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

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-783,281, an antidiabetic fungal metabolite that has previously been shown to activate insulin signaling in CHO cells, was tested for its effect on intracellular Ca(2+) ([Ca(2+)](i)) and insulin secretion in single mouse pancreatic beta-cells. Application of 10 micromol/l L-783,281 for 40 s to isolated beta-cells in the presence of 3 mmol/l glucose increased [Ca(2+)](i) to 178 +/- 10% of basal levels (n = 18) as measured by fluo-4 fluorescence. L-767,827, an inactive structural analog of the insulin mimetic, had no effect on beta-cell [Ca(2+)](i). The L-783,281-evoked [Ca(2+)](i) increase was reduced by 82 +/- 4% (n = 6, P < 0.001) in cells incubated with 1 micromol/l of the SERCA (sarco/endoplasmic reticulum calcium ATPase) pump inhibitor thapsigargin and reduced by 33 +/- 6% (n = 6, P < 0.05) in cells incubated with 20 micromol/l of the L-type Ca(2+)-channel blocker nifedipine. L-783,281-stimulated [Ca(2+)](i) increases were reduced to 31 +/- 3% (n = 9, P < 0.05) and 48 +/- 10% (n = 6, P < 0.05) of control values by the phosphatidylinositol 3-kinase (PI3-K) inhibitors LY294002 (25 micromol/l) and wortmannin (100 nmol/l), respectively. In beta-cells from IRS-1-/- mice, 10 micromol/l L-783,281 had no significant effect on [Ca(2+)](i) (n = 5). L-783,281 also resulted in insulin secretion at single beta-cells. Application of 10 micromol/l L-783,281 for 40 s resulted in 12.2 +/- 2.1 (n = 14) exocytotic events as measured by amperometry, whereas the inactive structural analog had no stimulatory effect on secretion. Virtually no secretion was evoked by L-783,281 in IRS-1-/- beta-cells. LY294002 (25 micromol/l) significantly reduced the effect of the insulin mimetic on beta-cell exocytosis. It is concluded that L-783,281 evokes [Ca(2+)](i) increases and exocytosis in beta-cells via an IRS-1/PI3-K-dependent pathway and that the [Ca(2+)](i) increase involves release of Ca(2+) from intracellular stores.
Diabetes 2002 Feb
PMID:Effect of the insulin mimetic L-783,281 on intracellular Ca2+ and insulin secretion from pancreatic beta-cells. 1181 57

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

The Ca(2+)-ATPase activity of rat brain microsomes was studied in streptozotocin (STZ)-induced diabetes. Male rats, 200-250 g, were rendered diabetic by injection of STZ (45 mg kg(-1) body weight) via the teil vein. Brain tissues were collected at 1, 4 and 10 weeks after diabetes was induced for determination of Ca(2+)-ATPase activity, lipid peroxidation and tissue calcium levels. Diabetic rats had significantly elevated blood glucose levels compared to controls. Blood glucose levels were 92.92 +/- 1.22 mg dl(-1) (mean +/- SEM) for the control group, 362.50 +/- 9.61 mg dl(-1) at 1 week and >500 mg dl(-1) at 4, 8 and 10 weeks for the diabetics. Enzyme activities were significantly decreased at 1, 4, 8 and 10 weeks of diabetes relative to the control group (p < 0.001). Ca(2+)-ATPase activity was 0.084 +/- 0.008 U l(-1), 0.029 +/- 0.005 U l(-1), 0.029 +/- 0.006 U l(-1), 0.033 +/- 0.003 U l(-1) and 0.058 +/- 0.006 U l(-1) (mean +/- SEM) at control, 1, 4, 8 and 10 week of diabetes respectively. The change in calcium levels in diabetic rat brain at 8 and 10 weeks of diabetes was significantly higher than that of the control group (p < 0.05). On the other hand lipid peroxidation measured as TBARS (thiobarbituric acid reactive substances) was significantly higher at 8 and 10 weeks of diabetes (p < 0.05). The increase in lipid peroxidation observed in diabetic rat brain may be partly responsible for the decrease in calcium ATPase activity.
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PMID:Diabetes-induced decrease in rat brain microsomal Ca2+-ATPase activity. 1547 5

Diabetes results in a cardiomyopathy characterized by reduced contractility that is primarily the result of changes in calcium handling within the myocyte. Because most of the calcium involved in excitation-contraction (EC) coupling is derived from the sarcoplasmic reticulum (SR), it is no surprise that many studies have found a reduction in sarco-endoplasmic reticulum calcium ATPase (SERCA) activity in the diabetic state. In this review, we outline the changes to SR calcium handling in the diabetic state and, through the use of transgenic mice and adenoviral gene therapy, we examine how SR function can be improved by the expression of various proteins that are directly and indirectly involved in calcium handling. Improving SERCA activity plays an important role in ameliorating the contractile phenotype associated with the diabetic state.
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PMID:Altered cardiac calcium handling in diabetes. 1552 85

