Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological and clinical data suggest a relationship between hyperinsulinism and macroangiopathy in non insulin-dependent diabetes. On the other hand, a relationship between the plasma free insulin level and macroangiopathy has not been documented in insulin-dependent diabetes. Other abnormalities in addition to hyperinsulinism and glucose intolerance are frequently associated in the presence of insulin resistance and have been grouped by Reaven under the term syndrome X: raised VLDL triglycerides, decreased HDL, and raised blood pressure. Iatrogenic hyperinsulinism appears to be an arterial risk factor, but by what mechanism may it also constitute an independent risk factor? The following theoretical aspects of a possible atherogenic role of hyperinsulinism are currently being investigated: a) insulin stimulates the proliferation and migration of smooth muscle cells either directly or via a rise in IGF1; b) insulin induces lipogenesis in the intima-media, but it has not been demonstrated that this in situ lipogenesis is atherogenic; c) insulin raises the VLDL production, decreases HDL and modifies the clearance of LDL; d) insulin increases blood pressure by stimulating both the renal reabsorption of sodium and the sympathetic nervous system; insulin resistance may also be expressed at the level of the Na-K-ATPase of vascular smooth muscle cells by decreasing the vasodilator effect of the hormone; e) lastly, insulin induces a defect of fibrinolysis mediated by an increase in the level of plasminogen activator inhibitors (PAI1). In conclusion, the combination of hyperglycemia and hyperinsulinism is probably damaging to the artery. Therapeutic intervention studies are necessary to confirm and define the role of hyperinsulinism in macroangiopathy and to answer the unresolved questions: direct or indirect role? effect of endogenous and/or exogenous hyperinsulinism?
...
PMID:[Theoretical aspects of the relationship between diabetic macroangiopathy and hyperinsulinism]. 143 1

Insulin augments Na(+)-K(+)-ATPase activity in skeletal muscles. It has been proposed that the sequence of events is activation of Na(+)-H+ antiporter, increased intracellular Na+ concentration ( [Na+]i), and stimulation of Na(+)-K+ pump. We have used isolated rat soleus muscles to test this hypothesis. Insulin increased the ouabain-suppressible K+ uptake in a dose- and time-dependent manner. The maximal effect was observed at 50-100 mU/ml insulin. Stimulation of K+ uptake was accompanied by increased specific [3H]ouabain binding and lowered [Na+]i. The ionophore monensin, which promotes Na(+)-H+ exchange, also increased the rate of ouabain-suppressible K+ uptake in soleus muscle, with a maximal effect obtained at 10-100 microM ionophore. However, this increase was accompanied by an elevation of [Na+]i. In the presence of 10-100 microM monensin, addition of 100 mU/ml insulin further increased K+ uptake but reduced [Na+]i. The effect on K+ uptake was additive. Ouabain (10(-3) M) completely suppressed the effect of insulin on [Na+]i. Insulin had no effect on the magnitude or the time course of insulin stimulation of K+ uptake. Thus equal stimulation of Na(+)-K(+)-ATPase by insulin was observed when [Na+]i was elevated (under monensin) or lowered (under amiloride). These data suggest that activation of Na(+)-K(+)-ATPase in soleus muscle by insulin is not secondary to stimulation of Na(+)-H+ antiporter.
...
PMID:Mechanism of insulin-induced activation of Na(+)-K(+)-ATPase in isolated rat soleus muscle. 165 50

