Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cadmium, in addition to producing a variety of toxic manifestations, is known to accumulate in certain "target" organs which include liver and kidney where histological and functional damage becomes apparent. The daily intraperitoneal injection of cadmium chloride for 21 or 45 days stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase and glucose-6-phosphatase elevated blood glucose and urea, and lowered hepatic glycogen in rats. Whereas chronic Cd treatment failed to alter adenosine-3', 5'-monophosphate phosphodiesterase (PDE) activity, cyclic AMP (cAMY and the activity of basal and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased. However, the cAMP binding to hepatic protein kinase was decreased as was the kinase activity ration. An acute dose of Cd decreased hepatic glycogen content and increased blood glucose, serum urea, and hepatic cAMP. Chronic exposure to Cd induced adrenal hypertrophy and augmented adrenal norepinephrine and epinephrine as well as the activity of adrenal tyrosine hydroxylase. This treatment decreased prostatic and testicular weights of mature rats. Although cAMP as well as AC activity of the prostate gland were reduced, cAMP binding to the prostatic protein kinase was increased as was the activity of the cAMP-dependent form of the enzyme. Testicular AC and PDE activities, however, were stimulated, although cAMP remained unaffected. Whereas the activities of the cAMP-dependent and the independent forms of testicular protein kinase were significantly depressed, the binding of cAMP to protein kinase from testes of Cd-treated rats was not affected. In most cases, the observed metabolic alterations persisted up to 28 days on cessation of Cd administration. Subacute Cd treatment suppressed pancreatic function as evidenced by lowered serum immunoreactive insulin (IRI) in presence of hyperglycemia, as well as by partial inhibition of phentolamine-stimulated increases in serum IRI. Although chronic Cd treatment failed to alter the concentration of brain stem norepinephrine and cerebrocortical acetylcholine esterase activity, serotonin levels of brain stem were depressed and the concentration of striatal dopamine and cerebrocortical acetylcholine were significantly elevated when compared with the values seen in control nonexposed animals.
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PMID:Aspects of the biochemical toxicology of cadmium. 17 84

The covalent modification of receptor proteins via phosphorylation and dephosphorylation is one of the principal mechanisms controlling carbohydrate metabolism and is known to be regulated by various protein kinases. Recent studies indicated that many hormones may exert their effects on cellular metabolism by regulating intracellular c-AMP levels and by activating a c-AMP dependent protein kinase, i.e., protein kinase A. The metabolic disturbances during sepsis are characterized by an initial hyperglycemia followed by a progressive hypoglycemia and a depletion of hepatic glycogen content. The latter is coupled with a slowdown in glycogenesis, an accelerated glycogenolysis, and a depression in gluconeogenesis in the liver. Since the liver is the major organ that regulates the homeostatic level of blood glucose, it is conceivable that the sepsis-induced glucose dyshomeostasis might be mediated by changes in protein kinase activity and the kinetic characteristics of enzymes. The present experiment was designed to study the correlation between protein kinase A and the pathophysiology of hepatic glucose dyshomeostasis during sepsis. Sepsis was induced in rats by cecal ligation and puncture (CLP). Late sepsis occurred 18 hours after CLP. Protein kinase A was extracted from the rat livers by acid precipitation and ammonium sulfate fractionation, and then partially purified by DEAE-cellulose. The results show that in the late sepsis, type-I protein kinase A (eluted at low ionic strength) activity was significantly decreased by 34-52% (P < 0.01). The kinetic parameters such as Vmax's for ATP, histone, and c-AMP were also significantly decreased from the control values of 6.1 +/- 0.9, 5.4 +/- 0.8, and 5.1 +/- 1.9 nmoles/mg.min. to 3.6 +/- 0.5, 2.8 +/- 0.3, and 2.5 +/- 0.5 nmoles/mg.min., respectively. Analysis using Hill's equation indicates that the S0.5 and n (Hill coefficient) values of the various substrates and activators for type-I protein kinase A remained unchanged. In the case of type-II protein kinase A (eluted at high ionic strength), the Vmax, S0.5, and n values for ATP, histone, and c-AMP were unchanged during late sepsis. The results of the present study indicate that the activities and kinetic characteristics of type I protein kinase A in rat liver are modified during late sepsis. Since protein kinase A is known to regulate glucose metabolism through adrenergic receptor mediation, these findings may have a pathophysiological significance in the understanding of hepatic glucose dyshomeostasis during sepsis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Kinetic studies of protein kinase A in rat liver during late sepsis]. 129 61

