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)

Updated guidelines on percutaneous coronary intervention recommend increasing the dose of clopidogrel to 150 mg in high-risk patients if <50% platelet inhibition is demonstrated. However, to date, the functional impact of this recommendation has been poorly explored. The aim of this study was to assess the functional implications associated with the use of clopidogrel 150 mg/day in patients with inadequate platelet inhibition while receiving standard 75 mg/day maintenance treatment. Patients with diabetes mellitus have a higher prevalence of inadequate clopidogrel-induced antiplatelet effects and stent thrombosis compared with those without diabetes and were selected for this analysis. Platelet inhibition was assessed using the VerifyNow P2Y12 assay in patients with type 2 diabetes receiving dual-antiplatelet therapy. Patients (n = 17) with <50% platelet inhibition were treated with clopidogrel 150 mg/day for 1 month. Adenosine diphosphate-induced aggregation and the P2Y12 reactivity ratio were also assessed. Platelet function profiles were compared with that of a control group (n = 17) with >or=50% inhibition. Platelet inhibition increased from 27.1 +/- 12% to 40.6 +/- 18% in patients treated with clopidogrel 150 mg/day (p = 0.009; primary end point). All other functional measures also showed enhanced clopidogrel-induced antiplatelet effects. The degree of platelet inhibition achieved after treatment with clopidogrel 150 mg/day varied broadly, and only 35% of patients yielded a degree of platelet inhibition >or=50%. Increasing the dose in patients with inadequate response to clopidogrel did not reach the same degree of antiplatelet effects as those achieved in patients with adequate response while receiving 75 mg/day. In conclusion, the use of a 150 mg maintenance dose of clopidogrel in patients with type 2 diabetes with <50% platelet inhibition is associated with enhanced antiplatelet effects. However, the antiplatelet effects achieved are nonuniform, and a considerable number of patients persist with inadequate platelet inhibition.
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PMID:Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment. 1831 54

Adenosine infusion, as is used in stress single photon-emission computed tomographic (SPECT) imaging, produces an increase in heart rate (HR) and a decrease in blood pressure (BP). The increase in HR is most likely due to direct sympathetic stimulation rather than a reflex to the decrease in BP. In this study, it was hypothesized that the HR response to adenosine is different in patients with versus without diabetes mellitus (DM) in the setting of normal SPECT imaging results. We studied 60 patients with DM (53% women, mean age 62 +/- 10 years) and 60 controls (50% women, mean age 61 +/- 12 years) (p = NS). All patients underwent adenosine SPECT imaging (140 mug/kg/min for 5 minutes) for clinical indications and had normal perfusion and systolic left ventricular function. HR and BP were measured at baseline and during adenosine infusion. HR ratio was defined as peak HR divided by baseline HR and the change as peak HR minus baseline HR. The change in HR (17 +/- 12 vs 22 +/- 14 beats/min, p = 0.034) and the ratio (1.24 +/- 0.20 vs 1.33 +/- 0.25, p = 0.048) were significantly lower in patients with DM compared with those without DM. The baseline and change in mean BP were not significantly different between the 2 groups. In a stepwise regression analysis model, DM was identified as a predictor of the change in HR (p = 0.022). In conclusion, HR response to adenosine infusion is diminished in patients with DM with normal SPECT imaging results. This is likely due to cardiovascular autonomic neuropathy and may carry important prognostic information.
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PMID:Heart rate response to adenosine in patients with diabetes mellitus and normal myocardial perfusion imaging. 1892 17

