Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over 200 risk factors for cardiovascular disease (CVD) have now been identified. Among these, the three most important are (1) abnormal lipids, including the fact that there are more than 15 types of cholesterol-containing lipoproteins and four different types of triglyceride-rich particles, some of which are very atherogenic, (2) high blood pressure, and (3) cigarette smoking. In addition, many other factors including diabetes, haemostatic factors such as fibrinogen, factor VII, plasminogen activator inhibitors, and new factors such as apolipoprotein E4 and homocysteine, are known to increase the risk of developing clinical CVD. A low risk for CVD requires that these various factors are present in the circulation in the correct proportions. Two simple tests for determining plasma lipid levels can be used to identify those individuals with an atherogenic lipid profile and who are, therefore, at increased risk for CVD. Firstly, the ratio of total cholesterol to high density cholesterol (HDL cholesterol) should be determined, followed by measurement of plasma triglyceride concentrations. This will allow differentiation of whether the low density lipoproteins (LDL), HDL cholesterol or triglyceride-rich particles such as the small dense beta-very low density lipoproteins (VLDL) are the major cause for concern. Once identified, those individuals with a high lipid risk profile should be treated before, rather than after, experiencing coronary heart disease (CHD).
 ...
PMID:Lipids, risk factors and ischaemic heart disease. 883 10

Disturbances of the haemostatic system may favour the development of vascular damage and the final occlusion events in the progress of coronary heart disease (CHD). It has been shown recently in epidemiological studies, that increased concentration of several factors, mainly fibrinogen, factor VII, von Willebrand factor (vWF), and the fibrinolytic variables plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA), can be considered as risk factors for CHD. As morbidity and mortality through coronary atherosclerosis are higher in type 2 diabetic patients than in nondiabetic subjects and as insulin resistance represents a situation which favours the development of atherothrombosis, evaluation of the haemostatic factors which are recognized as risk factors may be interesting to consider in these situations. In fact, it has been shown that the fibrinolytic parameters PAI-1 and t-PA antigen are strongly related to the metabolic disorder of insulin resistance, whereas the link with fibrinogen, factor VII, and vWF remains weak. Many cross-sectional studies conducted in different populations have shown that PAI-1 and t-PA antigen (which represents t-PA/PAI-1 complexes) are strongly correlated with insulin, triglyceride, high-density lipoprotein (HDL) cholesterol, body mass index, walst-to-hip ratio and blood pressure, and that the improvement of insulin resistance improves in parallel the metabolic abnormalities and the concentration of the fibrinolytic parameters. Attempts at explaining the elevated PAI-1 and t-PA antigen levels in the insulin resistance syndrome have involved many clinical and in vitro studies, in which the role of insulin, insulin propeptides, very-low-density lipoprotein (VLDL) triglyceride, insulin resistance per se, glucose, and adipose tissue have successively been analysed and the main results of these studies are presented in this review. Due to recent experimental data from animal models of thrombosis, a pathogenic role of decreased fibrinolytic activity or increased PAI-1 levels can be proposed and could play a role in the development of vascular disease in subjects with Type 2 diabetes or insulin resistance.
 ...
PMID:Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus. 886 93