In human diabetes, inherent impaired insulin secretion can be exacerbated by desensitization of the beta cell by chronic hyperglycemia. Interest in this phenomenon has generated extensive studies in genetic or experimentally induced diabetes in animals and in fully in vitro systems, with often conflicting results. In general, although chronic glucose causes decreased beta-cell response to this carbohydrate, basal response and response to alternate stimulating agents are enhanced. Glucose-stimulated insulin synthesis can be increased or decreased depending on the system studied. Using a two-compartment beta-cell model of phasic insulin secretion, a unifying hypothesis is described which can explain some of the apparent conflicting data. This hypothesis suggests that glucose-desensitization is caused by an impairment in stimulation of a hypothetical potentiator singularly responsible for: 1) some of the characteristic phases of insulin secretion; 2) basal release; 3) potentiation of non-glucose stimulators; and 4) apparent "recovery" from desensitization. Review of some of the pathways that regulate insulin secretion suggest that phosphoinositol metabolism and protein kinase-C production are regulated similarly to the theoretical potentiator and their impairment is a major contributor to glucose desensitization in the beta cell.
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PMID:Desensitization of the insulin-secreting beta cell. 131 59

Skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin; i.e., the effect of insulin on glucose disposal is reduced compared with the effect in control subjects. This defect has been found to be localized to the nonoxidative pathway of glucose disposal; hence, the deposition of glucose, as glycogen, is abnormally low. This defect may be inherited, because it is present in first-degree relatives to NIDDM patients two to three decades before they develop frank diabetes mellitus. The cellular defects responsible for the abnormal insulin action in NIDDM patients is reviewed in this article. The paper focuses mainly on convalent insulin signaling. Insulin is postulated to stimulate glucose storage by initiating a cascade of phosphorylation and dephosphorylation events, which results in dephosphorylation and hence activation of the enzyme glycogen synthase. Glycogen synthase is the key enzyme in regulation of glycogen synthesis in the skeletal muscles of humans. This enzyme is sensitive to insulin, but in NIDDM patients it has been shown to be completely resistant to insulin stimulation when measured at euglycemia. The enzyme seems to be locked in the glucose-6-phosphate (G-6-P)-dependent inactive D-form. This hypothesis is favored by the finding of reduced activity of the glycogen synthase phosphatase and increased activity of the respective kinase cAMP-dependent protein kinase. A reduced glycogen synthase activity has also been found in normoglycemic first-degree relatives of NIDDM patients, indicating that this abnormality precedes development of hyperglycemia in subjects prone to develop NIDDM. Therefore, this defect may be of primary genetic origin. However, it does not appear to be a defect in the enzyme itself, but rather a defect in the covalent activation of the enzyme system. Glycogen synthase is resistant to insulin but may be activated allosterically by G-6-P. This means that the defect in insulin activation can be compensated for by increased intracellular concentrations of G-6-P. In fact, we found that both hyperinsulinemia and hyperglycemia are able to increase the G-6-P level in skeletal muscles. Thus, insulin resistance in the nonoxidative pathway of glucose processing can be overcomed (compensated) by hyperinsulinemia and hyperglycemia. In conclusion, we hypothesize that insulin resistance in skeletal muscles may be a primary genetic defect preceding the diabetic state. The cellular abnormality responsible for that may be a reduced covalent insulin activation of the enzyme glycogen synthase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin resistance in skeletal muscles in patients with NIDDM. 155 9