Epidemiologic studies have shown that insulin is a risk factor for coronary heart disease (CHD). Clinical studies have also demonstrated positive correlations between insulin and blood pressure, triglycerides, total cholesterol, fibrinogen, and plasminogen activator inhibitor. Moreover, there is an inverse correlation between insulin and high-density lipoprotein (HDL). These studies have provided evidence in support of the biologic plausibility of epidemiologic observations, but they have not clearly established insulin's role in the pathogenesis of human cardiovascular diseases (CVD) such as hypertension. In fact, there is considerable evidence that insulin resistance (abnormal nonoxidative glucose disposal), not hyperinsulinemia, is the primary insulin-related abnormality in human hypertension, and that hyperinsulinemia occurs as a response to insulin resistance. Skeletal muscle appears to be the primary site of insulin resistance in essential hypertension, although other organs, such as the kidneys and liver--key sites for cell and water homeostasis and lipoprotein regulation, respectively--may respond normally to insulin. Adipocytes also appear to be a site of insulin resistance. Thus, the putative interrelationship between hyperinsulinemia and insulin resistance, on the one hand, and with blood pressure and lipoproteins, on the other, is a complex one and may involve organ-specific insulin resistance. Altered cation transport is one of several mechanisms by which insulin resistance might raise blood pressure. The Na+, K(+)-ATPase and Ca(2+)-ATPase pumps are insulin sensitive. Thus, when insulin resistance is present, the activity of these pumps in the smooth muscle of the arterial wall might be reduced. This would lead to an intracellular accumulation of sodium and calcium, thereby sensitizing the vascular wall to pressor substances. Moreover, secondary hyperinsulinemia will occur, and insulin has been shown to stimulate sympathetic nervous system activity and to increase renal tubular absorption of sodium. Insulin is also a growth factor and therefore might have a trophic effect on the vessel wall, one that could initiate and/or sustain hypertension as well as atherosclerosis. Abnormal lipoprotein metabolism is yet another possible explanation for the accelerated atherosclerosis that has been observed in persons with abnormal carbohydrate tolerance and insulin resistance. Hyperinsulinemia and insulin resistance both play a role in the expression of elevated very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels as well as in the depression of HDL levels. Coronary risk reduction has been disappointing when blood pressure has been lowered with treatment regimens based on thiazide diuretics and/or beta blockers. Thiazides and some beta blockers may further impair tissue insulin sensitivity and often cause blood lipoprotein abnormalities.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Epidemiologic and clinical aspects of insulin resistance and hyperinsulinemia. 186 24

Hypertension in insulin resistance states is generally attributed to hyperinsulinemia, with resulting increases in renal sodium retention and/or sympathetic nervous system activity. However, recent data from our laboratory suggest that cellular insulin resistance, rather than hyperinsulinemia per se, may lead to hypertension. The basic tenet proposed in this review is that the common mechanism involved in the development of hypertension in both type I and type II diabetes mellitus is a deficiency of insulin at the cellular level. Recent observations suggest that impaired cellular response to insulin predisposes to increased vascular smooth muscle (VSM) tone (the hallmark of hypertension in the diabetic state). For example, recently reported studies from our laboratory demonstrate that insulin in physiological doses attenuates the vascular contractile response to phenylephrine, serotonin, and potassium chloride. Thus, insulin appears to normally modulate (attenuate) VSM contractile responses to vasoactive factors, and insulin resistance should accordingly be associated with enhanced vascular reactivity. Abnormal VSM cell calcium [Ca2+]i homeostasis may be the nexus between insulin resistance and increased VSM tone. The genetically obese, hyperinsulinemic, insulin-resistant Zucker rat demonstrates increased vascular reactivity, reduced membrane Ca2(+)-ATPase activity, increased cellular Ca2+ levels, and a marked impairment in vascular smooth muscle Ca2+ efflux compared to lean controls. Insulin stimulates membrane Ca-ATPase, blocks Ca2+ currents, and Ca2(+)-driven action potentials. Thus, an insulin-resistant state as exists in the Zucker rat may be associated with increased Ca2+ influx through voltage-dependent sarcolemmal Ca2+ channels and/or decreased production or activation of the VSM cell Ca-ATPase pump.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Mechanisms of hypertension in diabetes. 202 49

