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)

Plasminogen activator inhibitor-1 is elevated in obesity and may be a risk factor for obesity/NIDDM related cardiovascular disease. In spite of this, little is known about the tissue and cellular origin of elevated PAI-1 in obesity or of the mediators and molecular mechanisms that regulate it. We have begun to systematically address these issues using genetically obese (ob/ob, db/db) mice. Plasma PAI-1 levels were 5-fold higher in obese mice compared to their lean counterparts. Subsequent RT-PCR and in situ hybridization studies suggest that the increased plasma PAI-1 originates primarily from the adipocyte in response to chronically elevated levels of tumor necrosis factor-alpha (TNF-alpha), insulin, and transforming growth factor-beta (TGF-beta). Thus, the signals and mechanisms that lead to elevated plasma PAI-1 observed in obesity are complex, and appear to involve interactions between multiple mediators and the adipose tissue itself.
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PMID:The fat mouse: a powerful genetic model to study elevated plasminogen activator inhibitor 1 in obesity/NIDDM. 919 33

Clustering of risk factors for cardiovascular disease related to insulin resistance may account for the increased incidence of vascular disease in these conditions and in non-diabetic subjects. To investigate the relationship between a coding polymorphism in the insulin receptor substrate-1 gene and the presence of cardiovascular risk factors, 209 patients with NIDDM and 452 subjects investigated for coronary artery disease (CAD) were studied. In the NIDDM subjects 22 (10.5%) were heterozygous at codon 972 for a polymorphism which codes for a glycine to arginine substitution and 187 (89.5%) were homozygous for the wild type. Patients with the mutation had lower levels of cholesterol compared with wild type (mean, 95% confidence intervals), 5.3 (4.9-5.8) vs 6.0 (5.9-6.2) mmol/l, respectively (P = 0.002), triglyceride 1.7 (1.4-2.1) vs 2.2 (2.0-2.4) mmol/l (P = 0.051), factor VII:C activity 109.5 (85.5-133.5) vs 133.5 (127-140)% (P = 0.057) and PAI-1 antigen, 16.0 (10.5-24.3) vs 22.2 (20.0-24.6) ng/ml (P = 0.054). There were no differences in body mass index, indices of glycaemic control, fasting insulin or the prevalence of hypertension. In patients with CAD, 55 (12.7%) were carriers of the mutation (including three homozygotes) (NIDDM vs CAD, NS). Although similar trends in cholesterol, factor VII, PAI-1 antigen and triglyceride existed between carriers of the mutation and the wild type, none reached statistical significance. The results indicate that the IRS-1 gene is not implicated in the pathogenesis of NIDDM or CAD.
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PMID:Insulin receptor substrate-1 gene polymorphism and cardiovascular risk in non-insulin dependent diabetes mellitus and patients undergoing coronary angiography. 921 52

To elucidate the relationship between hyperlipidemias and insulin resistance in the elderly, we conducted three studies: 1) determination of the prevalence of hyperlipidemias in elderly subjects with impaired glucose tolerance or non-insulin dependent diabetes mellitus, 2) measurement of plasma glucose and insulin levels in patients with phyerlipidemias and atherosclerotic vascular disease, and 3) computation of correlation between levels of substances involved in coagulation and fibrinolysis (F-VII, F-X, and PAI-1) and levels of triglycerides and insulin in serum in hyperlipidemic patients with atherosclerotic vascular disease. The prevalence of hypertriglyceridemia was 4% in non-diabetic control subjects, 38% in subjects with impaired glucose tolerance, 22% in those with diabetes, and 29% in those with both conditions. Levels of glucose and insulin in plasma were measured after oral intake of 75 g of glucose. The insulin response was greater in the group with hypertriglyceridemia than in the group with normal triglyceride levels, although the glucose responses did not differ between the groups. The activities and levels of F-VII, F-X, and PAI-1 correlated with triglycerides in serum and also with fasting insulin levels in hyperlipidemic patients with atherosclerotic vascular disease. We conclude that hypertriglyceridemia plays an important role in the development of atherothrombotic vascular disease; it accompanies elevation of coagulation and antifibrinolytic activities in elderly patients with insulin resistance.
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PMID:[Insulin resistance and hyperlipidemia in the elderly]. 926 49

