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 view of the possible implication of multifactorial mechanisms in the pathogenesis of diabetic neuropathy, the aldose reductase inhibitor (ARI), Statil, which ameliorates abnormal sorbitol or myo-inositol metabolism in diabetic nerves, and the prostaglandin E1 (PGE1) analogue, OP1206.alpha CD (OP), which improves diabetic vascular derangements, were administered simultaneously for 2 months to streptozocin (STZ)-induced diabetic rats with 5 months' duration of diabetes, and the effects on sciatic motor nerve conduction velocity (MNCV), Na(+)-K(+)-adenosine triphosphatase (ATPase) activity, and morphology of myelinated nerve fibers (MNF) were compared with the effects of a monotherapy with OP. The combination regimen ameliorated abnormal nerve sorbitol and myo-inositol levels and normalized decreased MNCV and enzyme activity. In contrast, neither sorbitol nor myo-inositol metabolism was ameliorated, and only insufficient improvement of MNCV and morphology of MNF was obtained with a monotherapy with OP. In addition, the combination therapy reversed both a decrease in the percent of large MNF and an increase in the percent of small MNF in diabetic rats, whereas a monotherapy with OP reversed only a decrease in the percent of large MNF. The results might suggest that a multiple-drug therapy with different mechanisms of action has greater effects on diabetic neuropathy than a single-drug therapy and is worthy of clinical consideration.
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PMID:A combination of the aldose reductase inhibitor, statil, and the prostaglandin E1 analogue, OP1206.alpha CD, completely improves sciatic motor nerve conduction velocity in streptozocin-induced chronically diabetic rats. 132 Jan 79

Phospholipid methylation was quantified in non-diabetic and streptozotocin diabetic rat erythrocytes. While the total mass of methylated lipids remained the same in both groups, the relative abundance of individual methylated lipid species differed significantly in diabetic erythrocytes. Moreover, incubation of erythrocytes membranes with S-adenosyl methionine, a substrate for methyl transferases, not only increased membrane lipid methylation but also decreased Na+, K+ ATPase activity significantly. These results suggest that phospholipid methylation may cause the observed depression of erythrocyte Na+, K+ ATPase activity in diabetes and could contribute to the altered rheology of erythrocytes in diabetes.
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PMID:Phospholipid N-methylation in diabetic erythrocytes: effects on membrane Na+, K+ ATPase activity. 132 Oct 9

We examined changes in guanosine triphosphate-dependent signal transduction mechanisms in the retina from the early stages of the streptozotocin-diabetic rat, a model for Type 1 (insulin-dependent) diabetes mellitus. Guanosine triphosphate binding, guanosine triphosphatase activity, and binding of (azido) guanosine triphosphate decreased significantly in the retina as early as 2 weeks after the induction of diabetes. The ability of guanosine triphosphate to inhibit forskolin-stimulatable adenyl cyclase was also abolished. These data suggest functional deterioration of G-proteins, especially Gi, in diabetic retina. Further studies using retinal rod outer segments revealed deterioration in light-sensitive, guanosine triphosphate-dependent functions of transducin in diabetic rats. Pertussis toxin-catalysed ADP ribosylation of the alpha subunit of transducin, a heterotrimeric G-protein of rod outer segments, was also reduced in diabetes. No functional effects were seen in purified subunits of transducin subjected to non-enzymatic glycation in vitro. On the other hand, incubation of non-diabetic rod outer segments with (12-0-tetradeconyl) phorbol-13-acetate, a protein kinase C agonist, in the presence of magnesium and adenosine triphosphate resulted in the reduction of guanosine triphosphate-binding and hydrolysis, thus indicating that protein kinase C may be involved in the regulation of these activities. The significance of these observations in the early visual abnormalities associated with diabetes is discussed.
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PMID:Functional alterations of G-proteins in diabetic rat retina: a possible explanation for the early visual abnormalities in diabetes mellitus. 132 50