Diabetes produces extensive alterations of collagen metabolism including enhanced gingival collagenase activity. However, the mechanism for this enhanced enzyme activity is unclear. Collagenase is secreted from cells in a latent form and plasmin has been proposed as an important in vivo activator of procollagenase. Plasmin is converted from its precursor, plasminogen, by the proteolytic action of a serine proteinase, plasminogen activator (PA). The current study was therefore undertaken to determine the effect of diabetes on gingival PA activity in the rat. Since doxycycline is a potent collagenase inhibitor, the effect of doxycycline on gingival PA activity was also investigated. Eighteen male, Sprague-Dawley rats were made diabetic by streptozotocin injection (7 mg/100 g). Control rats (N = 8) were sham-treated. Doxycycline (5 mg/day/rat) was administered to 9 of the 18 diabetic rats by gavage on a daily basis. The other 9 diabetic rats were administered with saline. After 3 weeks, blood and gingival tissue were collected from each rat for the determination of glucose level and gingival PA activity. The tissues were then minced and extracted with 5 mM sodium phosphate containing 1% Triton X-100. PA assay was performed using chromatogenic substrate to determine PA activity in the extracts. Gingival PA activity in the diabetic rats was significantly reduced compared to the control (13.5 +/- 1.6 vs. 36.0 +/- 3.3 microunits/100 micrograms protein, P < 0.01). Doxycycline administration to diabetic rats had no effect on the already reduced gingival PA activity (10.4 +/- 3.5 in doxycycline-treated rats vs. 13.5 +/- 1.6 mu units/100 micrograms protein in untreated diabetic rats). PA activities in gingival tissues from the diabetic, nondiabetic control and doxycycline-treated diabetic groups were also demonstrated on zymographs as lytic bands. Regarding the well-known fact that gingival collagenase activity is enhanced during diabetes, our results did not support the notion that this biochemical alteration is attributed to increased activation of procollagenase by PA.
 ...
PMID:Plasminogen activator activity is decreased in rat gingiva during diabetes. 886 12

To assess whether plasminogen activator inhibitor 1 (PAI-1) activity is elevated in the progeny of young coronary men, 193 young subjects were recruited and divided into two groups. Group A consisted of 104 children whose fathers had suffered a myocardial infarction before the age of 55 ("cases"). Eighty-nine young subjects matched for age, sex, body mass index (BMI) and smoking habits without familial history of coronary artery disease (CAD) served as controls (group B). Children with a family history of diabetes mellitus or hypertension were excluded from both groups. We measured PAI-1 activity, tissue-type plasminogen activator (t-PA) antigen, a2-antiplasmin, fibrinogen, lipids and apolipoproteins in both groups. PAI-1 activity levels were also determined in the men who suffered a premature myocardial infarction 4 months after their discharge. PAI-1 activity levels were higher in cases compared to controls (3.13 +/- 1.9 vs 2.17 +/- 1.9 U/ml, p = 0.0014). t-PA antigen and a2-antiplasmin did not differ significantly between the two groups, while fibrinogen, total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) were significantly higher in group A. PAI-1 was positively correlated with triglycerides (r = 0.22, p = 0.024), apolipoprotein B (r = 0.21, p = 0.039) and fibrinogen (r = 0.22, p = 0.029) in cases and with BMI in both cases (r = 0.37, p = 0.0003) and controls (r = 0.23, p = 0.044). In stepwise multiple regression analysis, only apolipoprotein B (p = 0.008) and BMI (p = 0.0014) were significant determinants of PAI-1 activity in cases. There was also a positive correlation between PAI-1 activity levels of the affected fathers and their children (r = 0.30, p = 0.01). The present data support the hypothesis that elevated PAI-1 levels in the offspring of men with premature myocardial infarction impair their fibrinolytic capacity contributing to their familial predisposition to CAD.
 ...
PMID:Plasminogen activator inhibitor 1 is elevated in the children of men with premature myocardial infarction. 888 80

Tissue-type plasminogen activator (tPA) is an endothelium-derived vasoactive substance which is released to the blood stream by exercise, blood occlusion, and desmopressin (DDAVP). The increased capacity of the plasma tPA level raised by these factors is thought to reflect in vivo endothelial function. On the other hand, endothelial dysfunction has been reported in patients with hypercholesteremia as well as in those with diabetes mellitus. Therefore, diabetic patients with hypercholesteremia were administered 5 mg of simvastatin daily for one month and plasma tPA responses evoked by DDAVP were examined before and after treatment for hypercholesteremia. While the treatment of simvastatin for one month significantly reduced serum cholesterol levels from 257 +/- 12 mg to 206 +/- 10 mg (no change in HbA1c was observed during the study), plasma tPA levels and % delta vWF (von Willebrand factor) following DDAVP infusion significantly increased from 11.4 +/- 1.2 ng/ml to 13.4 +/- 1.4 ng/ml and from 69.3 +/- 23.4% to 126.5 +/- 47.4%, respectively. However, neither increase in plasma levels of guanosine 3', 5'-cyclic monophosphate (cGMP) nor change in the depressive response of blood pressure was observed following DDAVP infusion after the treatment of simvastatin. In addition, no change in urinary albumin excretion rate was observed with the treatment of hypercholesteremia. Therefore, it was suggested that improvement in hypercholesteremia may ameliorate vascular endothelial dysfunction in diabetic patients with hypercholesteremia and that hypercholesteremia may enhance endothelial dysfunction in these patients.
 ...
PMID:[Effect of hypercholesteremia on vascular endothelial function and albumin excretion rate in patients with diabetes mellitus]. 895 5