Most people with diabetes die from thrombotic complications superimposed to degenerative arterial vascular lesions, mostly myocardial infarction. Diabetes is a risk factor per se for such complications, but often clusters with dyslipoproteinemia, hypertension and obesity. In NIDDM (Type-II) patients this is referred to as "metabolic syndrome" and often operates on a genetically programmed susceptibility which accelerates the pathogenesis of coronary artery disease in front of a much wider diabetes specific cardiopathy. From a pathophysiological point of view none of these associated risk factors explains the pathogenetic series of events leading to the precipitation of an occlusive thrombus at sites of complicated coronary plaques. In patients with diabetes the coagulation system is switched towards a prethrombotic state, involving increased plasmatic coagulation, diminished fibrinolysis, decreased endothelial thromboresistance and predominantly platelet hyperreactivity ("diabetic thrombocytopathy"). Some of these factors are associated with an increased coronary risk (e.g. fibrinogen, PAI-1, platelets), but are also directly linked to the pathogenesis of "atherothrombosis". Altered cardiac remodelling together with adhesion and coagulation mechanisms appears suitable to explain decreased functional performance of infarcted organs, decreased success of acute (reduced fibrinolytic response, reperfusion injury) and longterm intervention strategies (PTCA, CABG) in diabetes. Glucose adjustment alone will not adequately neutralize these complex mechanisms. Particularly in diabetes a multidimensional interventional repertoire is required including antihypertensive, antidyslipoproteinemic and antithrombotic drugs, customized according to the individual patients needs as assessed by early diagnostic measures ("early secondary prevention").
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PMID:Heart disease in diabetes mellitus: a challenge for early diagnosis and intervention. 951 54

The prevention of coronary artery disease is based on the control of several factors associated with a disease or clinical condition and suspected to play a pathogenetic role, defined as 'risk factors'. Smoking is a powerful risk factor for coronary artery disease, with risk of events increasing in relation to the number of cigarettes smoked daily. Smoking cessation is associated within 3-4 years, with a significant reduction in cardiovascular risk. Hyperlipidaemia is a powerful predictor of coronary disease with a strong, independent, continuous and graded positive association between cholesterol levels and risk of coronary events. Several large studies have shown the benefit of cholesterol reduction, and there is clear evidence of the efficacy of statins in the reduction of events in primary and secondary prevention. Hypertension is a significant, strong and independent risk factor for coronary artery disease morbidity and mortality and the reduction of events and mortality by antihypertensive treatment is well documented. Obesity is associated with an increase in all-cause mortality and cardiovascular mortality, with a particularly high risk for subjects with central obesity. Central obesity is also part of the so-called 'metabolic X syndrome' including insulin resistance, which appears to be associated with a particularly high risk of coronary artery disease. Type 1 and type 2 diabetes mellitus are associated with an increased risk of cardiovascular disease, especially in women. Several studies have shown that good metabolic control and multifactorial risk factor reduction significantly lower the coronary risk in these patients. Recent evidence is accumulating that some clotting factors (fibrinogen, factor VII, von Willebrand factor) and fibrinolytic factors (t-PA and PAI-1) are associated with an increased risk of coronary artery disease. The European Concerted Action on Thrombosis (ECAT) showed that the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent coronary syndromes in patients with angina pectoris, and that low fibrinogen is associated with a low risk of events despite high cholesterol levels. Post-menopausal status is associated with increased risk of coronary artery disease, particularly when menopause is premature (before the age of 45) or abrupt (surgical). There is strong, thought not yet completely definite evidence that post-menopausal hormone replacement therapy may significantly reduce the risk of events and improve survival. Hyperhomocysteinaemia is an emerging risk factor independently associated with an increased risk of coronary artery disease, cerebral vascular disease, and peripheral vascular disease. The administration of vitamin B6, B12 or folate seems to be useful and is currently under further evaluation. Recently, attention has been focused on the correlation between coronary artery disease and genetic factors, such as ACE gene polymorphism or the gene polymorphism for the IIIa-moiety of the platelet fibrinogen receptor IIb-IIIa. In primary prevention, control of the major risk factors mainly in patients with clustered factors will substantially reduce the risk of ischaemic events. Secondary prevention of CHD is based on: aggressive behavioural advice, blood pressure reduction in hypertensives, good metabolic control of diabetes, and cholesterol reduction. Aspirin, beta-blockers, ACE inhibitors, and oral anticoagulants, may be useful in selected patients.
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PMID:Classical risk factors and emerging elements in the risk profile for coronary artery disease. 951 44