Mitochondrial dysfunction is implicated in the pathogenesis of diabetic cardiomyopathy, a common complication of diabetes. Adenosine nucleotide translocase (ANT) translocates ADP/ATP across the inner mitochondrial membrane. Our study aimed to test the hypothesis that overexpression of ANT1 in cardiomyocytes has cardioprotective effects in diabetic cardiomyopathy induced by streptozotocin (STZ). Mice specifically overexpressing murine ANT1 in the heart were generated using alpha-myosin heavy chain promoter. Expression of ANT1 mRNA and protein in hearts was characterized by real-time polymerase chain reaction and Western blot analysis. Five- to 6-month-old male transgenic mice and their age-matched wild-type littermates were subjected to type 1 diabetes induced by STZ. Six weeks later, haemodynamic measurement was performed to assess cardiac function. Ventricular mRNA expression of atrial natriuretic peptide, a molecular marker of heart failure, was characterized by RNase-protection assay. Both ANT1 mRNA and ANT1 protein were specifically overexpressed in the heart of transgenic mice. Heart weight was decreased and cardiac function was dramatically impaired in wild-type mice 6 weeks after induction of diabetes, but ANT1 overexpression prevented these significant changes. The mRNA expression level of atrial natriuretic peptide confirmed the haemodynamic findings, being upregulated in wild-type mice receiving STZ, but showing no statistical differences in ANT1 transgenic mice. Cardiomyocyte-restricted overexpression of ANT1 prevents the development of diabetic cardiomyopathy; therefore, accelerated ADP/ATP exchange could be a new promising target to treat diabetic cardiomyopathy.
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PMID:Myocardial overexpression of adenine nucleotide translocase 1 ameliorates diabetic cardiomyopathy in mice. 1894 56

Diabetic neuropathic pain is generally considered to be one of the most troublesome complications affecting diabetic patients and current therapy provides inadequate pain relief. In the present study, the effect of adenosine was investigated in a model of diabetic neuropathic pain. Diabetes was induced by streptozotocin (65 mg/kg, ip) in male Sprague Dawley rats and subjected to thermal (cold and hot) and chemical (formalin) stimuli. Diabetic rats developed hyperalgesia by the end of six weeks in thermal and chemical stimuli test. Adenosine (100, 200 and 500 mg/kg, ip) produced significant reversal of responses to thermal and chemical stimuli in diabetic rats. 8-Cyclopentyl-1, 3-dipropylxanthine (DPCPX 1 mg/kg, ip), an adenosine A1-receptor antagonist, but not 3,7-dimethyl-1-propargylxanthine (DMPX 1 mg/kg, ip), an adenosine A2A-receptor antagonist, reversed the protective effect of adenosine. These results indicate that adenosine is an effective analgesics in a model of diabetic neuropathy, and the protection produced by adenosine is via stimulation of adenosine A1-receptors.
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PMID:Protective effect of adenosine in diabetic neuropathic pain is mediated through adenosine A1-receptors. 1955 53

Adenosine mediates its diverse effects via four subtypes (A(1), A(2A), A(2B) and A(3)) of G-protein-coupled receptors. The A(1) adenosine receptor (A(1)AR) subtype is the most extensively studied and is well characterized in various organ systems. The A(1)ARs are highly expressed in adipose tissue, and endogenous adenosine has been shown to tonically activate adipose tissue A(1)ARs. Activation of the A(1)ARs in adipocytes reduces adenylate cyclase and cAMP content and causes inhibition of lipolysis. The role of A(1)ARs in lipolysis has been well characterized by using several selective A(1)AR agonists as well as A(1)AR knockout mice. However, the contribution of A(1)ARs to the regulation of lipolysis in pathological conditions like insulin resistance, diabetes and dyslipidemia, where free fatty acids (FFA) play an important role, has not been well characterized. Pharmacological agents that reduce the release of FFA from adipose tissue and thus the availability of circulating FFA have the potential to be useful for insulin resistance and hyperlipidemia. Toward this goal, several selective and efficacious agonists of the A(1)ARs are now available, and some have entered early-phase clinical trials; however, none have received regulatory approval yet. Here we review the existing knowledge on the role of A(1)ARs in insulin resistance, diabetes and obesity, and the progress made in the development of A(1)AR agonists as antilipolytic agents, including the challenges associated with this approach.
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PMID:A1 adenosine receptor: role in diabetes and obesity. 1963 85