Cardiomyopathy is a major cause of mortality for both type 1 and 2 diabetic patients. However, experimental analysis of diabetic cardiomyopathy has focused on type 1 diabetes and there are few reports on cardiomyocyte dysfunction in the widely used type 2 diabetic model, db/db. In the current study, we assessed function in isolated ventricular myocytes from type 1 diabetic OVE26 mice and from type 2 diabetic db/db mice. When compared with their respective control strains, both diabetic models showed significant impairment in contractility, as assessed by percent peak shortening, maximal rate of contraction, and maximal rate of relaxation. The calcium decay rate was also significantly reduced in both types of diabetes, but the decrement was much greater in OVE26 myocytes, approx 50% vs only 20% in db/db myocytes. To understand the basis for slow calcium decay in diabetic myocytes and to understand the molecular basis for the quantitative difference between calcium decay in OVE26 and db/db myocytes, we measured cardiac content of the SERCA2a calcium pump. SERCA2a was significantly decreased in OVE26 diabetic myocytes but not reduced at all in db/db myocytes. The reduction of SERCA2a in OVE26 myocytes was completely prevented by overexpression of the antioxidant protein metallothionein, confirming that oxidative stress is an important component of diabetic cardiomyopathy. The current results demonstrate that though contractility is impaired in individual myocytes of db/db hearts and deficits are similar to what is seen in a severe model of type 1 diabetes, impairment in calcium reuptake is less severe, probably as a result of maintenance of normal levels of SERCA2a.
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PMID:Cardiomyocyte dysfunction in models of type 1 and type 2 diabetes. 1624 73

In investigating genetic competence, Reusch and collaborators have found that the concentration of short chain poly-(R)-3-hydroxybutyrate (PHB) and polyphosphate (polyP) complexes increases with genetic transformability and that interrupting DNA uptake yields single-stranded donor DNA complexed with short chain PHB. This would be consistent with the organic polyphosphate, DNA, replacing the inorganic polyphosphate, polyP, in the PHB pore so allowing the DNA to be drawn into the cell. Reusch has gone on to show that PHB and polyphosphate, extracted from membranes or synthesized chemically, together form a voltage-activated calcium-selective channel. One may wonder whether the classical proteinaceous calcium channels have a short chain PHB/polyP core--and whether other ion channels have this core too. It is therefore significant that in Streptomyces lividans the potassium channel KcsA, which resembles that of eukaryotes, forms tetramers that contain polyP whilst both monomers and tetramers are covalently linked to short chain PHB. Pumps are the counterparts of channels. Reusch has also shown that a model pump, the calcium ATPase pump of human erythrocytes, contains both cPHB and polyP and has strongly implicated these polymers in its functioning. Again, one may wonder whether these polymers are essential constituents of other pumps. Reusch has gone on to show that a wide range of proteins are modified post-translationally by covalent addition of short chain PHB in both prokaryotes and eukaryotes including DNA-binding proteins such as histones. Finally, Reusch has extended the importance of short chain PHB to medicine by showing its likely involvement in atherogenic plaques and diabetes. And yet this opus has gone largely unnoticed.
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PMID:Poly-(R)-3-hydroxybutyrate and the pioneering work of Rosetta Natoli Reusch. 1635 14

Intrauterine growth restriction is associated with a range of alterations in placental transport functions: the activity of a number of transporters is reduced (Systems A, L and Tau, transporters for cationic amino acids, the sodium-proton exchanger and the sodium pump), placental glucose transporter activity and expression are unchanged whereas the activity of the calcium pump is increased. In contrast, accelerated fetal growth in association to diabetes is characterized by increased activity of placental Systems A and L and glucose transporters. Evidence suggests that these placental transport alterations are the result of specific regulation and that they, at least in part, contribute to the development of pathological fetal growth rather than representing a consequence to altered fetal growth. One interpretation of this data is that the placenta functions as a nutrient sensor, altering placental transport functions according to the ability of the maternal supply line to provide nutrients. Placental transporters are subjected to regulation by hormones. Insulin up-regulates several key placental transporters and maternal insulin may represent a "good nutrition" signal to increase placental nutrient transfer and the growth of the fetus. Preliminary evidence suggests that placental mammalian target of rapamycin, a protein kinase regulating protein translation and transcription in response to nutrient stimuli, may be involved in placental nutrient sensing.
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PMID:IFPA 2005 Award in Placentology Lecture. Human placental transport in altered fetal growth: does the placenta function as a nutrient sensor? -- a review. 1644 15

In brain, muscle, and pancreatic islets, depolarization induces an increase in respiration, which is dependent on calcium influx. The goal of this study was to assess the quantitative significance of this effect in islets relative to glucose-stimulated ATP turnover, to examine the molecular mechanism mediating the changes, and to investigate the functional implications with respect to insulin secretion. Glucose (3-20 mmol/l) increased steady-state levels of cytochrome c reduction (32-66%) in isolated rat islets, reflecting an increased production of NADH, and oxygen consumption rate (OCR) by 0.32 nmol/min/100 islets. Glucose-stimulated OCR was inhibited 30% by inhibitors of calcium influx (diazoxide or nimodipine), whereas a protein synthesis inhibitor (emetine) decreased it by only 24%. None of the inhibitors affected cytochrome c reduction, suggesting that calcium's effect on steady-state OCR is mediated by changes in ATP usage rather than the rate of NADH generation. 3-isobutyl-1-methylxanthine increased insulin secretion but had little effect on OCR, indicating that the processes of movement and exocytosis of secretory granules do not significantly contribute to ATP turnover. At 20 mmol/l glucose, a blocker of sarcoendoplasmic reticulum calcium ATPase (SERCA) had little effect on OCR despite a large increase in cytosolic calcium, further supporting the notion that influx of calcium, not bulk cytosolic calcium, is associated with the increase in ATP turnover. The glucose dose response of calcium influx-dependent OCR showed a remarkable correlation with insulin secretion, suggesting that the process mediating the effect of calcium on ATP turnover has a role in the amplification pathway of insulin secretion.
Diabetes 2006 Dec
PMID:Contribution of calcium influx in mediating glucose-stimulated oxygen consumption in pancreatic islets. 1713 Apr 99


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