The effects of insulin and glucose, alone and combined, on diacylglycerol (DAG), protein kinase-C (PKC), and glucose transport were compared in rat adipocytes and solei incubated in medium containing 0-20 mM glucose. In both tissues insulin rapidly stimulated [3H]DAG production from [3H]glycerol; extracellular glucose masked this effect in adipocytes, but not in solei. [3H]Glucose was avidly converted to DAG in adipocytes, and this conversion was enhanced by insulin. In contrast, [3H]glucose was poorly converted to DAG in solei. Glucose alone (5-20 mM) stimulated PKC translocation in adipocytes, but not in solei. Insulin stimulated PKC translocation in both tissues at all glucose concentrations. However, glucose modulated this effect of insulin in adipocytes by 1) decreasing cytosolic PKC and the absolute amount of PKC translocated, and 2) promoting apparent turnover of membrane PKC. In contrast, in solei, glucose did not affect PKC levels or translocation responses to insulin. In keeping with DAG-PKC signalling, the relative glucose transport effects of insulin were influenced by extracellular glucose in adipocytes, but not in solei. These results suggest that 1) glucose-induced PKC translocation requires metabolism of glucose to DAG; 2) glucose activates DAG-PKC signalling in adipocytes, but not in solei; 3) insulin activates DAG-PKC signalling in both tissues at all glucose levels; and 4) glucose may modulate the effects of insulin on DAG-PKC signalling in adipocytes, but not in solei. Consistent with in vitro results, in solei taken directly from diabetic rats, membrane PKC was decreased, and cytosolic PKC was increased, presumably reflecting diminished PKC translocation due to hypoinsulinemia. In contrast, in adipose tissue, cytosolic PKC was decreased, presumably reflecting hyperglycemia-induced PKC translocation. Accordingly, DAG levels were increased in adipose tissue, but not in solei, in diabetic rats, and insulin increased DAG in both tissues.
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PMID:Interrelated effects of insulin and glucose on diacylglycerol-protein kinase-C signalling in rat adipocytes and solei muscle in vitro and in vivo in diabetic rats. 203 70

The effect of oral administration of sodium orthovanadate for 5 wk on hepatic glycogen metabolism was studied in control and streptozocin-induced diabetic rats. Diabetes caused hyperglycemia (5-fold increase), hypoinsulinemia (85% decrease), and hyperglucagonemia (4-fold increase). There were also marked decreases in liver glycogen and activities of glycogen-metabolizing enzymes in liver. Although vanadate administration in control animals showed no significant effect on the various parameters measured except for a 70% decrease in plasma insulin, this treatment in diabetic rats restored these parameters to near control values. In diabetic rats, glycogen synthase a and the activity ratio (activity of glycogen synthase a divided by activity of total glycogen synthase) decreased to 30% of control levels and were restored to approximately 70-80% of control values after vanadate administration. A similar pattern was observed for the activity of synthase phosphatase. The activities of glycogenolytic enzymes, i.e., phosphorylase (activity of phosphorylase a and activity of total phosphorylase), phosphorylase kinase, and protein kinase (in presence or absence of cAMP), were significantly decreased by 40-70% in diabetic rats. These enzyme activities were recovered to 70-100% of control values after vanadate treatment. Phosphorylase phosphatase was not altered by diabetes, but the vanadate treatment of both groups, i.e., control and diabetic rats, showed a 25% increase in its activity (P less than 0.01). In conclusion, these results show insulinlike in vivo action of vanadate on various parameters related to hepatic glycogen metabolism.
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PMID:Insulinlike effects of vanadate on hepatic glycogen metabolism in nondiabetic and streptozocin-induced diabetic rats. 211 14

Increased hepatic glucose production is responsible for fasting hyperglycemia in type II diabetes. Insulin resistance is the key in this process because of the inability of insulin to suppress hepatic glucose production, thereby allowing an unopposed glucagon effect. Glyburide, one of the second-generation sulfonylureas, decreases glucose production and enhances insulin action in the liver. Available data suggest that glyburide: (1) enhances glycogen synthesis in the liver by increasing glycogen synthase; (2) inhibits glycogenolysis by decreasing phosphorylase alpha activity; and (3) decreases gluconeogenesis and stimulates glycolysis by decreasing A-kinase activity, which results in increased fructose 2,6-bisphosphate, one of the key regulators of carbohydrate metabolism in the liver. The effect of glyburide on the insulin-signaling mechanism(s) is distal to the insulin binding site of the alpha-subunit of the insulin receptor and the tyrosine kinase activation site of the beta-subunit.
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PMID:Effects of glyburide on carbohydrate metabolism and insulin action in the liver. 211 86

The site(s) of action of a bovine pituitary diabetogenic peptide that produces hyperglycemia and hyperinsulinemia in vivo (dogs or humans) was investigated in vitro. When rat diaphragms were incubated with the peptide in the presence of insulin, the peptide depressed insulin-mediated (a) glucose uptake, (b) glycogen synthesis, and (c) glycogen synthase activation (conversion of D to I form). Incubation with the peptide alone resulted in small increases in (a), (b), and (c). Insulin-mediated glycogen synthase kinase inactivation was inhibited when both insulin and peptide were present (d), whereas glycogen synthase kinase activity was lowered by the peptide alone. High doses of insulin completely reversed inhibitory effects of the peptide on glycogen synthesis. Therefore, the hyperglycemic and anti-insulin properties of this peptide in vivo can possibly be explained by the partial blocking action of the peptide on insulin-mediated glucose uptake and glycogenesis.
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PMID:Anti-insulin actions of a bovine pituitary diabetogenic peptide on glycogen synthesis. 462 94

