Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In diabetes, glucosylation of the Na,K-ATPase of the lens epithelium makes the pump inefficient. K+ transport and ATP hydrolysis (at near saturating ATP concentrations) are inhibited and the kinetics of ATP hydrolysis become substrate inhibition type. The AR inhibitor (AL1576, Alcon Laboratories) stimulates K+ transport and ATP hydrolysis by glucosylated bovine lens Na,K-ATPase. This inhibitor has a slight stimulatory effect upon the unmodified enzyme function also. The AR inhibitor is not able to prevent glucosylation of the pump in high-glucose-containing medium.
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PMID:Stimulation of glucosylated lens epithelial Na,K-ATPase by an aldose reductase inhibitor. 282 Jul 75

Changes in tissue levels of sorbitol, myo-inositol, and Na+-K+-ATPase enzyme activity have been implicated in the development of diabetic complications in animal models of the disease and in humans. The ability of the aldose reductase inhibitor sorbinil to reverse the hyperglycemia-induced changes in these lenticular metabolite and enzyme-activity levels in the streptozocin-induced diabetic rat was examined to determine what, if any, relationship exists between these changes. Two weeks of untreated diabetes did not change ouabain-inhibitable ATPase enzyme activity assayed in lens homogenates but did result in a decrease in the Na+-K+-ATPase transport activity as measured by 86Rb uptake in the intact lens. This was accompanied by a 100-fold increase in the levels of sorbitol and significant decreases in the levels of myo-inositol, ATP, and glutathione in the lens. Whereas all of these changes could be reversed by sorbinil treatment, the dose required for restoration of the depleted myo-inositol level (ED50 greater than 20 mg.kg-1.day-1) was much higher than the dose required to reverse the other changes (ED50 range 2-5 mg.kg-1.day-1). These results suggest that the restoration of lenticular Na+ -K+ -ATPase activity is not secondary to a normalization of myo-inositol levels and may provide evidence that the two parameters are not strictly associated in diabetic tissues.
Diabetes 1987 Dec
PMID:Na+-K+-ATPase pumping activity is not directly linked to myo-inositol levels after sorbinil treatment in lenses of diabetic rats. 282 60

Vanadium compounds are known to affect multiple membrane and cytosolic phosphoenzymes from various tissues; the most characterized effect is the inhibition of Na+-K+-ATPase. Since we previously reported that immunoreactive insulin (IRI) secretagogues tend to inhibit rat islet cation-dependent ATPases, we examined the effects of sodium vanadate on rat IRI secretion from incubated and perifused rat islets. In the presence of 2.4 mM Ca2+, vanadate (10(-3) M) induced biphasic IRI secretion with a background glucose of 100 mg/dl. In the absence of extracellular Ca2+, IRI released from incubated islets by vanadate at 100 and 300 mg/dl glucose was doubled and tripled, respectively. Furthermore, this stimulatory effect was completely abolished by known inhibitors of IRI release such as somatostatin, epinephrine, and diphenylhydantoin. Although we found the expected dose-dependent inhibition by vanadate of islet membrane Na+-K+-ATPase activity, the mechanism of action of vanadate on IRI secretion remains unknown. Vanadate probably interacts in a complex fashion with different islet phosphoenzymes and may prove to be a useful probe to further unravel the mechanisms leading to insulin secretion.
Diabetes 1987 Dec
PMID:Insulinotropic effects of vanadate. 282 62

