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)

Factors contributing to modifications in the capability for enzyme adaptation as an expression of aging are reviewed. Specific examples of altered enzyme adaptations during aging include the responses of hepatic glucokinase activity to glucose and hepatic tyrosine aminotransferase activity to starvation in Sprague-Dawley rats. These impaired enzyme adaptations apparently are not the consequence of alterations in hepatic function during aging. Instead, they reflect disturbances in extrahepatic hormonal regulatory mechanisms. Specific examples include modifications in the control of circulating levels of insulin glucagon, corticosteroids, and thyroid hormones. Age-dependent changes in the regulation of circulating levels of insulin probably originate within the impaired ability of pancreatic islets of Langerhans to secrete the hormone in response to glucose. The rationale for exploiting this experimental approach as a means to understand biological aging is discussed.
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PMID:Loss of adaptive mechanisms during aging. 3 73

The isolated hepatocyte preparation (from 24-hour fasted rats) comprised a homogeneous population of intact cells as shown by electron microscopy. Homogenates of hepatocytes were incubated for 10 minutes in an ionic buffer solution containing 1.5% gelatin with and without hormones and centrifuged at 27,500 X g for 30 minutes, and the supernatant fractions were assayed for enzyme activities. Hexokinase activity was absent, although it was easily detectable in the same fraction of intact liver. The activity of glucokinase was uninfluenced by any of the hormones. The assayable activity of fructose diphosphatase was not increased by glucagon, monobutyryl cyclic adenosine-3',5'-monophosphate (mb-cAMP), or epinephrine, nor was it inhibited by insulin. The activities of phosphofructokinase and pyruvate kinase were not increased by insulin; however, glucagon and mb-cAMP inhibited the assayable activity of phosphofructokinase and pyruvate kinase to 20 to 25% of control values. Epinephrine did not influence the assayable activity of either enzyme, although it stimulated gluconeogenesis as markedly as did glucagon and mb-cAMP. When liver cell homogenates were subjected to centrifugation at higher forces (37,400 X g for 60 minutes or greater), the assayable activity of phosphofructokinase in supernatant fractions began to diminish. Additional loss of phosphofructokinase activity was observed in supernates prepared from cells that had been incubated with epinephrine; however, in these supernatant fractions, pyruvate kinase activity did not differ from control values. The results reported here demonstrate (1) a behavior of phosphofructokinase which is not predictable on the basis of its known solubility properties, and (2) differential effects of glucagon and epinephrine on the activity of phosphofructokinase which suggest that separate mechanisms are operative in stimulation of glucoeogenesis by glucagon and epinephrine.
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PMID:Gluconeogenesis in isolated rat hepatic parenchymal cells. IX. Differential effects of glucagon and epinephrine on phosphofructokinase and pyruvate kinase. 13 35

1. Glucokinase is one of four glucose phosphorylating enzymes present in rat liver. Its distinctive features are a high K-m for glucose (high-K-m isozyme) and a rather narrow substrate specificity. In contrast, the other three enzymes, collectively called hexokinases or low-K-m isozymes, exhibit low K-m values for glucose and a wider substrate specificity. 2. Glucokinase is present in the liver os mammals (with some exceptions), amphibians and lower reptiles; It is absent from higher reptiles and birds. The presence or absence of glucokinase may represent an evolutionary adaptation to feeding habits and other physiological peculiarities. Differences in the immunological behavior and in the kinetic parameters of glucokinases from different taxa suggest the operation of divergent evolution. 3. The levels of glucokinase in rat liver depend strictly on the supply of carbohydrate in the diet. Glycogen phosphorylase and glycogen synthetase behave similarly, whereas other carbohydrate-metabolizing enzymes depend on the provision of either protein or protein plus carbohydrate. Glucokinase decays with a half-life of 33 hr when rats are starved or fed a carbohydrate-free diet, and is induced by the administration of glucose. The adaptive character is not exhibited by all mammals, indicating evolutionary discrimination within the same class and even within the same single order Rodentia. Enzyme adaptation in the liver may partially explain the condition known as 'hunger diabetes'. 4. The endocrine system plays a paramount role in glucokinase adaptation, since insulin is essential for glucose-dependent glucokinase induction and, on the other hand, glucagon, catecholamines and cyclic AMP prevent the induction. Glucocorticoids and some pituitary hormones modulate the rate of induction. The mechanisms underlying the hormonal regulation of glucokinase levels are not well known. 5. The variations in liver glucokinase correspond to changes in the amount of enzyme protein as assessed by immunochemical titration. This fact agrees with the effects of inhibitors of protein synthesis on glucokinase induction. 6. An antiserum against rat glucokinase reacts with the enzyme from mammals and turtles but not with the amphibian enzyme. It does not react with low-K-m hexokinases from different sources. 7. The saturation function for glucose is sigmoidal in mammalian and amphibian glucokinases but not in glucokinase from lower reptiles. The Hill's coefficient is very constant with values about 1.6. The K0.5 (concentration for half saturation) values in the different species studied vary between 1.5 and 8 mM. These kinetic parameters may be considered as another adaptive feature aimed to give maximal efficiency to the liver uptake of glucose at the changeable concentrations in the blood resulting from variations in the amount of dietary glucose.
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PMID:Adaptive character of liver glucokinase. 16 20

