Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes in humans is associated with a significant hypercoagulable state; however, the effects of this on stroke and cardiovascular disease are not completely understood. The genetic mutations in db/db and ob/ob mice produce metabolic abnormalities similar to type 2 diabetes, but little is known about their platelet or coagulation properties. The objective of this study was therefore to examine platelet function and coagulation in db/db and ob/ob mice to determine the degree of alteration induced by type 2 diabetes. Male db/db and ob/ob mice, 8-16 weeks old, and their respective genetic control mice were used for all experiments. To examine platelet function and coagulation, we measured ADP-induced whole blood aggregation at baseline and after inhibition with aspirin and fucoidan, whole blood coagulation by thromboelastography, and platelet CD61 expression by flow cytometry. Both db/db and ob/ob mice demonstrated significantly less ADP-induced whole blood aggregation compared with control mice (db/db mice, P < 0.001; ob/ob mice, P < 0.01). Aggregation was significantly inhibited with aspirin in all groups; however, fucoidan inhibited aggregation only in control mice. The db/db and ob/ob mice demonstrated significantly less maximal clot strength compared with control mice (P < 0.01), and ob/ob mice demonstrated premature clot fibrinolysis measured by thromboelastography. In conclusion, the db/db and ob/ob type 2 diabetes mouse models do not demonstrate a hypercoagulable state similar to humans with this disease. We caution their use for studying cardiovascular and cerebrovascular disease in the setting of type 2 diabetes.
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PMID:Whole blood aggregation and coagulation in db/db and ob/ob mouse models of type 2 diabetes. 1827 33

Closure of pancreatic beta-cell ATP-sensitive potassium (K(ATP)) channels links glucose metabolism to electrical activity and insulin secretion. It is now known that saturated, but not polyunsaturated, long-chain acyl-coenyzme A esters (acyl-CoAs) can potently activate K(ATP) channels when superfused directly across excised membrane patches, suggesting a plausible mechanism to account for reduced beta-cell excitability and insulin secretion observed in obesity and type 2 diabetes. However, reduced beta-cell excitability due to elevation of endogenous saturated acyl-CoAs has not been confirmed in intact pancreatic beta-cells. To test this notion directly, endogenous acyl-CoA levels were elevated within primary mouse beta-cells using virally delivered overexpression of long-chain acyl-CoA synthetase-1 (AdACSL-1), and the effects on beta-cell K(ATP) channel activity and cell excitability was assessed using the perforated whole-cell and cell-attached patch-clamp technique. Data indicated a significant increase in K(ATP) channel activity in AdACSL-1-infected beta-cells cultured in medium supplemented with palmitate/oleate but not with the polyunsaturated fat linoleate. No changes in the ATP/ADP ratio were observed in any of the groups. Furthermore, AdACSL-1-infected beta-cells (with palmitate/oleate) showed a significant decrease in electrical responsiveness to glucose and tolbutamide and a hyperpolarized resting membrane potential at 5 mm glucose. These results suggest a direct link between intracellular fatty ester accumulation and K(ATP) channel activation, which may contribute to beta-cell dysfunction in type 2 diabetes.
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PMID:Elevation in intracellular long-chain acyl-coenzyme A esters lead to reduced beta-cell excitability via activation of adenosine 5'-triphosphate-sensitive potassium channels. 1837 36

Silibinin, the most biologically active component of the polyphenolic extract from milk thistle seeds, is widely used to prevent many types of hepatobiliary disorders. Recent evidence suggests new applications for this ancient medication, notably for the treatment of type 2 diabetes owing to its antihyperglycemic properties. As we have lately demonstrated that silibinin lowered glucose production from various gluconeogenic substrates in perifused rat hepatocytes, the aim of this study was to examine the effect of silibinin on both oxidative glucose utilization and reactive oxygen species (ROS) generation since the release of ROS secondary to an increased mitochondrial metabolism may contribute to diabetic damage. We found that silibinin dose-dependently reduced glycolysis from carbohydrates in a cell perifusion system via an inhibitory effect targeted on pyruvate kinase activity. Furthermore, a dramatic effect upon oxidative phosphorylation was shown, as evidenced by a fall in ATP-to-ADP ratio, together with an increase in lactate-to-pyruvate ratio. The most attractive finding was that silibinin, at a concentration as low as 10 microM, fully mitigated the rise in metabolic flow-driven ROS formation. In addition, studies on isolated liver mitochondria revealed that this low dose of silibinin depressed ROS production linked to the electron transfer chain activity. From these results, one may tentatively suggest that interesting activities for silibinin, beyond its general antioxidant status, could be expected from its potential clinical use, especially in pathological conditions when mitochondrial ROS formation is severely enhanced.
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PMID:Interrelation between the inhibition of glycolytic flux by silibinin and the lowering of mitochondrial ROS production in perifused rat hepatocytes. 1844 25