The chronic complications of diabetes are thought to be caused by an interaction between hyperglycemia, or other metabolic consequences of insulin deficiency, and independent genetic or environmental factors that are poorly defined. Several potentially relevant biochemical sequelae to hyperglycemia have been identified in tissue susceptible to diabetic complications. Among these, a rise in tissue sorbitol secondary to concentration-dependent activation of polyol pathway activity by glucose, and an accompanying fall in tissue myo-inositol and Na-K-ATPase activity have recently been linked to a self-reinforcing cyclic metabolic defect that accounts for rapidly reversible slowing of conduction in peripheral nerve in diabetes. Impaired Na-K-ATPase activity also appears to be responsible for intracellular Na+ accumulation and resultant localized axonal paranodal swelling that characterizes diabetic neuropathy in both humans and laboratory animals. These swellings are thought to be responsible for the subsequent disruption of the nodal apparatus (axo-glial disjunction) and some component of the loss of large and small myelinated fibers. Recent studies have suggested that microvascular insufficiency may also contribute to diabetic neuropathy, especially in non-insulin-dependent diabetes. Aldose reductase activity is concentrated in endoneurial vessels, and similar biochemical mechanisms (ie, sorbitol accumulation, myo-inositol deficiency, and impaired Na-K-ATPase activity) are thought to be operative in the endoneurial microvessels in diabetes. Administration of an aldose reductase inhibitor to patients with diabetic neuropathy is associated with repair of damaged nerve fibers and the appearance of newly generated fibers, presumably secondary to metabolic correction within the nerve fibers themselves or their supporting microvasculature.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The pathogenesis and prevention of diabetic neuropathy and nephropathy. 282 23

Sorbitol accumulation, myo-inositol depletion, and reduced Na+-K+-ATPase activity have been identified in experimental diabetes in several tissues in which diabetic complications occur. However, a reduction in renal Na+-K+-ATPase activity has not been universally reported, prompting us to examine the influence of diabetes duration on the activity of this enzyme complex in isolated glomeruli. Additionally, we examined the ability of the aldose reductase inhibitor sorbinil to directly stimulate glomerular Na+-K+-ATPase activity in vitro, an area of interest in view of the central position that the ability of sorbinil to restore Na+-K+-ATPase activity in vivo occupies in the interpretive scheme that links associated changes in sorbitol, myo-inositol, and Na+-K+-ATPase to enhanced polyol-pathway activity. Glomerular Na+-K+-ATPase activity was significantly decreased in rats with acute (less than 18 days) streptozocin-induced diabetes but was significantly greater than control values in rats with more chronic (greater than 32 days) diabetes. In vitro addition of sorbinil (1 x 10(-7) M) directly stimulated Na+-K+-ATPase in control (0.627 +/- 0.090 vs. 0.843 +/- 0.098 mumol P1.mg-1.min-1) but not diabetic glomeruli. These results indicate that the time of examination after induction of diabetes critically influences glomerular Na+-K+-ATPase activity and suggest that sorbinil, at least in normal glomerular tissue, has a membrane-associated effect that may be independent of its aldose reductase-inhibiting property.
Diabetes 1988 May
PMID:Glomerular Na+-K+-ATPase activity in acute and chronic diabetes and with aldose reductase inhibition. 283 50

Alterations in myo-inositol and phosphoinositide metabolism, induced by hyperglycemia and prevented by aldose reductase inhibitors, are implicated in impaired Na+-K+-ATPase regulation in peripheral nerve and other tissues prone to diabetic complications by an increasing range of scientific observations. However, the precise role of these related metabolic derangements in various stages of clinical complications is complex. For instance, it appears that these biochemical defects may play a role not only in the initiation of diabetic neuropathy but also in its later progression. Therefore, full appreciation of the potential pathogenetic role of altered phosphoinositide metabolism in diabetic complications requires detailed studies of both the earliest and the more mature stages of these disease processes.
Diabetes 1988 Jun
PMID:Are disturbances of sorbitol, phosphoinositide, and Na+-K+-ATPase regulation involved in pathogenesis of diabetic neuropathy? 283 51

Six weeks after induction of diabetes, the rate of ouabain-sensitive 86Rb+ accumulation, a parameter which reflects Na+ + K+-ATPase pumping activity, was significantly reduced in endoneurial preparations of sciatic nerve from untreated diabetic rats compared with that in control rats (Trial, 1, 0.19 +/- 0.09 versus 0.48 +/- 0.13 pmol/min per mg wet weight of tissue, p less than 0.001; Trial 2, 0.27 +/- 0.16 versus 0.47 +/- 0.18, p less than 0.01). This decrease in ouabain-sensitive 86Rb+ uptake was not observed in nerves from diabetic rats maintained on sorbinil (an aldose reductase inhibitor) or myo-inositol diets. Protein kinase C activity was demonstrated in the soluble fraction of a sciatic nerve homogenate by assaying for lipid-activated, Ca+-dependent phosphorylation of calf thymus histone. No significant difference in the time course of kinase C activity was observed between cytosol fractions of nerve homogenates from control and diabetic rats (control, 6.22 +/- 0.97 pmol 32P incorporated/mg cytosol protein in 50 min; diabetic, 5.32 +/- 0.71). Three low molecular weight neural proteins (each with Mr less than 29,000) were identified as substrates for protein kinase C.
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PMID:Reduced Na+ + K+-ATPase activity in peripheral nerve of streptozotocin-diabetic rats: a role for protein kinase C? 284 Mar 14