The specific activity of Na(+)-K(+)-ATPase in the renal medulla and cortex of 50-day-old streptozotocin (STZ)-induced diabetic mice was increased 58% and 50%, respectively, as compared to controls. Km values of Na+ and K+ for this enzyme were unaltered, while that of ATP was decreased in diabetic mice. The Na(+)-K(+)-ATPase in control medulla and cortex was activated by both cholera and pertussis toxins, while this effect was abolished in diabetics. Since dibutyryl cAMP stimulates cortical Na(+)-K(+)-ATPase activity in control mice, the activation effect of cholera toxin on this enzyme might be due to its interaction with a Gs-protein and the persistent stimulation of adenylate cyclase activity, while the effect of pertussis toxin might be due to its masking of the inhibitory action of a Gi-protein on adenylate cyclase activity. However, the protein kinase C (PKC)-associated Na(+)-K(+)-ATPase might also be quiescent in diabetes, because the stimulating effect of phorbol 12,13-dibutyrate (PDBu) and phorbol 12-myristate 13-acetate (PMA) on this enzyme was abolished in diabetic cortex. In addition, nicardipine and ouabain were found to have differential effects on this enzyme derived from control and diabetic mice.
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PMID:Differentiation of renal Na(+)-K(+)-ATPase in control and streptozotocin-induced diabetic mice by G-protein acting toxins and phorbol esters. 132 74

Effects of alloxan-diabetes on kinetic attributes of Na(+)+K(+)-ATPase were examined in rat kidney, brain and erythrocyte membranes. The enzyme activity decreased significantly from 60-80% in the three membrane systems as a result of diabetic state. Kinetic analysis revealed that Km of the enzyme increased by 5- and 10-fold respectively in the kidney and brain membranes while registering a 50-60% decrease in Vmax. Ouabain binding studies revealed that in the kidney membranes the I50 value increased by 150-fold in diabetic animals with a significant decrease in number of ouabain molecules bound; at concentrations beyond 10(-7) M de-binding of ouabain occurred. For the brain membranes the I50 values for ouabain increased even more significantly (2000-fold increase) without any change in Hill coefficient for ouabain binding. Glycosylation studies revealed that its extent was highest for the brain and least for the kidney membranes which correlated to some extent with the I50 and Km values but not with Vmax. The results thus suggest that glycosylation in critical domains of the membrane and/or enzyme structure may play an important regulatory role. Physiological significance of these findings is discussed.
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PMID:Altered kinetic attributes of Na(+)+K(+)-ATPase activity in kidney, brain and erythrocyte membranes in alloxan-diabetic rats. 132 27

Hyperglycemia has been shown to diminish Na(+)-K+ ATPase activity in rabbit aorta. To examine the basis for this effect, aortic rings were incubated for 3 h in Krebs-Henseleit solution containing 5.5 or 44 mM glucose, and Na(+)-K+ ATPase activity was then quantified on the basis of ouabain-sensitive (OS) 86Rb-uptake. Incubation with 44 mM glucose medium caused a 60% decrease in Na(+)-K+ ATPase activity in rings with intact endothelium (from 0.22 +/- 0.01 to 0.091 +/- 0.006 nmol/min per mg dry wt; P less than 0.01). Similar decreases (45%; P less than 0.01) in Na(+)-K+ ATPase activity were seen when rings incubated with 5.5 mM glucose were exposed to NG-monomethyl L-arginine (300 microM), an inhibitor of endothelium-derived nitric oxide (EDNO) synthesis or when the endothelium was removed (43% decrease). The decrease in Na(+)-K+ ATPase activity induced by hyperglycemia was totally reversed upon adding to the medium either L-arginine, a precursor of EDNO biosynthesis or sodium nitroprusside, which bypasses endothelium and directly activates the soluble guanylate cyclase in vascular smooth muscle. A decrease in Na(+)-K+ ATPase activity (42%; P less than 0.05), only seen in the presence of endothelium, was also observed in aortas taken directly from alloxan-induced diabetic rabbits. These studies suggest that the decrease in vascular Na(+)-K+ ATPase activity induced by hyperglycemia is related, at least in part, to a decrease in the basal release of EDNO. They also suggest that alterations in basal EDNO release and possibly Na(+)-K+ ATPase activity contribute to the impairment in vascular relaxation caused by hyperglycemia and diabetes.
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PMID:Endothelium-dependent inhibition of Na(+)-K+ ATPase activity in rabbit aorta by hyperglycemia. Possible role of endothelium-derived nitric oxide. 132 96

