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)

At clinically achievable concentrations (10(-9) to 5 X 10(-6) M), tolbutamide and tolazamide are in vitro inhibitors of Ca2+-transporting ATPase activity in sarcolemma-enriched rabbit myocardial membranes (sulfonylurea IC50, 10(-7) M). Thyroid hormone stimulation of this calcium pump-associated enzyme in vitro has been previously reported; in our study, this hormonal action was shown to be inhibited by tolbutamide and tolazamide. In contrast to these two sulfonylureas, glyburide (up to 5 X 10(-6) M) had no effect on basal or thyroid hormone-stimulable Ca2+-ATPase activity in vitro. Studies of binding of radiolabeled purified calmodulin to heart membranes showed that tolbutamide and tolazamide inhibited this interaction, whereas glyburide had no effect on calmodulin binding. Addition of purified calmodulin (5-40 ng/micrograms membrane protein) to myocardial membranes incubated with 10(-7) M tolbutamide or tolazamide restored Ca2+-ATPase activity and thyroid hormone responsiveness of the enzyme. Inhibition by tolbutamide and tolazamide of myocardial sarcolemmal Ca2+-ATPase is a mechanism by which these two sulfonylureas may at least transiently raise resting sarcoplasmic Ca2+ concentration. This effect of sulfonylureas on Ca2+-ATPase is not expressed in the presence of the benzamide side chain of glyburide. The inhibitory action of certain sulfonylureas on Ca2+-ATPase is mediated by interference of the agents with the binding of calmodulin to cardiac membranes.
Diabetes 1986 Sep
PMID:Differential activities of tolbutamide, tolazamide, and glyburide in vitro on rabbit myocardial membrane Ca2+-transporting ATPase activity. 294 19

Long-chain acylcarnitines are membrane-active intermediates of fatty acid metabolism whose intracellular accumulation has been implicated in the myocardial injury associated with both streptozotocin-induced diabetes and acute ischemia. In the present study, rats treated with streptozotocin (50 mg/kg i.v.) exhibited increases in myocardial long-chain acylcarnitines comparable to those previously reported to occur in moderate to severe ischemic injury. With the exception of a reduction in the sedimentable (lysosome-associated) fraction of myocardial N-acetyl-beta-glucosaminidase and a decrease in sarcoplasmic reticulum K+, Ca++-stimulated ATPase activity, other characteristic indices of myocardial ischemic damage, notably inhibition of sarcolemmal and mitochondrial ATPase activities as well as alterations in the ionic composition of myocardial tissue, were not apparent in the hearts of the streptozotocin-diabetic animals. On the basis of in vitro studies using palmitylcarnitine, it does not seem that differential sensitivity to long-chain acylcarnitine inactivation can explain the preferential inhibition of the sarcoplasmic reticulum ATPase enzyme observed in vivo. Our data are consistent with the findings of others suggesting that long-chain acylcarnitines are unlikely to be the most important or sole mediators of myocardial ischemic injury. However, a modulatory role of these substances in myocardial ischemic injury or in determining the increased susceptibility of diabetics to the complications of ischemic heart disease cannot be excluded at present.
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PMID:Subcellular myocardial abnormalities in experimental diabetes: role of long-chain acylcarnitines. 294 27

