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)

This investigation was a prospective, follow-up study to assess whether baseline clinical and investigational parameters were predictors of cardiovascular morbidity and mortality in patients enrolled into the cardiac rehabilitation program. A cohort of 418 patients (70% were men) with coronary heart disease was followed up 3.2 +/- 1.1 years. Two hundred twenty-seven of them (54%) had a recent myocardial infarction (MI), with a thrombolytic rate of 54%. Percutaneous transluminal coronary angioplasty (PTCA) was performed in 45% of patients. The covariates assessed include age, gender, smoking habit, body mass index, the presence of hypertension or diabetes mellitus, exercise habit, site and severity of MI, status of thrombolytic therapy, peak creatine phosphokinase, plasma lipid profiles, ejection fraction, PTCA performed, number of diseased coronary arteries, and exercise capacity. Low-density lipoprotein cholesterol decreased significantly (3.2 +/- 1.0 vs 2.7 +/- 0.7 mmol/L, p < 0.001). The cumulative mortality was 13%. In a univariate model, the parameters that significantly predict mortality included older age, diabetes, low exercise capacity (< or = 4 metabolic equivalents) 3-vessel disease, those without PTCA performed, and a low ejection fraction. In the Cox proportional-hazards model analysis, the independent factors were coexisting diabetes (chi-square 6.1, p = 0.01) and a low metabolic equivalent (chi-square 6.5, p = 0.01). One hundred six patients were rehospitalized for nonfatal cardiovascular events that included unstable angina (48%), heart failure (21%), acute MI (6%), symptomatic arrhythmia (6%), and severe hypertension (1%). Factors that independently predicted rehospitalization were low exercise capacity (p = 0.02) and the presence of diabetes (chi-square 4.8, p = 0.03). Diabetes was also associated with more episodes of hospital admission (2.3 +/- 2.1 vs 1.6 +/- 1.4, p = 0.04) and a longer cumulative hospital stay (25.5 +/- 34.6 vs 11.4 +/- 19.6 days, p = 0.02). Thus, in patients with MI or after PTCA receiving conventional medical therapy, the cardiac rehabilitation program should focus on aggressive diabetic control and enhancement of exercise capacity.
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PMID:Clinical predictors of morbidity and mortality in patients with myocardial infarction or revascularization who underwent cardiac rehabilitation, and importance of diabetes mellitus and exercise capacity. 1107 4

3-Guanidinopropionic acid (1, PNU-10483) has been demonstrated to both improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate 4. In an effort to identify novel entities that maintain antidiabetic potency without susceptibility to creatine-like metabolism, an analogue program was undertaken to explore the effects of various structural modifications, including homologation, simple substitution, single atom mutations, and bioisosteric replacements for the guanidine and carboxylic acid. Overall, the scope of activity encompassed by the set of new analogues proved to be exceedingly narrow. Notable exceptions demonstrating equivalent or improved antidiabetic activity included the alpha-amino derivative 29, aminopyridine 47, isothiourea 67, and aminoguanidine 69. On the basis of its superior therapeutic ratio, aminoguanidine 69 was selected for preclinical development and became the foundation for a second phase of analogue work. Furthermore, in vitro studies demonstrated that 69 is markedly less susceptible to phosphorylation by creatine kinase than the lead 1, suggesting that it should have less potential for accumulation in muscle tissue than 1.
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PMID:Synthesis and biological activity of analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid: discovery of a novel aminoguanidinoacetic acid antidiabetic agent. 1131 22

3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as alpha-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob/ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.
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PMID:Synthesis and biological activity of aminoguanidine and diaminoguanidine analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid. 1131 23