The effects of a new aldose reductase inhibitor (ARI), (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamide (SNK-860), on the slowing of motor nerve conduction velocity (MNCV) and metabolic abnormalities in sciatic nerve were investigated in acute streptozotocin (STZ)-induced diabetic rats. MNCV in the diabetic rats was significantly slower 2 weeks after STZ injection. In the following 2 weeks, treatment with SNK-860 improved MNCV in a dose-dependent manner. The efficacy of 1 mg/kg SNK-860 was equipotent to that of 20 mg/kg sorbinil. Four weeks after STZ injection, increases in sorbitol levels, decreases in myo-inositol levels, and reductions in Na+, K(+)-adenosine triphosphatase (ATPase) activity were observed in sciatic nerves of diabetic rats. Administration of SNK-860 for 14 days beginning 2 weeks after the induction of diabetes inhibited these metabolic abnormalities in a dose-dependent manner. SNK-860 restored all of these parameters to normal levels at a dose of 2 mg/kg. In addition, close correlations were observed between MNCV and sorbitol levels (r = -.95) and between MNCV and myo-inositol levels (r = .93) in the sciatic nerve; a close correlation was also observed between sorbitol and myo-inositol levels in the sciatic nerve (r = -.86). Therefore, it is suggested that the effect of SNK-860 on the slowing of MNCV results from normalizing the above-mentioned metabolic abnormalities in the sciatic nerve of diabetics. Thus, SNK-860 may be useful in the treatment of diabetic neuropathy.
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PMID:Effects of a new aldose reductase inhibitor, (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamid e (SNK-860), on the slowing of motor nerve conduction velocity and metabolic abnormalities in the peripheral nerve in acute streptozotocin-induced diabetic rats. 132 19

Although inhibition of Na(+)-K+ ATPase has been described in the diabetic heart, K+ loss from myocardium has not been observed in a canine model of mild diabetes. The finding of tissue Na+ accumulation and a potential relation to alteration of left ventricular inositol as observed in other tissues in diabetes form the basis of this investigation. Diabetes was induced with alloxan in three groups of male mongrel dogs who were studied after 1 yr. In the initial experiment the tissue compartment volumes, determined with intravenous 51Cr EDTA as a marker, were found to be normal. Calculated cell sodium was increased to 32.8 +/- 2.6 mEq/kg cell H2O vs 18.7 +/- 1.1 in controls (p < 0.01). Cell potassium in diabetes was normal. In the second group, myocardial polyols were analyzed by gas-liquid chromatography. Inositol was diminished in diabetes to 0.61 +/- 23 microM/g of left ventricle, vs the respective control levels of 1.9 +/- 0.57 microM/g (p < 0.02). Sorbitol concentration was unaltered. Left ventricular sodium increments were not associated with altered tissue calcium. In group III the hypothesis that inhibition of Na(+)-K+ ATPase in diabetes might not elicit the expected alteration of K+ transport was assessed during intracoronary infusion of acetyl strophanthidin. No difference in cation responses from control was observed. It is postulated that a change in the conformation of Na(+)-K+ ATPase, with high affinity sodium binding sites facing the intracellular compartment, may render sodium less releasable from cell membrane.
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PMID:Myocardial inositol and sodium in diabetes. 133 48

We examined the production and secretion of IAPP in a beta-cell line, MIN6, which is derived from an insulinoma obtained by targeted expression of the SV40 T-antigen gene in a transgenic mouse. RNA blot analysis revealed an abundance of IAPP and insulin II mRNA in the cells, findings comparable with those in the pancreas of a normal mouse. The presence of IAPP and insulin was confirmed immunohistochemically and by RIA. Analysis of the reverse-phase HPLC identified IAPP in cells with authentic mouse IAPP. Raising the glucose concentration from 5.6 to 25 mM failed to induce increments in IAPP and insulin II mRNAs. The cells secrete IAPP and insulin for short- and long-term incubations in response to concentration of glucose in the medium. These features resemble those of islet cells from normal animals. This beta-cell line will aid in analyzing the regulation of IAPP gene expression and the mechanisms of IAPP biosynthesis and secretion.
Diabetes 1992 Nov
PMID:Islet amyloid polypeptide/amylin in pancreatic beta-cell line derived from transgenic mouse insulinoma. 138 68

The influence of diabetes mellitus, streptozotocin-induced diabetes and ageing on the non-enzymatic glycosylation of myosin from cardiac and skeletal muscles was investigated. In cardiac muscle, and to a lesser extent also in skeletal muscles of the rat, non-enzymatic glycosylation of myosin increases with the age, as measured in 6-, 12- and 29-month-old animals. Skeletal muscle myosin from diabetic humans and also that from diabetic rat cardiac muscle are more glycosylated when compared with control myosin preparations. Ca(2+)-ATPase activity of myosin is lower in muscles of diabetic individuals as compared with control muscles.
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PMID:Non-enzymatic glycosylation of myosin: effects of diabetes and ageing. 142 77


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