High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are independently associated with an increased risk of atherothrombotic events. However, despite this positive correlation, the definitions of both HCPR and HAPR vary largely throughout studies and between different platelet function assays. The aim of the present study was to explore clinical and laboratory parameters that are associated with HCPR and HAPR as measured with different platelet function tests. 530 clopidogrel and aspirin pre-treated patients undergoing elective PCI (percutaneous coronary intervention) were enrolled. Platelet function measurements were performed with: optical aggregometry, the VerifyNow device and PFA-100 cartridges (including the novel INNOVANCE P2Y assay). HCPR as measured with Adenosin-Di-Phospate-induced (ADP) aggregation based tests was associated with clinical factors such as older age, female gender and Diabetes mellitus (DM). The VerifyNow P2Y12 assay was significantly influenced by haemoglobin and haematocrit levels. HAPR as measured with aggregation based tests was significantly influenced by the presence of malignancy, BMI (Body-Mass Index), older age and increased levels of hsCRP (high sensitivity c-reactive proteine). The PFA-100 COL/EPI (collagen-epinephrine) and COL/ADP (collagen-ADP) cartridges were significantly influenced by monocyte count, hs-CRP, MPV (mean platelet volume), vWF-antigen (von Willebrand factor) and vWF-activity. HCPR as measured with the novel INNOVANCE P2Y cartridge was associated with clinical determinants such as BMI, female gender, impaired LVEF (left ventricular ejection fraction), renal failure and dosing of clopidogrel. Laboratory markers that were associated with HCPR as measured with INNOVANCE P2Y were platelet count, white blood cells (WBC), hsCRP and fibrinogen. Both HCPR and HAPR are highly dependent on the type of platelet function assay. Each platelet function assay, in turn, is significantly influenced by distinct clinical and laboratory variables.
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PMID:The influence of clinical characteristics, laboratory and inflammatory markers on 'high on-treatment platelet reactivity' as measured with different platelet function tests. 1988 10

Peripheral arterial occlusive disease (PAOD) of lower extremities is becoming more prevalent worldwide. The general prognosis is particularly negative with a high prevalence of coronary heart disease and cerebrovascular disease. Diabetic foot ulcers occur in 15% of all the patients with diabetes and proceed to lower-leg amputations. In diabetic ulcers, wound healing is impaired because of delayed angiogenesis. In both pathological conditions, therapeutic angiogenesis using angiogenic growth factors, particularly Vascular Endothelial Growth Factor VEGF, is expected to be a valuable treatment. The most used approaches are based on VEGF local delivery or gene therapy, but they failed to meet the expected primary goals of therapy. Adenosine receptor stimulation can induce VEGF expression in many types of cells and this may be achieved by stimulating the A(2A) or A(2B) receptor or both, following the signalling pathways activated by hypoxia. Polideoxyribonucleotide (PDRN) is obtained from sperm trout by an extraction process. The compounds hold a mixture of deoxyribonucleotides polymers with chain lengths ranging between 50 and 2000 bp. PDRN is able to stimulate VEGF production during pathological conditions of low tissue perfusion. It likely acts through the stimulation of A(2A) receptors. Furthermore, acute and chronic toxicity studies showed a good safety profile. PDRN has been shown to be effective in an experimental model of PAOD, hind limb ischemia, impaired wound healing and burn injury. Preliminary studies and ongoing clinical trials predict a significant therapeutic efficacy in patients. These data lead to hypothesize a role for PDRN in therapeutic angiogenesis.
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PMID:Polydeoxyribonucleotide (PDRN): a safe approach to induce therapeutic angiogenesis in peripheral artery occlusive disease and in diabetic foot ulcers. 1986 Jun 58