Reported discrepancies in the effects of tumor necrosis factor (TNF)-alpha in modulating insulin sensitivity of cultured cells may relate both to cell types studied and to the time course of exposure to the cytokine. Additionally, the relationship of effects on glucose metabolism to changes in the insulin signaling pathway cannot be assumed. For in vitro study, the cell type most relevant to insulin resistance in humans is the cultured human muscle cell. In the present study, TNF brought about no change in the rate of glycogen synthesis in cultured human muscle cells unless present during differentiation. The presence of TNF (5 ng/ml) during the process of differentiation of myoblasts into mature myotubes diminished the response of glycogen synthesis to acute insulin stimulation. This finding was associated with an impairment of differentiation-dependent increases in total cellular glycogen synthase (GS) activity. Under the same conditions of TNF exposure, there was no effect on the response to acute insulin stimulation of the fractional activity of GS. Similarly, there was no effect on the insulin stimulation of protein kinase B (PKB) and inhibition of glycogen synthase kinase 3 (GSK-3). Acute insulin stimulation brought about a 4.08 +/- 0.44-fold stimulation of activity of PKB in the absence of TNF, with 4.81 +/- 0.70-fold stimulation in cells exposed to TNF. GSK-3 activity decreased to 74.0 +/- 5.8% of basal after insulin stimulation without TNF and 78.3 +/- 5.0% after TNF exposure. However, differentiation of myocytes, as defined by an increase in the acetylcholine receptor, myogenin, and mature creatine kinase isoform expression, was impaired in TNF-treated cells. These studies demonstrate that TNF, if present during differentiation, decreases insulin-stimulated rates of storage of glucose as glycogen and total GS activity but does not downregulate the insulin-signaling system to GS. More generally, TNF also inhibits differentiation of human muscle cells in culture.
Diabetes 2001 May
PMID:Effects of tumor necrosis factor-alpha on insulin action in cultured human muscle cells. 1133 14

The predictive value of Killip classification of acute myocardial infarction (AMI) in patients undergoing percutaneous coronary intervention (PCI) is not well established. We performed a pooled analysis of 2,654 patients with AMI enrolled in 3 primary angioplasty trials. Of these, 2,305 patients were class I, 302 were class II, and 47 were class III (class IV patients were excluded). Univariate and multivariate analyses were performed to determine if Killip class at admission was a predictor of in-hospital and 6-month mortality. Higher Killip classification was associated with greater in-hospital (2.4%, 7%, and 19% for class I, II, and III, respectively) and 6-month mortality (4%, 10%, and 28% for class I, II, and III, respectively). Higher Killip class was associated with increased age (p <0.001), history of diabetes (p <0.02), lower systolic blood pressure and higher heart rate at presentation (p <0.0001 for both), more 3-vessel disease (p <0.001), lower left ventricular ejection fraction (p <0.0001), and higher peak creatine phosphokinase (p <0.0001). With each increasing Killip class, there was an increased need for an intra-aortic balloon counterpulsation (p <0.001) and greater incidence of renal failure (p <0.001), major arrhythmia (p <0.001), and major bleeding (p <0.001). After controlling for potential confounding variables, Killip classification remained a multivariate predictor of mortality at both time end points. Killip classification at hospital admission remains a simple and useful independent predictor of in-hospital and 6-month mortality in patients with AMI who are undergoing primary PCI.
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PMID:Predictive value of the Killip classification in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. 1134 98