Cadmium (Cd) produces injurious effects on reproductive function and has been implicated in the pathogeneses of hypertension. The present article summarizes available data on alterations in the cyclic AMP system of testicular and prostatic tissue as well as in catecholamine metabolism in adrenal glands following exposure to Cd and subsequent withdrawal. Daily Cd (1 mg/kg IP) for 45 days decreased prostatic and testicular weights of mature male rats. In prostate, chronic treatment with Cd reduced cyclic AMP levels to 57% of normal values which appeared to be due to the decrease in adenylate cyclase activity since cyclic AMP metabolism by phosphodiesterase was not significantly altered. Cyclic AMP binding to prostatic protein kinase was increased following Cd administration as was the activity of the cyclic AMP-dependent form of protein kinase. In contrast to the prostate, testicular adenylate cyclase was stimulated by Cd treatment. However, the endogenous cyclic AMP levels remained unaffected since the increase in testicular adenylate cyclase was offset by a concomitant increase in the activity of phosphodiesterase. Although the activities of the cyclic AMP-dependent and the independent forms of testicular protein kinase were significantly depressed, the binding of cyclic AMP to protein kinase from testes of Cd-treated rats was not affected. Discontinuation of treatment for 28 days in rats that had previously been given the heavy metal for 45 days resulted in at least a partial reversal of several of the cadmium-induced changes in cyclic AMP metabolism of the rat prostate and testes. However, the weight of the prostate glands remained essentially in the same range as that seen in the "treated group."Data suggest that cyclic AMP metabolism in both the primary and the secondary reproductive organs is altered following chronic Cd treatment and that some changes persist even 28 days following the termination of daily exposure to the heavy metal.Cd treatment also increased adrenal weights and augmented the levels of adrenal norepinephrine and epinephrine as well as the activity of tyrosine hydroxylase. Discontinuation of the heavy metal treatment for 28 days, in rats previously injected with Cd for 45 days, restored the activity of tyrosine hydroxylase as well as the amount of norepinephrine and epinephrine. In contrast, adrenal weights were restored only partially following withdrawal of Cd treatment. Evidence indicates that the changes in adrenal catecholamine metabolism may be the result of stress induced by chronic exposure to this heavy metal. In addition, some of the untoward effects such as hyperglycemia and arterial hypertension seen during Cd toxicity might be related to increased synthesis of epinephrine in adrenal glands.
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PMID:Testicular cyclic nucleotide and adrenal catecholamine metabolism following chronic exposure to cadmium. 611 36

In the insulin-secreting beta-cell line beta TC3, stimulation with 11.2 mmol/l glucose caused a rise in the intracellular free Ca2+ concentration ([Ca2+]i) in only 18% of the tested cells. The number of glucose-responsive cells increased after pretreatment of the cells with glucagon-like peptide I (GLP-I)(7-36)amide and at 10(-11) mol/l; 84% of the cells responded to glucose with a rise in [Ca2+]i. GLP-I(7-36)amide induces a rapid increase in [Ca2+]i only in cells exposed to elevated glucose concentrations (> or = 5.6 mmol/l). The action of GLP-I(7-36)amide and forskolin involved a 10-fold increase in cytoplasmic cAMP concentration and was mediated by activation of protein kinase A. It was not associated with an effect on the membrane potential but required some (small) initial entry of Ca2+ through voltage-dependent L-type Ca2+ channels, which then produced a further increase in [Ca2+]i by mobilization from intracellular stores. The latter effect reflected Ca(2+)-induced Ca2+ release and was blocked by ryanodine. Similar increases in [Ca2+]i were also observed in voltage-clamped cells, although there was neither activation of a background (Ca(2+)-permeable) inward current nor enhancement of the voltage-dependent L-type Ca2+ current. These observations are consistent with GLP-I(7-36) amide inducing glucose sensitivity by promoting mobilization of Ca2+ from intracellular stores. We propose that this novel action of GLP-I(7-36)amide represents an important factor contributing to its insulinotropic action.
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PMID:Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting beta TC3-cells by enhancement of intracellular calcium mobilization. 778 44


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