Adenosine-triphosphate-sensitive potassium channels (KATP) are regulated by adenosine nucleotides, and, thereby, couple cellular metabolism with electrical activity in multiple tissues including the pancreatic beta-cell. The critical involvement of KATP in insulin secretion is confirmed by the demonstration that inactivating and activating mutations in KATP underlie persistent hyperinsulinemia and neonatal diabetes mellitus, respectively, in both animal models and humans. In addition, a common variant in KATP represents a risk factor in the etiology of type 2 diabetes. This review focuses on the mechanistic basis by which KATP mutations underlie insulin secretory disorders and the implications of these findings for successful clinical intervention.
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PMID:K(ATP) channelopathies in the pancreas. 1992 Dec 46

Adenosine and regadenoson cause an increase in heart rate (HR) during myocardial perfusion imaging (MPI). It has been shown that patients with diabetes mellitus have a blunted HR response due to cardiac autonomic dysfunction. It is not known whether the HR response is related to hyperglycemia and the metabolic syndrome (MS). HR changes were assessed in 2,000 patients (643 with diabetes mellitus [DM]) in the Adenoscan Versus Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging (ADVANCE MPI 1 and ADVANCE MPI 2) trials in relation to MS status and blood sugar level on the day of MPI. The HR response was lower in patients with MS (32.43 +/- 0.52% vs 36.15 +/- 0.71%, p <0.001). An increase in the number of features of MS was associated with a stepwise decrease in the HR response (-0.92% per MS criterion, p <0.05), irrespective of the presence of DM. Increasing blood sugar levels resulted in blunting of the HR response even after controlling for DM and MS (0.60 +/- 0.08% per 10 mg/dl, p <0.001). MS was independently related to the HR response on top of DM, renal function, left ventricular function, gender, age, baseline HR, blood pressure, and beta-blocker use. The overall model was highly associated with the HR response (p <0.001) and able to explain 30% of its variation. In conclusion, the HR response to adenosine and regadenoson is blunted in patients with hyperglycemia and in those with MS. These results suggest that factors that precede the development of DM may be associated with cardiac autonomic neuropathy and may help explain the contribution of hyperglycemia and MS to cardiovascular risk.
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PMID:Blunting of the heart rate response to adenosine and regadenoson in relation to hyperglycemia and the metabolic syndrome. 2021 28

Platelet membrane glycoproteins (GPs) are critical for normal platelet adhesion, activation and aggregation. To define the abnormalities in surface GP expression on circulating platelets and provide a better biomarker of bleeding and thrombotic disorders, we have developed a accurate, time-saving and high-throughput biotin-avidin enzyme-linked immunosorbent assay (BA-ELISA) with the monoclonal antibodies (mAbs), 7E3 against the complex of GPIIb and GPIIIa (GPIIb/IIIa), SZ-51 against P-selectin, and SZ-2 against GPIb, respectively. The levels of P-selectin and GPIIb/IIIa were measured in patients with acute myocardial infarction (AMI), intracerebral hemorrhage (ICH), or diabetes mellitus (DM)) and healthy subjects. Inhibition of GP expression was evaluated with SZ-21, an inhibitory mAb against GPIIIa and aspirin, respectively. The sensitivity of BA-ELISA is high enough to detect platelet count as low as 3.13 x 10(9)/L in platelet-rich plasma (PRP). Both the inter-assay and intra-assay coefficient variation are less than 10%. Adenosine diphosphate (ADP)-induced or non-ADP-induced expression of P-selectin and GPIIb/IIIa was significantly higher in AMI, ICH or DM than that in controls (P < 0.01 for each). Either SZ-21 or aspirin can inhibit the ADP-induced expression of P-selectin and GPIIb/IIIa. Importantly, a high correlation was detected between BA-ELISA and flow cytometry methods. These observations indicate that BA-ELISA is a sensitive and high-throughput assay for evaluating platelet GP expression. The newly developed BA-ELISA can be popularized in community hospitals, because it does not require sophisticated equipments and reagents. This method is suitable for screening inhibitors of platelet activation and has a potential in use for diagnostic purposes.
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PMID:A high-throughput biotin-avidin-ELISA for studying expression of platelet membrane glycoproteins and its clinical application. 2082 66


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