Two isoforms of hexokinase (type I and type II) are expressed in skeletal muscle; however, the intracellular distribution of these hexokinase isoforms in human skeletal muscle is unclear. The current study was undertaken to assess this issue because binding of hexokinase to subcellular structures is considered to be an important mechanism in the regulation of glucose phosphorylation. Vastus lateralis muscle was obtained from healthy lean individuals. Muscle homogenate was separated at 45,000g into particulate and cytosolic fractions. The activity and subcellular distribution of hexokinase isozymes in human skeletal muscle was determined using ion-exchange chromatography and a highly sensitive high-performance liquid chromatography-based hexokinase assay. This criterion method was used to validate a modified thermal inactivation method for distinguishing type I and type II isoforms. Mean hexokinase activity was 3.88 +/- 0.65 U/g wet wt or 0.64 +/- 0.11 U/mU creatine kinase (CrK) in the particulate fraction and 0.45 +/- 0.22 U/g wet wt or 0.07 +/- 0.03 U/mU CrK in the cytosolic fraction. Hexokinase I and II accounted for 70-75 and 25-30% of total hexokinase activity, respectively. Nearly all (95%) of hexokinase I activity (0.52 +/- 0.09 U/mU CrK) was found in the particulate fraction, consistent with the known high affinity of hexokinase I for mitochondria. Hexokinase II activity was also largely bound to the particulate fraction (72%), but 28% was found within the cytosolic fraction. Thus, within the particulate fraction, the relative contributions of hexokinase I and hexokinase II were 81 and 19%, whereas within the cytosolic fraction, the relative contributions for hexokinase I and hexokinase II were 37 and 63%.
Diabetes 2001 Jun
PMID:Hexokinase isozyme distribution in human skeletal muscle. 1137 24

1. It has been suggested that calcitonin gene-related peptide (CGRP) is involved in the protection provided by ischaemic preconditioning in rat hearts and that ischaemic preconditioning is absent in diabetic rat hearts. 2. In the present study, we tested the relationship between sensory nerve function and ischaemic preconditioning in diabetic rats. 3. In 4- and 8-week diabetic rats and age-matched non- diabetic controls, 30 min global ischaemia and 40 min reperfusion caused a significant decrease in cardiac function and a marked increase in creatine kinase (CK) release. Ischaemic preconditioning, by three cycles of 5 min ischaemia and 5 min reperfusion, improved the recovery of cardiac function and decreased CK release during reperfusion in 4-week diabetic rat hearts. However, the cardioprotection afforded by ischaemic preconditioning was lost in 8-week diabetic rat hearts. Pretreatment with CGRP for 5 min also significantly improved the recovery of cardiac function and decreased CK release in rats subjected to 4 or 8 weeks of diabetes. 4. The content of CGRP in the coronary effluent during ischaemic preconditioning was significantly increased in 4-week diabetic rat hearts (P < 0.05). However, only a slight increase in the release of CGRP was shown in 8-week diabetic rat hearts (P > 0.05). 5. In summary, the present results suggest that the protection afforded by ischaemic preconditioning is attenuated in diabetic rats and that the change may be related to the reduction in CGRP release in diabetic rat hearts.
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PMID:Role of calcitonin gene-related peptide in ischaemic preconditioning in diabetic rat hearts. 1138 May 12

Troponin I is a predictive marker of short- and intermediate-term adverse cardiac events in patients with acute coronary syndromes (ACS). These high-risk patients may benefit from early percutaneous coronary intervention. However, whether additional myocardial injury, defined as postprocedural troponin I elevation, may be associated with adverse short- and intermediate-term outcomes has not been fully explored. Accordingly, we studied 132 consecutive patients with non-ST-elevation ACS (62% with non-Q-wave myocardial infarction) and elevated troponin I levels at admission (>0.15 ng/ml) who underwent percutaneous coronary intervention > or =48 hours after admission. Troponin I levels were routinely measured at 6 and 18 to 24 hours after intervention and patients were stratified according to the presence or absence of troponin I re-elevation, defined as postprocedural troponin I levels >1 times the admission levels. In-hospital and cumulative 6-month clinical outcomes were compared between groups. Patients with troponin I re-elevation (n = 51) were older (68 +/- 13 vs 64 +/- 12 years, p = 0.05) and had experienced prior myocardial infarction more frequently (92.5 vs 82.1, p = 0.09), but otherwise had similar baseline clinical characteristics. Patients with troponin I re-elevation had significantly higher in-hospital mortality (9.8% vs 0%, p = 0.016) and a higher 6-month cumulative death rate (24% vs 3.7%, p = 0.001). There was a trend for an increased 6-month myocardial infarction rate in patients with troponin I re-elevation (13.7% vs 3.7%, p = 0.11) and target vessel revascularization was similar between groups (16.7% vs 17.4%, p = 0.92). By multivariate analysis, troponin I re-elevation (odds ratio [OR] 6.2, p = 0.011) and diabetes mellitus (OR 5.7, p = 0.014) were the strongest independent predictors for increased 6-month cumulative mortality, whereas creatine kinase MB-fraction re-elevation had no prognostic value. We conclude that troponin I re-elevation after percutaneous coronary intervention in high-risk patients with ACS is associated with a substantial increase in mortality and reduced event-free survival at 6-month follow-up.
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PMID:Prognostic value of cardiac troponin I re-elevation following percutaneous coronary intervention in high-risk patients with acute coronary syndromes. 1144 8