Hyperglycaemia and hyperinsulinaemia have both been related to accelerated atherosclerosis in non-insulin-dependent diabetes mellitus (NIDDM). Plasma fibrinolytic potential is reduced in NIDDM and it is known that glucose and insulin can modulate plasminogen activator inhibitor (PAI-1) and tissue-plasminogen activator (t-PA) secretion and can therefore regulate local fibrinolysis. Vascular smooth muscle cells (vSMC) play an important role in the development of atherosclerotic lesions; however, the role of insulin and glucose in regulating PAI-1 and t-PA production in vSMC is presently not known. Therefore, we cultured arterial vSMC explanted from human umbilical cords and exposed them to increasing concentrations of glucose (5, 12, 20, 27, 35 mmol/l) or insulin (0.1, 0.5, 1, 10 nmol/l) in a serum free medium. After 24 h, PAI-1 and t-PA antigens and activity were evaluated in the culture medium; in cells exposed to 20 mmol/l glucose and to 0.5 nmol/l insulin PAI-1 gene expression was also evaluated. An increase in PAI-1 antigen was observed at each glucose concentration (by 138, 169, 251 and 357% as compared to 5 mmol/l glucose) which was paralleled by an increase in PAI-1 activity. t-PA concentration was also increased by glucose but its activity was sharply reduced. An increase in PAI-1 antigen was detected at each insulin level (by 121, 128, 156 and 300% as compared to no insulin). PAI-1 activity was slightly increased at the lowest insulin concentrations but markedly increased by 10 nmol/l insulin. t-PA antigen was also increased by insulin; however, its activity was markedly reduced at each concentration. As compared to control cells, PAI-1 mRNA was increased by 2.5 and 2.0 fold by 20 mmol/l glucose and 0.5 nmol/l insulin, respectively. We conclude that in human vSMC both glucose and insulin can affect the fibrinolytic balance so as to reduce fibrinolytic potential. This might contribute to decreased local fibrinolysis and thereby might accelerate the atherothrombotic process in NIDDM subjects.
 ...
PMID:Glucose and insulin independently reduce the fibrinolytic potential of human vascular smooth muscle cells in culture. 896 Aug 22

Fibrinogen has been recognised in recent years as an independent risk factor in athero/thrombogenesis. However, the mechanism by which elevated fibrinogen translates into higher incidence of atherosclerosis is not known. One possible mechanism may be through the modification of fibrin. While it is already known that fibrin network is altered in disease states like peripheral vascular disease, diabetes, hypercholesterolaemia and myocardial infarction, the influence of altered fibrin network structure on growth and function of endothelial cells (EC) and fibroblasts (FB) requires investigation. Fibrin network structure in plasma clots was modified by changing pH and characterised using established biophysical methods. PGI(2), von Willebrand Factor (vWF), t-PA and PAI-1 were measured to evaluate changes in cell function induced by modified fibrin structure. In general, networks composed of thin fibres induced growth over their entire layer. Networks composed of thick fibres and open matrix promoted infiltration of cells into gel matrix and growth of macrovascular structures. Furthermore, thin fibres promoted a more prothrombotic environment as observed from changes in cell biochemical function. Fibrin, whilst initially acting as a scaffolding for cellular and biochemical processes, may also alter cell function and determine the progress of atherosclerosis.
 ...
PMID:Interaction of endothelial cells and fibroblasts with modified fibrin networks: role in atherosclerosis. 906 11