Glucokinase activity in rat hepatocyte cultures declined with a half-time, t1/2, of 32 h during 3 days under serum-free conditions. Addition of insulin and triamcinolone to the culture medium prevented this decay. Glucokinase levels in hepatocytes derived from fasted rats could be elevated from 7.4 to 16.4 mU/mg protein in the presence of insulin and triamcinolone. In 2-day-old cultures glucokinase was induced in the presence of both hormones with a half time, t1/2, of 5.1 h. In cultures treated for 2 days with triamcinolone, insulin induced a 80% increase of glucokinase even in the absence of glucocorticoids. Insulin induction was dependent on protein synthesis but occurred in the absence of RNA synthesis. Glucocorticoid action, however, depended on RNA synthesis suggesting that glucocorticoids control transcription. Insulin evoked half-maximal effects at 3 nM and dexamethasone and triamcinolone at 0.1 and 1 nM respectively. Degradation of glucokinase was initiated in 2-day-old hepatocytes after removal of triamcinolone and insulin. Protein synthesis was essential for the onset of degradation and glucagon did not affect the rate of glucokinase degradation.
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PMID:Hormonal regulation of glucokinase in primary cultures of rat hepatocytes. 46 50

Streptozotocin treatment (125 mg/kg) in the Chinese hamster induced hyperglycaemia, hypoinsulinaemia, hyperglucagonaemia and changes in body, liver, pancreas, stomach, kidney and adipose tissue weights. The pancreatic reserves of insulin and glucagon in the diabetic animals were low, but stomach glucagon high. These animals showed high levels of phosphoenolpyruvate carboxykinase and low levels of glucokinase, hexokinase, isocitrate dehydrogenase and malic enzyme, but normal levels of pyruvate kinase in the liver. Increases in lactate dehydrogenase subunit B and isozymes 2, 3 and 4 were also observed in the liver, but not in the epididymal fat pad, of the diabetic animals. N-Acetyl-beta-D-glucosaminidase was elevated in plasma, liver and heart, but not in the kidney of the treated animals. Renal alpha-galactosidase and beta-glucosidase were depressed, whereas beta-galactosidase and alpha-glucosidase remained essentially normal. These features indicated that there were considerable differences between the biochemical disorders associated with streptozotocin-diabetes in the Chinese hamster and the published observations in the rat.
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PMID:Streptozotocin-induced diabetes in the Chinese hamster. Biochemical and endocrine disorders. 59 Jun 51