Endogenous factors cross-reacting with antidigoxin antibodies have been found in several tissues and body fluids of animals and humans, using commercially available digoxin radioimmunoassay or enzyme immunoassay methods. The chemical characteristics of these endogenous factors are, at present, unknown, although it has been suggested that they could be substances with low molecular weight. Experimental studies and theoretical considerations indicate that endogenous digitalis-like factors (DDLFs), in addition to the ability to react with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K(+)-ATPase (sodium pump). Therefore, EDLF can be an endogenous modulator of the membrane sodium-potassium pump and several authors have suggested that EDLF could play a role in the regulation of fluids and electrolytes, muscular tone of myocardial and also in the pathogenesis of arterial hypertension. In this review, the authors discuss the hypothesis that, in metabolic diseases such as diabetes mellitus, obesity and acromegaly, the sodium retention and volume expansion, possibly due to exaggerated sodium intake, and/or exogenously induced peripheral hyperinsulinemia and high levels of growth hormone, could trigger a sustained release of EDLF, which in turn increases the blood pressure.
...
PMID:Is the endogenous digitalis-like factor the link between hypertension and metabolic disorders as diabetes mellitus, obesity and acromegaly? 222 23

In a recent study in acutely parathyroidectomized, fasted rats, infused with parathyroid hormone (PTH), superimposition of euglycemic hyperinsulinemia within the physiologic range completely reversed the decline in tubular reabsorption of Pi (TRPi) induced by PTH. As an extension of these observations on insulin as a counterregulator of Pi homeostatis, the present results demonstrated that similar insulin administration prevented a decrease in TRPi when PTH infusion was superimposed. This was, moreover, observed in the fed state and at doses of insulin which did not stimulate renal cortical Na-K-ATPase activity. Subsequent studies addressed the role of insulin in a PTH-independent phosphaturic state, namely that induced by Pi loading. Under such conditions and while the resultant hypocalcemia of hyperphosphatemia was circumvented by the addition of calcium to the infusate, insulin substantially increased the renal tubular reabsorptive capacity for Pi, thereby demonstrating an antiphosphaturic action of insulin independent of PTH. Furthermore, when increased filtered loads of Pi and PTH administration were combined during insulin infusion, TRPi was greater than when PTH was administered alone during similar insulin infusion. When calcium infusion did not accompany Pi loading with a resultant fall in serum calcium, euglycemic hyperinsulinemia did not affect TRPi, indicating abolition of the antiphosphaturic action of insulin by hypocalcemia.
...
PMID:Effects of physiologic hyperinsulinemia on renal phosphate handling in the rat: a role for calcium. 269 27

Insulin resistant, Type II diabetes mellitus (NIDD) in a rat animal model results in profound changes in basal and insulin-stimulated membrane (Ca2+ +Mg2+)-ATPase activity in kidney basolateral membrane (BLM) preparations. We find that NIDD in these animals does not result in similar changes in membrane (Na+ +K+)-ATPase activity. Basal enzyme activity was the same in diabetic and control animals. Insulin treatment of diabetic animals in vivo resulted in hyperinsulinemia and increased BLM (Na+ +K+)-ATPase, while food restriction for 18 hr resulted in lowered enzyme activity. There was no direct effect of insulin on (Na+ +K+)-ATPase activity in isolated membranes from any of the animal groups. Thus, physiologic perturbations which alter insulin sensitivity and glucose homeostasis are accompanied by altered levels of (Na+ +K+)-ATPase activity. Lower levels of this membrane enzyme activity appear to be associated with optimal insulin action.
...
PMID:(Na+ +K+)-ATPase activity in kidney basolateral membranes of non insulin dependent diabetic rats. 302 Nov 55

Studies with a subcellular system demonstrated that the interaction of insulin with the adipocyte plasma membrane resulted in the generation from the plasma membrane of a mediator that activated mitochondrial pyruvate dehydrogenase (EC 1.2.4.1). The insulin-sensitive chemical mediator from the plasma membrane has been partially characterized. It has a molecular weight of 1000-1500. The chemical mediator has been extracted from skeletal muscle, adipocytes, hepatoma cells, and IM-9 lymphocytes. Insulin increased the amount or activity of the mediator in the first three cell types, whereas insulin decreased the activity or amount of the mediator in IM-9 lymphocytes. These insulin-induced variations were consistent with the biological responses of these cells to insulin treatment. The activities of insulin-sensitive enzymes, including pyruvate dehydrogenase, adipocyte low Km 3':5'-cyclic-AMP phosphodiesterase (EC 3.1.4.17), and adipocyte plasma membrane [Ca2+ + Mg2+]-ATPase were shown to be altered by the chemical mediator. The mediator may act by altering various protein kinases and phosphoprotein phosphatases that modulate the state of phosphorylation and activity of these enzyme systems. The existence of two mediators is proposed. The first may mediate dephosphorylation of various substrates, and the second may influence phosphorylation.
...
PMID:Chemical mediator or mediators of insulin action: response to insulin and mode of action. 628 77