We have recently reported that streptozocin (STZ)-induced diabetes in rats was associated with i) reduced Ca2+ pumping by rat brain synaptic plasma membrane Ca(2+)-ATPase (PMCA) and ii) a substantial reduction in the partial pressures of halothane and xenon required to prevent movement in response to stimulation (minimum effective dose or MED). MED for both agents correlated well with the degree of hemoglobin glycation and with PMCA activity. We now report that MEDs for isoflurane, enflurane, and desflurane were also substantially reduced in STZ-diabetic rats, compared with placebo-injected controls. In addition, we examined the effect of insulin treatment, begun 2 weeks after induction of diabetes and continued for 3 more weeks, on isoflurane MED and on brain synaptic PMCA and phospholipid-N-methyltransferase I (PLMT I), another enzyme altered by inhalation anesthetics (IA). Partial treatment of diabetes, as indicated by decreased glycated hemoglobin (GHb) compared to untreated diabetic rats, was associated with an isoflurane MED of 1.05 vol%, intermediate between a control mean of 1.57 vol% and an untreated diabetic mean of 0.82 vol% (p < 0.01), with a trend toward normalization of both PMCA and PLMT I activity. We also examined isoflurane MED and PMCA activity in the cerebrum and diencephalon-mesencephalon (D-M) of control and diabetic rats 2 and 12 weeks after induction of diabetes. Isoflurane MED was substantially reduced in diabetic rats from both treatment periods. Cerebral and D-M PMCA activities were each reduced to about 90% of control values 2 weeks after STZ induction. At 12 weeks, cerebral PMCA pumping in SPM from diabetic rats did not differ from control values, but PMCA pumping in SPM from the D-M was reduced to about 85% of control levels. Good correlation (r = 0.89, p < 0.01) was found between isoflurane MED and GHb in all treatment groups. These findings provide further evidence for an important role for PMCA in IA action. They also suggest that anesthetic effects on the calcium pump at specific anatomic sites may be of major importance in producing anesthesia.
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PMID:Reduced anesthetic requirements, diminished brain plasma membrane Ca(2+)-ATPase pumping, and enhanced brain synaptic plasma membrane phospholipid methylation in diabetic rats: effects of insulin. 775 6

Red cell membrane cholesterol, 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-[(4-trimethylammonium)phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH) anisotropies and basal and calmodulin-stimulated calcium pump activities were compared in 16 normolipidaemic Type 2 (non-insulin-dependent) diabetic patients and 20 normolipidaemic control subjects using the Mann-Whitney U-test. Serum cholesterol, membrane cholesterol, and membrane DPH and TMA-DPH anisotropies were similar in the two groups but both basal and calmodulin-stimulated calcium pump activities were reduced in the diabetic group: basal activity (median (inter-quartile range), mumol mg-1 h-1) 1.66 (1.18-1.97) vs 2.09 (1.90-2.50), p < 0.005 and calmodulin-stimulated activity 4.19 (3.07-5.48) vs 5.53 (4.70-6.88), p < 0.006. Although there were no correlations between glycaemic control and membrane anisotropy and between glycaemic control and calcium pump activity, the reduction in calcium pump activity is most likely due to a direct effect of diabetes on the calcium pump protein itself.
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PMID:Human red cell membrane fluidity and calcium pump activity in normolipidaemic type II diabetic subjects. 785 Oct 70

Altered cytosolic Ca2+ is implicated in the aetiology of many diseases including diabetes but there are few studies on the mechanism(s) of the altered Ca2+ regulation. Using human lymphocytes, we studied cytosolic calcium (Cai) and various Ca2+ transport mechanisms in subjects with Type 2 diabetes mellitus and control subjects. Ca2+-specific fluorescent probes (Fura-2 and Fluo-3) were used to monitor the Ca2+ signals. Thapsigargin, a potent and specific inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), was used to study Ca2+-store dependent Ca2+ fluxes. Significant (P<0.05) elevation of basal Ca, levels was observed in lymphocytes from diabetic subjects. Cai levels were positively correlated with fasting plasma glucose and HbA1c. There was also a significant (P<0.05) reduction in plasma membrane calcium (PMCA) ATPase activity in diabetic subjects compared to controls. Cells from Type 2 diabetics exhibited an increased Ca2+ influx (as measured both by Fluo-3 fluorescence and 45Ca assays) as a consequence of thapsigargin-mediated Ca2+ store depletion. Upon addition of Mn2+ (a surrogate of Ca2+), the fura-2 fluorescence decayed in an exponential fashion and the rate and extent of this decline was steeper and greater in cells from type 2 diabetic patients. There was also a significant (P<0.05) difference in the Na+/Ca2+ exchange activity in Type 2 diabetic patients, both under resting conditions and after challenging the cells with thapsigargin, when the internal store Ca2+ sequestration was circumvented. Pharmacological activation of protein kinase C (PKC) in cells from patients resulted in only partial inhibition of Ca2+ entry. We conclude that cellular Ca2+ accumulation in cells from Type 2 diabetes results from (a) reduction in PMCA ATPase activity, (b) modulation of Na+/Ca2+ exchange and (3) increased Ca2+ influx across the plasma membrane.
Int J Exp Diabetes Res 2001
PMID:Evidence for mechanistic alterations of Ca2+ homeostasis in Type 2 diabetes mellitus. 1146 18