In unanesthetized normal and methylprednisolone (MP)-treated dogs the rate of appearance of glucose was measured simultaneously with 2-3H (RA2 = hepatic glucose output), 6-3H (Ra6 = hepatic glucose production), and 14C-glucose (U) (RaC) as tracers (primed constant rate infusion). The substrate ("futile") cycle of glucose (SC: gl in equilibrium gl-6-P) was obtained from Ra2 - Ra6, and Ra6 -RaC gave the recycling (RC) of radiocarbons. In normal dogs SC and RC represented 13% and 11% of Ra6, respectively. MP increased SC almost eightfold without altering RC. Infusion of glucagon (increased breakdown of glycogen, inhibition of glycogen synthetase) or mannoheptulose (inhibition of glucokinase) as well as exercise increased SC. MP greatly potentiated the effect causing SC to rise to 20 times the normal baseline. In both groups there was a direct correlation between Ra6 and SC. Glucose infusion did not alter SC in the controls, but increased it in the MP-treated dogs by suppressing Ra6 more than Ra2. It is suggested that the multifunctional character of gl-6-Pase is at least partly responsible for the glucose substrate cycle, using gl-6-P as one of the phosphate donors: gl-6-P + 3H-gl in equilibrium 3H-gl-6-P+gl. The activity of this enzyme is greatly elevated by the glucocorticoid, and it can be further enhanced by increasing the availability of gl-6-P by raising Ra6.
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PMID:Studies on hepatic glucose cycles in normal and methylprednisolone-treated dogs. 83 49

In cultured rat hepatocytes, transcription of the glucokinase gene is turned on by insulin and turned off by glucagon/cAMP, the latter being the dominant effector system. It is thus possible that in the absence of hormones the gene is maintained in a repressed state by the basal level of cAMP and that insulin turns on transcription by relieving cAMP repression, for instance via activation of a cyclic-nucleotide phosphodiesterase. Three inhibitors of this class of enzymes were tested for their effect on the insulin-dependent induction of the glucokinase gene in hepatocytes. Isobutyl methylxanthine, the prototype inhibitor, abrogated the gene response to insulin, as shown by run-on transcription assay. Among the drugs investigated, Ly186126, a preferential inhibitor of type-III phosphodiesterase, proved the most potent in inhibiting insulin-induced accumulation of glucokinase mRNA. Type-III phosphodiesterase is inhibited by cGMP. Induction of glucokinase mRNA was prevented in hepatocytes challenged with insulin in presence of 8-bromoguanosine-3',5'-phosphate. These results are consistent with the involvement of type-III phosphodiesterase in transduction of the insulin signal to the glucokinase gene. However, we were unable to detect significant decreases in total cellular cAMP level or cAMP-dependent-protein-kinase ratio after the addition of insulin to hepatocytes. Many effects of glucagon are mediated via cAMP-dependent protein-kinase phosphorylation of regulatory proteins and, conversely, insulin effects are often accompanied by protein dephosphorylation. A specific inhibitor of protein phosphatases PP1 and PP2A, okadaic acid, was shown to abolish the transcriptional response of the glucokinase gene to insulin. Thus, interference of insulin with the cAMP signal transduction pathway at several steps may be a critical aspect of insulin action on hepatic glucokinase gene expression. In addition, insulin induction of glucokinase mRNA was suppressed by inhibitors of protein synthesis. The underlying mechanism was a severe inhibition of the transcriptional effect of insulin, rather than mRNA destabilization, as demonstrated by run-on transcription assays with nuclei from cycloheximide-treated or pactamycin-treated cells. Transcription of the glucokinase gene may therefore depend on de novo synthesis of the product of an early-response gene induced by insulin, or may require a short-lived trans-acting or accessory factor of transcription. Alternatively, insulin signalling may be compromised in hepatocytes by a mechanism indirectly related to the arrest of protein synthesis.
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PMID:Insulin signalling and regulation of glucokinase gene expression in cultured hepatocytes. 128 Feb 18