Mesangium enlargement is a central feature of diabetic nephropathy and almost certainly plays a pathogenic role in this condition. Previous studies have shown that mesangium degradation is reduced in a high glucose mileau. Plasmin has been shown to play an important role in extracellular matrix degradation, both directly and through its ability to activate the matrix metalloproteinases. We therefore investigated how high glucose concentration may affect the various components of the plasminogen cascade on mesangial cells and whether it impairs the ability of the mesangial cell to generate plasmin activity. Result showed decreased binding of plasminogen and the urokinase type plasminogen activator to the mesangial cell surface while the tissue type plasminogen activator and the plasminogen activator-1 associated with mesangial cells were increased. The net effect of these changes was a reduced capacity of mesangial cell layers to generate plasmin activity in a high glucose environment. We postulate that this may be of importance in the reduced mesangium degradation which occurs in diabetes.
 ...
PMID:High glucose reduces generation of plasmin activity by mesangial cells. 914 50

Elevated fibrinogen levels as well as an impaired activity of the fibrinolytic system are regarded as important cardiovascular risk factors. To elucidate a potential interrelation between fibrinogen as an indicator of a hypercoagulable state and the endogenous fibrinolytic function hemostatic and rheological as well as lipid parameters were determined in 224 consecutive patients, who underwent elective coronary angiography. In the selected study population of 81 men and 19 women with fibrinogen concentration either > or = 3.5 g/l (n = 70) or < or = 2.5 g/l (n = 30) hyperfibrinogenemia was found to be significantly associated with increased concentrations of plasmin-alpha 2-antiplasmin complex [PAP [median (25.-75. percentile)], 534 (361-680) micrograms/l vs. 289 (243-440) micrograms/l; p < 0.001] and tissue plasminogen activator (t-PA) antigen [9 (6-11) micrograms/l vs 8 (5-9) micrograms/l; p < 0.05] while this association was lost in the subgroup of patients with angiographically normal coronary arteries (n = 26). In addition to these findings fibrinogen was significantly correlated with PAP (r = 0.40, p < 0.001; n = 224) and t-PA antigen (r = 0.2, p < 0.01; n = 224) after adjustment for age, diabetes mellitus, lipid parameters and leucocyte counts. It can be argued that elevated fibrinogen levels in patients with coronary artery disease are concomitant with an activation of the fibrinolytic system.
 ...
PMID:Activation of the fibrinolytic system in patients with coronary artery disease and hyperfibrinogenemia. 918 12

Oestrogen replacement therapy is associated with a decreased risk of cardiovascular disease in postmenopausal women. Patients with non-insulin-dependent diabetes mellitus (NIDDM) have an increased cardiovascular risk. However, oestrogen replacement therapy is only reluctantly prescribed for patients with NIDDM. In a double blind randomized placebo controlled trial we assessed the effect of oral 17 beta-estradiol during 6 weeks in 40 postmenopausal women with NIDDM. Glycated haemoglobin (HbA1c), insulin sensitivity, suppressibility of hepatic glucose production, lipoprotein profile and parameters of fibrinolysis were determined. The oestrogen treated group demonstrated a significant decrease of HbA1c and in the normotriglyceridaemic group a significantly increased suppression of hepatic glucose production by insulin. Whole body glucose uptake and concentrations of non-esterified fatty acids did not change. LDL-cholesterol- and apolipoprotein B levels decreased, and HDL-cholesterol, its subfraction HDL2-cholesterol and apolipotrotein A1 increased. The plasma triglyceride level remained similar in both groups. Both the concentration of plasminogen activator inhibitor-1 antigen and its active subfraction decreased. Tissue type plasminogen activator activity increased significantly only in the normotriglyceridaemic group. Oestrogen replacement therapy improves insulin sensitivity in liver, glycaemic control, lipoprotein profile and fibrinolysis in postmenopausal women with NIDDM. For a definite answer as to whether oestrogens can be more liberally used in NIDDM patients, long term studies including the effect of progestogens are necessary.
 ...
PMID:Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. 924 7


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>