Na, K-ATPase activity may have a significant role in cellular thermogenesis. Reduced thermogenesis and an increased accumulation of unused calories in the form of fat could result from reduced basal or insulin-stimulated Na,K-ATPase activity in obese insulin-resistant man. We have previously demonstrated reduced Na,K-ATPase activity in intact red cells and their isolated membranes from obese humans. To determine if the reduced enzyme activity in obese subjects is the result of inherent cellular defects in the regulation of Na,K-pump activity, basal and insulin-stimulated rates of ouabain-inhibitable Rb uptake were measured in diploid fibroblasts from subjects with a range of body mass indices (BMI). Cell cultures were established from five extremely obese subjects (BMI greater than 40 kg/m2) with fasting hyperinsulinemia (38 +/- 6 microU/mL) and in four control (BMI less than 30 kg/m2) normoinsulinemic (14 +/- 3 microU/mL) subjects. Basal (17 +/- 3 v 23 +/- 2 nmol/L/min/10(10) cells +/- SEM) and maximal insulin-stimulated Na,K-pump activities (26 +/- 3 v 32 +/- 3 nmol/L/min/10(10) cells) were similar in the obese and control subjects. Maximal insulin stimulation for both groups was observed in four to eight minutes, and one-half maximal response required 2.5 ng/ml insulin. Cell density was negatively correlated with basal (r = 0.75, p less than 0.001) and maximally stimulated Na,K-pump activity (r = -0.73, p less than 0.001). Adjustment for this relationship did not influence the conclusions. Comparison of the results from the obese and control groups indicates (a) no evidence for an intrinsic cellular difference in basal Na,K-pump activity related to obesity and (b) no difference in insulin regulation of Na,K-pump activity, in fibroblasts from obese subjects.
...
PMID:Sodium-potassium pump in cultured fibroblasts from obese donors; no evidence for an inherent decrease of basal or insulin-stimulated activity. 632 14

The Na(+)-K(+)-ATPase presents several different isoforms of its alpha- and beta-subunits. We detected alpha 1- and beta 1-mRNA transcripts and polypeptides in 3T3-L1 fibroblasts; during differentiation into adipocytes, alpha 1-mRNA decreased, alpha 2-mRNA was induced, beta 1-mRNA dropped to undetectable levels, and beta 2-mRNA was never expressed, suggesting that 3T3-L1 adipocytes may express an unidentified Na(+)-K(+)-ATPase beta-subunit isoform. Insulin rapidly increased ion pump activity [ouabain-sensitive 86Rb+(K+) uptake] in 3T3-L1 fibroblasts and adipocytes without changing the plasma membrane concentration of alpha 1- or alpha 2-subunits as determined by subcellular membrane fractionation and immunoblotting or by [3H]ouabain binding to intact cells. Monensin, which raises the concentration of intracellular Na+, increased Na(+)-K+ pump activity, and no further stimulation was achieved with insulin. The stimulation of the pump by insulin was reduced by bumetanide, an inhibitor of the Na(+)-K(+)-2Cl- cotransporter, and was prevented by omission of extracellular Cl-. Insulin increased both ouabain-sensitive and bumetanide-sensitive 86Rb+(K+) uptake. These results suggest that insulin activation of the Na(+)-K(+)-ATPase in 3T3-L1 adipocytes is mediated by an elevation in intracellular Na+ that is likely the consequence of Na(+)-K(+)-2Cl- cotransporter activation.
...
PMID:Action of insulin on Na(+)-K(+)-ATPase and the Na(+)-K(+)-2Cl- cotransporter in 3T3-L1 adipocytes. 763 48


1 2 3 4 5 6 Next >>

---