Hepatocytes isolated from the liver of rats after a necrotizing dose of thioacetamide (6.6 mmol/kg) were used to study the postnecrotic process of liver regeneration. Flow cytometry analysis revealed populations of dedifferentiated hepatocytes exhibiting physical properties (size and fluorescence emission at 530 nm) similar to those found in fetal (22 days old) liver cells. The percentage of these cells increased progressively from 24 to 48 and 72 hr after thioacetamide administration. In primary cultures of hepatocytes the effects of phorbol 12-myristate 13-acetate, bombesin and insulin were investigated on the 6-phosphofructo 2-kinase/fructose 2,6 bisphosphate system. Bombesin and insulin stimulated 6-phosphofructo 2-kinase activity and fructose 2,6-bisphosphate content both in control and in thioacetamide-treated hepatocytes. However, phorbol 12-myristate 13-acetate stimulated 6-phosphofructo 2-kinase activity and increased fructose 2,6-bisphosphate concentration in thioacetamide-treated liver cells, whereas no similar response was found in hepatocytes from control rats. The response of postnecrotic thioacetamide-treated hepatocytes to phorbol 12-myristate 13-acetate was similar to that obtained from 22-day-old fetal liver cells, which reveals that different methods might control fructose 2,6-bisphosphate content and therefore the mechanisms of glycolysis and gluconeogenesis at this regulatory step. The lack of response to glucagon of glycogen phosphorylase a and 6-phosphofructo 2-kinase from thioacetamide-treated hepatocytes may indicate that the expression of specific enzymes of carbohydrate metabolism undergoes transitions to less-differentiated isoenzymatic forms. Moreover, the isoenzyme pattern of hexokinases elicits a complete disturbance in glucokinase and hexokinases activities.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isoenzymes of carbohydrate metabolism in primary cultures of hepatocytes from thioacetamide-induced rat liver necrosis: responses to growth factors. 131 52

Hepatocyte-hepatoma hybrid cells were obtained by fusion of hepatocytes from adult rats and Fao hepatoma cells in the presence of polyethylene glycol. These hybrids were called hepatocytoma cells. The preservation of liver-specific enzyme activities and metabolic functions was studied in the hybrid clone 1E3. 1) The proliferating hepatocytoma cells formed monolayers presenting morphological similarity to primary cultures of hepatocytes. 2) In contrast to Fao hepatoma cells, activities of all gluconeogenic key enzymes were preserved at normal or reduced levels. 3) Lactate-dependent glucose formation was maintained at a state reduced to 36% of the gluconeogenesis in hepatocytes; no glucose formation was detected in Fao hepatoma cells. 4) The activity of the liver-specific glucokinase was reduced in hepatocytoma cells, but it was still present in contrast to Fao cells. The liver-specific isoenzyme pyruvate kinase type L was replaced by the isoenzyme type M2. 5) Gluconeogenic and glycolytic enzyme activities were regulated in hepatocytoma cells by glucagon (0.1 microM) and by insulin (0.1 microM). 6) The genome of hepatocytoma cells and its expression were stable for at least one year, when spontaneously dedifferentiating cells were removed by recloning in hypoxanthine-aminopterine-thymidine (HAT) medium.
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PMID:Hormone-sensitive carbohydrate metabolism in rat hepatocyte-hepatoma hybrid cells. 132 97

Short- and long-term regulation of hepatic carbohydrate metabolism by insulin-like growth factor II was studied in primary cultures of adult rat hepatocytes and compared to the metabolic potency of insulin. Insulin-like growth factor II stimulated glycogen synthesis from [14C]glucose, uptake of [3H]aminoisobutyric acid and [14C]lactate formation from [14C]glucose up to three-fold. Basal glycogenolysis was inhibited to about 10%, and glucagon-activated glycogenolysis was blocked completely. The enzymatic activity of glucokinase and pyruvate kinase was induced two-fold, the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was antagonized. Compared to insulin, half-maximal responses required up to 50 times higher insulin-like growth factor II concentrations ranging from 10-20 nmol/l. A similar difference was observed for binding affinity of insulin-like growth factor II to the insulin receptor. The interaction with the insulin-like growth factor II/mannose 6-phosphate (IGF-II/Man-6-P) receptor was examined by studying 125I-insulin-like growth factor II binding and uptake of lysosomal enzymes. The affinity of insulin-like growth factor II to the IGF-II/Man-6-P receptor was considerably higher than for the insulin receptor. Antibodies against the IGF-II/Man-6-P receptor did not affect metabolic responses to insulin-like growth factor II, while binding to its receptor and the receptor-mediated endocytosis of arylsulphatase A were strongly inhibited. Thus, in adult rat liver insulin-like growth factor II appeared to exert metabolic actions not via interaction with its own receptor but through low affinity binding to hepatic insulin receptors.
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PMID:Metabolic actions of insulin-like growth factor II in cultured adult rat hepatocytes are not mediated through the insulin-like growth factor II receptor. 134 10


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