The authors examined 25 patients with diabetes mellitus type 2 (NIDDM) without vascular complications, treated by sulphonyl urea preparations, 12 hyperinsulinaemic (HI) non-diabetic subjects and 11 normoinsulinaemic healthy subject s. Patients with NIDDM and HI non-diabetics had significantly elevated PAI-1 levels which correlated with the C-peptide level (r = 0.519, p < 0.001), triacylglycerols (TG) (r = 0.685, p < 0.001), BMI (r = 0.607, p < 0.001) and levels of endothelial markers such as von Willebrand s factor and thrombomodulin (TM). In the group of patients with NIDDM no relationship of PAI-1 and C-peptide was found and a significant correlation was found with TM levels (r = 0.609, p = 0.001) and TG levels (r = 0.476, p = 0.046). The results suggest that the endothelial department has an effect on the regulation of PAI-1 levels in patients with NIDDM.
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PMID:[Plasminogen activator inhibitor (PAI-1) and markers of endothelial dysfunction in patients with diabetes mellitus]. 965 May 6

Although low-density lipoprotein (LDL) cholesterol is a critically important factor in the development of atherosclerosis, nearly half the patients with coronary artery disease have LDL cholesterol levels within the National Cholesterol Education Program (NCEP) guidelines. Therefore, attention has focused on other modifiable risk factors that could strongly impact the development of coronary artery disease. Type 2 diabetics have a 3-fold increased risk of coronary artery disease; prediabetics, without chronic hyperglycemia, have a 2-fold increased risk compared with normal subjects. Insulin resistance has also been implicated as the cause of atherosclerosis. Insulin resistance is associated with hyperinsulinemia and a constellation of other factors, some of which are themselves independent risk factors for coronary artery disease. These include reduced levels of high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, increased small dense LDL particles, hypertension, visceral obesity, and increased levels of plasminogen activator inhibitor-1 (PAI-1). Hyperinsulinemia and insulin resistance at the vascular level also may contribute to vascular injury and the atherosclerotic process. Current studies suggest that controlling hyperglycemia, LDL cholesterol, and blood pressure are important to protect the diabetic from atherosclerosis. A key question, particularly in type 2 diabetes, is to define the best regimen for glucose control that will protect the vasculature. Sulfonylureas, metformin, and troglitazone have direct vascular actions. Metformin lowers LDL cholesterol and triglycerides, while troglitazone reverses many of the components associated with the insulin resistance syndrome. Clinical trials focusing on coronary artery disease outcomes are now warranted to prevent coronary artery disease, the major vascular complication and cause of mortality in diabetes.
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PMID:Cardiovascular risk continuum: implications of insulin resistance and diabetes. 970 62