We compared agonist-evoked responses in the perfused mesenteric vascular bed (MVB) of streptozotocin (STZ) diabetic Sprague-Dawley rats 2 and 14 weeks after induction of diabetes. Endothelin-1 (ET-1)-, methoxamine (MTX)-, and KCl-evoked vasoconstrictor responses were unchanged in 2-week-old diabetic rats. In contrast, both the sensitivity (P < 0.01) and the maximal vasoconstrictor responses (P < 0.05) to ET-1 were attenuated in 14-week-old diabetic rats, whereas endothelin plasma levels were increased (P < 0.05). Although no differences were observed in responses to KCl in either the 2- or 14-week-old diabetic groups, MTX-evoked maximal responses were attenuated in the 14-week-old group (P < 0.01). Changes in agonist-evoked responses in the 14-week-old diabetic group were unaffected by the protein kinase C (PKC) inhibitor, staurosporine, the phospholipase C (PLC) inhibitor, U73122, the calcium channel blocker, nifedipine, the calcium pump inhibitor, cyclopiazonic acid (CPA), or by endothelial denudation. Sodium fluoride (NaF), an activator of guanosine triphosphate binding proteins (G proteins) normalized the responses in the 14-week-old diabetic group. These data suggest that advanced stages of STZ are associated with alterations in G protein receptor coupling and/or activity leading to the attenuation of responses to vasoconstrictor agonists.
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PMID:Attenuated agonist evoked vasoconstrictor responses in the perfused mesenteric vascular bed of streptozotocin diabetic rats. 1168 1

A study of Ca++, Mg++-ATPase activity was carried out in normal (HHm) and diabetic Nigerians of both sexes with insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM). The results showed that protein concentration of erythrocyte ghost membranes of healthy humans (HHm) was the highest when compared with protein concentrations of IDDM and NIDDM patients. The protein concentration was lowest in IDDM, while the value in NIDDM was between those of HHm and IDDM. The basal activities of erythrocyte Ca++-ATPase from IDDM and NIDDM were determined and were found to be significantly lower than that of HHm. The addition of calmodulin (CaM) 2 microg/ml stimulated the activity of the calcium pump in all the groups (IDDM, NIDDM and HHm). The effects of calcium (Ca++) and adenosine triphosphate (ATP) on the activity of the pump from each group were determined. Enzyme kinetics (Km and Vmax) revealed that the activity of Ca++, Mg++-ATPase was initiated by ATP in the presence of Ca++ in a dose-dependent manner. Calmodulin also enhanced the activity of the enzyme in the presence of Ca++ in all the groups, though activities in IDDM and NIDDM were significantly lower than in HHm. There was no significant difference in the activities between IDDM and NIDDM. These results suggest a defective calcium translocating mechanism in diabetic Nigerians.
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PMID:Ca++, Mg++-ATPase activity in insulin-dependent and non-insulin dependent diabetic Nigerians. 1171 88

