Regulation of the expression of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by the major end product of the biosynthetic pathway, cholesterol, and by various hormones is critical to maintaining constant serum and tissue cholesterol levels in the face of an ever-changing external environment. The ability to downregulate this enzyme provides a means to buffer the body against the serum cholesterol-raising action of dietary cholesterol. The higher the basal expression of hepatic HMG-CoA reductase, the greater the "cholesterol buffering capacity" and the greater the resistance to dietary cholesterol. This review focuses on the mechanisms of feedback and hormonal regulation of HMG-CoA reductase in intact animals rather than in cultured cells and presents the evidence that leads to the proposal that regulation of hepatic HMG-CoA reductase acts as a cholesterol buffer. Recent studies with animals have shown that feedback regulation of hepatic HMG-CoA reductase occurs at the level of translation in addition to transcription. The translational efficiency of HMG-CoA reductase mRNA is diminished through the action of dietary cholesterol. Oxylanosterols appear to be involved in this translational regulation. Feedback regulation by dietary cholesterol does not appear to involve changes in the state of phosphorylation of hepatic HMG-CoA reductase or in the rate of degradation of this enzyme. Several hormones act to alter the expression of hepatic HMG-CoA reductase in animals. These include insulin, glucagon, glucocorticoids, thyroid hormone and estrogen. Insulin stimulates HMG-CoA reductase activity likely by increasing the rate of transcription, whereas glucagon acts by opposing this effect. Hepatic HMG-CoA reductase activity undergoes a significant diurnal variation due to changes in the level of immunoreactive protein primarily mediated by changes in insulin and glucagon levels. Thyroid hormone increases hepatic HMG-CoA reductase levels by acting to increase both transcription and stability of the mRNA. Glucocorticoids act to decrease hepatic HMG-CoA reductase expression by destabilizing reductase mRNA. Estrogen acts to increase hepatic HMG-CoA reductase activity primarily by stabilizing the mRNA. Deficiencies in those hormones that act to increase hepatic HMG-CoA reductase gene expression lead to elevations in serum cholesterol levels. High basal expression of hepatic HMG-CoA reductase, whether due to genetic or hormonal factors, appears to result in greater cholesterol buffering capacity and thus increased resistance to dietary cholesterol.
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PMID:Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. 1078 41

Mitochondrial uncoupling protein-2 and -3 (UCP2 and UCP3) may be involved in the modulation of resting metabolic rate and energy balance. To investigate their variability, the influence of this on the variability of energy expenditure, and potential regulatory factors of the expression of the corresponding genes, we measured their messenger ribonucleic acids (mRNAs) in muscle and white adipose tissue of lean, healthy men and correlated the abundance of these mRNAs (attomoles per microg total RNA) with measures of resting metabolic rate, hormone levels (thyroid hormones, insulin, glucagon, leptin, and catecholamines), and fuels potentially involved in energy balance regulation. We also investigated whether the thiazolidinedione, troglitazone, stimulates UCP2 and UCP3 mRNA levels to follow up on the observation that this antidiabetic drug increases the levels of expression in cultured cells. We found UCP2 and UCP3 mRNA levels to be highly variable and poorly correlated with measures of energy expenditure and with most factors affecting energy balance. Only nocturnal urinary norepinephrine excretion could explain a significant fraction of the variability in both UCP2 and UCP3 expression in muscle, but not adipose tissue. Thyroid hormone and norepinephrine excretion were found to contribute to the variability of resting metabolic rate, but this could not be explained by an effect on UCP mRNAs. Troglitazone affected neither the expression of UCPs nor the hormones or the measures of metabolic rate investigated. In conclusion, our results show that the expression of UCP2 and UCP3 genes is quite variable in healthy males and that this variability does not explain that in resting energy expenditure, and suggest that sympathetic activity is an important potential regulator of the expression of these proteins in skeletal muscle. However, the data do not support the concept that regulation of the expression of these genes is the most important level of control of UCP3 and UCP2 functions, and other levels of control have to be invoked.
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PMID:Uncoupling protein-2 and -3 messenger ribonucleic acids in adipose tissue and skeletal muscle of healthy males: variability, factors affecting expression, and relation to measures of metabolic rate. 1084 84


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