The aim of this study was to determine the effect of the lipid modifying agent gemfibrozil on lipid and coagulation risk factors in patients with Type 2 diabetes mellitus (Type 2 DM). Twenty-six subjects with Type 2 DM and dyslipidaemia were treated for 24 weeks with either gemfibrozil 600 mg orally twice daily or placebo in a double-blind randomized trial. Lipid profiles, fibrinogen, Factor VII, and plasminogen activator inhibitor-1 (PAI-1) were measured by routine laboratory methods. Low density lipoprotein (LDL) size was determined by gradient gel electrophoresis and the resistance of LDL to copper-induced oxidation was assessed by measuring absorbance at 234 nm. Gemfibrozil significantly reduced total cholesterol (-0.9 (-0.48, -1.32) mmol l(-1); p < 0.05) and triglycerides (-2.7 (-1.55, -1.35) mmol l(-1); p < 0.001) vs placebo. The fall in triglyceride was reflected by a fall in VLDL cholesterol levels in the gemfibrozil treated group vs placebo (-1.31 mmol l(-1); p < 0.001). LDL-cholesterol level did not change but LDL particle size increased by 0.5 nm (0.01, 0.93); P < 0.02. The increase in particle size was inversely correlated with the change of triglyceride level (r = -0.79, p < 0.0001) but did not result in any reduction of susceptibility to copper-induced oxidation. There were no significant changes in the coagulation parameters studied. Because of its ability to correct the lipid abnormalities associated with Type 2 DM particularly hypertriglyceridaemia, gemfibrozil provides a useful therapeutic option in the management of diabetic dyslipidaemia but it does not alter in vitro oxidizability of LDL.
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PMID:Gemfibrozil treatment increases low-density lipoprotein particle size in Type 2 diabetes mellitus but does not alter in vitro oxidizability. 979 89

Insulin resistance (IR) is associated with an elevated PAI-1 level and by correlation with insulin and triacylglycerol (TG) levels. While in IR non-diabetics this relationship is close, in patients with NIDDM the mutual relationship is less marked and there are other factors which raise the PAI-1 levels such as proinsulin, oxidation stress or cytokines. Therefore achievement of satisfactory metabolic control, reduction of insulin and TG levels need not be associated with normalization of PAI-1. As it is an independent risk factor of atherosclerosis, further examinations are necessary in order to differentiate in more detail the possible causes of its rising level in order to obtain a rational basis for effective therapy.
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PMID:[Plasminogen activator inhibitor (PAI-1) and diabetes mellitus. II. PAI-1 in insulin resistant conditions]. 982 87

Hyperinsulinemia is associated with the development of coronary heart disease. However, the underlying mechanisms are still poorly understood. Hypercoagulability and impaired fibrinolysis are possible candidates linking hyperinsulinism with atherosclerotic disease, and it has been suggested that proinsulin rather than insulin is the crucial pathophysiological agent. The aim of this study was to investigate the relationship of insulin and its precursors to markers of coagulation and fibrinolysis in a large triethnic population. A strong and independent relationship between plasminogen activator inhibitor-1 (PAI-1) antigen and insulin and its precursors (proinsulin, 32-33 split proinsulin) was found consistently across varying states of glucose tolerance (PAI-1 versus fasting insulin [proinsulin], r=0.38 [r=0.34] in normal glucose tolerance; r=0.42 [r=0.43] in impaired glucose tolerance; and r=0.38 [r=0.26] in type 2 diabetes; all P<0.001). The relationship remained highly significant even after accounting for insulin sensitivity as measured by a frequently sampled intravenous glucose tolerance test. In a stepwise multiple regression model after adjusting for age, sex, ethnicity, and clinic, both insulin and its precursors were significantly associated with PAI-1 levels. The relationship between fibrinogen and insulin and its precursors was significant in the overall population (r=0.20 for insulin and proinsulin; each P<0.001) but showed a more inconsistent pattern in subgroup analysis and after adjustments for demographic and metabolic variables. Stepwise multiple regression analysis showed that proinsulin (split products) but not fasting insulin significantly contributed to fibrinogen levels after adjustment for age, sex, clinic, and ethnicity. Decreased insulin sensitivity was independently associated with higher PAI-1 and fibrinogen levels. In summary, we were able to demonstrate an independent relationship of 2 crucial factors of hemostasis, fibrinogen and PAI-1, to insulin and its precursors. These findings may have important clinical implications in the risk assessment and prevention of macrovascular disease, not only in patients with overt diabetes but also in nondiabetic subjects who are hyperinsulinemic.
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PMID:Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS). 1007 58


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