The role of caspases in platelet function is not well understood. When platelets are activated, they express phosphatidylserine on the outer plasma membrane, form platelet microparticles, and aggregate (Pag). The aims of this study were to determine if caspases play a role in the platelet activation seen in type 2 diabetes. Diabetic rats (Zucker diabetic fatty) were treated with a broad-spectrum caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone, in vivo and platelets were evaluated for phosphatidylserine expression, platelet microparticle formation, and Pag. We found a decreased phosphatidylserine exposure in zVAD-Zucker diabetic fatty rats compared to Zucker diabetic fatty-phosphate-buffered saline when activated with 20 micromol/l ADP. Zucker diabetic fatty rats treated with benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone decreased platelet microparticle numbers compared to phosphate-buffered saline control Zucker diabetic fatty rats. Further, treatment with benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone significantly decreased Pag. These results indicate that caspases play a role in platelet activation, suggesting a unique physiologic role of these proteases and perhaps the underlying mechanisms involved in the chronic platelet activation observed in type 2 diabetes.
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PMID:Caspase inhibition of platelet activation. 1846 52

Human pyruvate dehydrogenase complex (PDC) is down-regulated by pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK4 is overexpressed in skeletal muscle in type 2 diabetes, resulting in impaired glucose utilization. Here we show that human PDK4 has robust core-free basal activity, which is considerably higher than activity levels of other PDK isoforms stimulated by the PDC core. PDK4 binds the L3 lipoyl domain, but its activity is not significantly stimulated by any individual lipoyl domains or the core of PDC. The 2.0-A crystal structures of the PDK4 dimer with bound ADP reveal an open conformation with a wider active-site cleft, compared with that in the closed conformation epitomized by the PDK2-ADP structure. The open conformation in PDK4 shows partially ordered C-terminal cross-tails, in which the conserved DW (Asp(394)-Trp(395)) motif from one subunit anchors to the N-terminal domain of the other subunit. The open conformation fosters a reduced binding affinity for ADP, facilitating the efficient removal of product inhibition by this nucleotide. Alteration or deletion of the DW-motif disrupts the C-terminal cross-tail anchor, resulting in the closed conformation and the nearly complete inactivation of PDK4. Fluorescence quenching and enzyme activity data suggest that compounds AZD7545 and dichloroacetate lock PDK4 in the open and the closed conformational states, respectively. We propose that PDK4 with bound ADP exists in equilibrium between the open and the closed conformations. The favored metastable open conformation is responsible for the robust basal activity of PDK4 in the absence of the PDC core.
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PMID:Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity. 1865 36