Diabetes increases both the incidence of cardiovascular disease and complications of myocardial infarction and heart failure. Studies using diabetic animals have shown that changes in myocardial sodium transporters result in alterations in intracellular sodium (Na(i)) homeostasis. Because the changes in sodium homeostasis can be due to increased entry of Na+ via the electroneutral Na+-K+-2Cl- cotransporter (NKCC), we conducted experiments in acute diabetic hearts to determine if 1) net inward cation flux via NKCC is increased, 2) this cotransporter contributes to a greater increase in Na(i) during ischemia, and 3) inhibition of NKCC limits injury and improves function after ischemia-reperfusion. These issues were investigated in perfused type I diabetic and nondiabetic rat hearts subjected to ischemia and 60 min of reperfusion. A group of diabetic and nondiabetic hearts was perfused with 5 microM of bumetanide, an inhibitor of NKCC. Flux via NKCC, Na(i), and ATP was measured in each group with the use of radiotracer 86Rb, 23Na, and 31P nuclear magnetic resonance spectroscopy, respectively, whereas ischemic injury was assessed by measuring creatine kinase release on reperfusion. Cation flux via NKCC, as measured by 86Rb uptake, was significantly increased in diabetic hearts. Inhibition of NKCC significantly reduced ischemic injury in diabetic hearts, improved functional recovery on reperfusion, attenuated the ischemic rise in Na(i), and conserved ATP during ischemia-reperfusion. Parallel studies in nondiabetic hearts showed that NKCC inhibition was not cardioprotective. These findings demonstrate that flux via NKCC is increased in type I diabetic hearts and that inhibition with bumetanide attenuates changes in Na(i) and ATP during ischemia and protects against ischemic injury. The data suggest a therapeutic role for pharmacological agents that inhibit flux via NKCC in diabetic patients with myocardial ischemia.
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PMID:Protection of ischemic myocardium in diabetics by inhibition of electroneutral Na+-K+-2Cl- cotransporter. 1145 52

Diagnosis and risk stratification of patients with acute coronary syndromes remain extremely important in order to avoid unnecessary hospitalizations on the one hand, and to improve prognosis of these patients on the other. For diagnosis of acute coronary syndromes, an ECG should be obtained at rest, troponin T and I should be measured on admission and again 6 to 12 h later, and myoglobin or CK-MB should be determined in patients with recent syndromes and those with recurring ischemia. Risk should be assessed upon admission and repeatedly during the hospital stay. Early risk indicators are: age, male sex, previous manifestation of coronary artery disease, history of left ventricular dysfunction or congestive heart failure and ongoing chest pain, as well as ST depression, transient ST segment elevation, and elevated levels of troponin T or I. Longer term risk assessment in unstable coronary artery disease includes rest and stress echocardiography, exercise ECG, thallium scintigraphy, as well as coronary angiography and left ventriculography. Markers of high long-term risk are old age, prior history of myocardial infarction, diabetes, elevated levels of C-reactive protein, and the extent of coronary artery disease and left ventricular dysfunction.
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PMID:Diagnosis and risk stratification in patients with acute coronary syndromes according to ESC guidelines. 1156 70


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