ATPase activities were measured in sciatic nerves from rats with alloxan-induced diabetes (ALX-D) of various duration (2 wk, 5 wk, 9 wk, and 6 mo). Our data confirm that sciatic nerve Na+-K+-ATPase abnormalities are present very early in ALX-D rats, similar to results previously described in streptozocin-induced diabetic rats, spontaneously diabetic BB Wistar rats, and ALX-D rabbits. Na+-K+-ATPase activity decreased by 26-47% in ALX-D rats compared with age-matched controls. Ganglioside treatment (10 mg/kg i.p. for 10 or 30 days starting 1 wk after ALX injection) completely impeded the enzyme reduction. The effect observed at the end of either 10 or 30 days of treatment lasted greater than or equal to 1 mo. Chronic diabetic groups treated for 30 days before killing also presented normal ATPase activity at the end of treatment. Therefore, gangliosides are effective on Na+-K+-ATPase even in animals with a longer duration of diabetes. The maintenance of fairly normal ATPase activity by ganglioside treatment could mirror a more general recovery from early metabolic dysfunction and/or late structural abnormalities in diabetic nerve fibers.
Diabetes 1988 Oct
PMID:ATPase activity defects in alloxan-induced diabetic sciatic nerve recovered by ganglioside treatment. 284 6

The Na+,K+-ATPase is a basic membrane element in all animal cells that maintain transmembrane gradients of Na+ and K+ ions. When integrated into artificial lipid vesicles the isolated Na+,K+-ATPase is capable of actively transporting Na+ and K+, thus establishing its identity with the well-known Na+ pump. Three isoforms of the catalytic subunit of Na+,K+-ATPase have recently been identified in the rat brain. Elucidating the regulatory processes which govern their biosynthesis in the brain is central to understanding the physiological alterations which accompany diabetes, chronic cardiotonic steroid intoxication and degenerative diseases of the retina. In this study, synthesis of the alpha-1 and alpha-2 isoforms was examined in the retina of rats following intraocular injection of citrate buffer. Incorporation of [35S]methionine into both isoforms was increased 60-100% by 6 hr, demonstrating that neuronal Na+ pump is subject to regulation, although the question of independent regulatory controls remains unanswered.
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PMID:Molecular isoforms of the sodium pump in brain. 284 14

An alteration in the enzymatic properties of the erythrocyte membrane acetylcholinesterase (AchE) and Na+,K+-ATPase has been described in experimental diabetes mellitus. We studied erythrocyte membrane fluidity and AchE and Na+,K+-ATPase activities in 15 insulin-dependent diabetic patients and 11 normal subjects. Fluidity was assessed by fluorescence polarization, using 1,6-diphenyl-1,3,5-hexatriene as a probe, and AchE and Na+,K+-ATPase activities were measured enzymatically. We found a significant increase in the enzymatic activity of AchE and a change in its enzymatic properties in diabetic patients compared with those in normal subjects. AchE activity correlated inversely with membrane fluorescence polarization, which was decreased in the diabetic patients, indicating an increase in membrane fluidity. Na+,K+-ATPase activity was reduced in the diabetic patients and correlated positively with the fluorescence polarization values. We hypothesize that the abnormal dynamic properties of the erythrocyte membrane may play a major role in determining the described change in enzymatic activity.
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PMID:Abnormal membrane fluidity and acetylcholinesterase activity in erythrocytes from insulin-dependent diabetic patients. 284 52


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