Diabetic cardiomyopathy is characterized by reduced cardiac contractility due to direct changes in heart muscle function independent of vascular disease. An important contributor to contractile dysfunction in the diabetic state is an impaired sarcoplasmic reticulum (SR) function, leading to disturbed intracellular calcium handling. We investigated whether overexpression of the SR calcium pump (SERCA2a) in transgenic mice could reduce the impact of diabetes on the development of cardiomyopathy. Diabetes was induced by streptozotocin injection (200 mg/kg), and left ventricular (LV) function was analyzed in isolated hearts 3 weeks later. In diabetic hearts systolic LV pressure was decreased by 15% and maximum speed of relaxation (-dP/dt) by 34%. Functional changes were also assessed in isolated papillary muscles. Active force was reduced by 61% and maximum speed of relaxation by 65% in the diabetic state. The contractile impairment was accompanied by a 30% decrease in SERCA2a protein in diabetic mice. We investigated whether increased SERCA2a expression in transgenic SERCA2a-overexpressing mice could compensate for the diabetes-induced decrease in cardiac function. Under normal conditions, SERCA2a overexpressors show improved contractile performance relative to wild-type (WT) mice (-dP/dt: 3,169 vs. 2,559 mmHg/s, respectively). Measurement of LV function in hearts from diabetic SERCA2a mice revealed systolic and diastolic functions that were similar to WT control mice and markedly improved relative to diabetic WT mice (-dP/dt: 2,534 vs. 1,690 mmHg/s in diabetic SERCA2a vs. diabetic WT mice, respectively). Similarly, the contractile behavior of isolated papillary muscles from diabetic SERCA2a mice was not different from that of control mice. SERCA2a protein expression was higher (60%) in diabetic SERCA2a mice than WT diabetic mice. These results indicate that overexpression of SERCA2a can protect diabetic hearts from severe contractile dysfunction, presumably by improving the calcium sequestration of the SR.
Diabetes 2002 Apr
PMID:Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy. 1191 40

Glucose is the main physiological secretagogue for insulin secretion by pancreatic beta-cells, and the major biochemical mechanisms involved have been elucidated. In particular, an increase in intracellular calcium is important for insulin exocytosis. More recently, it has become apparent that the beta-cell also has many of the elements of the insulin receptor signal transduction pathway, including the insulin receptor and insulin receptor substrate (IRS) proteins 1 and 2. Studies with transgenic models have shown that the beta-cell-selective insulin receptor knockout and the IRS-1 knockout lead to reduced glucose-induced insulin secretion. Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). We have thus postulated the existence of a novel autocrine-positive feedback loop of insulin on its own secretion involving interaction with the insulin receptor signal transduction pathway and regulation of intracellular calcium homeostasis. Our current working hypothesis is that this glucose-dependent interaction occurs at the level of IRS-1 and the sarco(endo)plasmic reticulum calcium ATPase, the calcium pump of the endoplasmic reticulum.
Diabetes 2002 Dec
PMID:Insulin receptor signaling and sarco/endoplasmic reticulum calcium ATPase in beta-cells. 1247 86

Neonates born after pregnancies complicated by diabetes or intrauterine growth restriction (IUGR) have increased incidence of hypocalcaemia. Furthermore, IUGR is associated with reduced bone mineralization in infancy and osteoporosis in adult life. We tested the hypothesis that placental calcium transport is altered in these pregnancy complications. Transport of calcium into syncytiotrophoblast basal plasma membrane (BM) vesicles was studied by rapid filtration and protein expression of Ca(2+) ATPase by Western blot. In IUGR Ca(2+) ATPase activity was increased by 48 per cent (n=13; P< 0.05) whereas protein expression was 15 per cent lower (n=13; P< 0.05) than in controls (n=16). Basal membrane ATP dependent calcium transport was unaltered in gestational diabetes (GDM) but increased by 54 per cent in insulin dependent diabetes (IDDM) compared to controls (P< 0.05; n =14). Diabetes did not affect Ca(2+) ATPase expression in BM. We have previously shown that the mid-molecular fragment of parathyroid hormone related peptide (PTHrP midmolecule) stimulates BM Ca(2+) ATPase in vitro. PTHrP midmolecule concentrations in umbilical cord plasma were measured using radioimmunoassay. The concentrations in umbilical cord plasma were increased in IUGR, but unaltered in diabetes. In conclusion, placental calcium pump is activated in IUGR and IDDM, which may be secondary to increased foetal calcium demand. We speculate that PTHrP midmolecule may be one mechanism for activating BM Ca(2+) ATPase in IUGR.
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PMID:ATP dependent Ca2+ transport across basal membrane of human syncytiotrophoblast in pregnancies complicated by intrauterine growth restriction or diabetes. 1274 20


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