The effects of therapy with aspirin 300 mg/day and with combined aspirin 100 mg/day plus clopidogrel 75 mg/day on platelet function were compared in patients with diabetes mellitus and coronary artery disease and impaired antiplatelet responses to aspirin 100 mg/day. The study population consisted of 151 outpatients with type II diabetes mellitus and coronary artery disease who were taking aspirin 100 mg/day. Of the 151 patients, a subgroup of subjects with impaired aspirin response were selected on the basis of the results of platelet aggregometry. Nonresponsiveness to aspirin was defined as mean aggregation > or =69% with 3 micromol/L adenosine diphosphate and mean aggregation > or =70% with 2 micromol/L collagen. Aspirin semiresponders were defined as meeting 1 but not both of these criteria. Nonresponders and semiresponders were randomized equally to aspirin 300 mg/day and aspirin 100 mg/day plus clopidogrel 75 mg/day, and aggregation tests were repeated after 2 weeks. Sixty of the 151 patients with diabetes (40%) were found to respond to aspirin inadequately. Platelet aggregation induced by adenosine diphosphate and collagen decreased significantly after aspirin 300 mg/day or combined therapy. Combined treatment was found to have a stronger inhibitory effect on platelet aggregation induced by adenosine diphosphate than aspirin 300 mg/day (p = 0.002). Impaired aspirin response was resolved by increasing the aspirin dose or adding clopidogrel to aspirin (p <0.0001 for each). However, desired platelet inhibition was achieved in significantly more patients by combined treatment than by aspirin 300 mg/day (p <0.05). In conclusion, aspirin 100 mg/day does not inhibit platelet function adequately in a significant number of patients with diabetes mellitus and coronary artery disease. Increasing the aspirin dose to 300 mg/day or adding clopidogrel to aspirin can provide adequate platelet inhibition in a significant number of those patients with impaired responses to low-dose aspirin.
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PMID:Comparison of increased aspirin dose versus combined aspirin plus clopidogrel therapy in patients with diabetes mellitus and coronary heart disease and impaired antiplatelet response to low-dose aspirin. 1867 94

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of beta-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in beta-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K(+) (K(ATP)) channels and activate voltage-gated Ca(2+) channels, leading to stimulation of insulin granule exocytosis. Whereas this K(ATP) channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet beta-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and alpha-ketoglutarate, in control of GSIS.
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PMID:Metabolic cycling in control of glucose-stimulated insulin secretion. 1872 21

In addition to lowering cholesterol, statins may reduce platelet activity and exert beneficial non-lipid (pleiotropic) effects. We evaluated the effects of two different simvastatin based treatment regimens on platelet reactivity in patients with dysglycemia and coronary artery disease (CAD). Thirty-two patients with type 2 diabetes or impaired glucose tolerance and stable CAD received six weeks of double-blind treatment with simvastatin 80 mg daily (S80; n = 16) or ezetimibe 10 mg and simvastatin 10 mg daily (E10/S10; n = 16). Total and low-density lipoprotein (LDL) cholesterol, and high sensitivity C-reactive protein (CRP) decreased similarly in the two groups. LDL (mM) decreased from 3.2 +/- 0.6 to 1.7 +/- 0.7 with E10/S10 and from 3.0 +/- 1.0 to 1.4 +/- 0.5 with S80 treatment. Platelet function was evaluated by whole blood flow cytometry and turbidimetric aggregometry with agonist stimulation ex vivo before and after treatment. Neither treatment affected basal or adenosine diphosphate (ADP)- or thrombin-induced platelet P-selectin expression, or fibrinogen binding, or platelet-leukocyte aggregation. Similarly, neither treatment affected ADP-induced platelet aggregation. In conclusion, lipid lowering treatment with high dose simvastatin or low dose simvastatin plus ezetimibe did not exert any substantial inhibitory effects on the basal or agonist-stimulated activity of circulating platelets in patients with stable CAD and type 2 diabetes or impaired glucose tolerance.
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PMID:No effect of lipid lowering on platelet activity in patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance. 1913 3

Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (Vo(2)). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak Vo(2). Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.
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PMID:Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice. 1961 6

The authors carried out a comparative analysis of the level of homocysteine and the state of haemostasis in patients with and without type 2 diabetes mellitus in the remote terms after endured reconstructive operations on the aorto-iliac segment. They examined a total of eighty-eight patients who had endured reconstructive operations on the aorto-iliac segment at various terms. Of these, forty-two patients were found to have a severe course of type 2 diabetes mellitus (59.9% with decompensation) and forty-six subjects without diabetes constituted the group of comparison. The average age of the patients amounted to 61.9 +/- 1.25 years, with all being smokers. The following parameters were assessed: patency of the bypasses and major arteries of the lower limbs (LL), homocysteine (Hey), fibrinolytic activity, fibrinogen, activated partial thromboplastin time (aPTT), factor XIII, thrombin time, prothrombin index, activity of antithrombin III (AIII), platelet aggregation with ADP, and glycosylated haemoglobin (Hb Aic).
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PMID:[Assessment of the level of homocysteine and the state of haemostasis in patients with and without type 2 diabetes mellitus in remote terms after reconstructive operations on the aorto-iliac segment]. 1980 38


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