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)

Among the traditional risk factors, dyslipidaemia and coagulation disorders play an important role in increasing the risk of coronary heart disease (CHD) in patients with type 2 diabetes. The lipid abnormalities of patients with insulin resistance and type 2 diabetes include increased triglycerides, lower high density lipoprotein (HDL)-cholesterol and the predominance of small dense low density lipoprotein (LDL)-particles. The composition of HDL particles is different from healthy controls and the concentration of the larger, more anti-atherogenic particles is decreased in patients with insulin resistance and type 2 diabetes. Subgroup analyses of several large studies have shown that lowering LDL-cholesterol with statin treatment decreased cardiovascular events in patients with type 2 diabetes. In other studies, gemfibrozil decreased cardiovascular events in a subgroup of patients with diabetes, although the decreases were not always statistically significant. Platelets from patients with diabetes are more sensitive to several aggregating agents, have increased numbers of glycoprotein receptors and a lower activity of guanylate cyclase. These factors may contribute to the documented hyperreactivity of platelets in patients with type 2 diabetes. Other factors in patients with type 2 diabetes include alterations in serum fibrinogen, PAI-1, tissue-type plasminogen activator (tPa) and factors V, II and VII, which have all been linked to the risk of myocardial infarction. Increased D-dimer, von Willebrand factor (vWf) antigen, A-II anti-plasmin and decreased anti-thrombin III were also reported in patients with type 2 diabetes. This pro-thrombotic risk profile of the circulating blood in type 2 diabetes patients, together with the lipid abnormalities, contributes to the increased risk of vascular events in this population.
 ...
PMID:Dyslipidaemia and coagulation defects of insulin resistance. 1196 26

Diabetics die mainly from thrombotic complications and there is clear evidence that diabetes is a hypercoagulable state. Epidemiological and prospective intervention data link hyperglycemia to vascular complications and glycation of proteins is one favored molecular basis to explain this fact. Cell surface receptors may support fibrinolytic surveillance in both intravascular and extravascular locations by stimulating plasmin generation and by protecting plasmin from its inhibitors. The existing experimental evidence suggests that annexin II in its tetrameric form is the main physiological receptor for plasminogen on the extracellular surface of endothelial cells. We have recently shown that annexin II is an extremely vulnerable target for glycation, quickly responding to restoration of normoglycemia. We hypothesize that glycation of endothelial membrane annexin II impairs the appropriate formation of the plasminogen/tissue plasminogen activator/annexin II complex, disrupting a key regulatory mechanism in fibrinolytic vigilance. This would in turn produce decreased fibrinolytic activity and indirectly promote a thrombophilic state in diabetic patients. We base our hypothesis on our observation and on evidence for the mechanism of action of two major independent risk factors for CV events: lipoprotein (a) and hyperhomocysteinemia. Binding of plasminogen to annexin II is inhibited by Lp (a) and binding of tissue plasminogen activator to annexin II is blocked by homocysteine. If our hypothesis is correct, one of the components of the increased thrombogenicity seen in diabetic patients might then be an acquired annexinopathy.
 ...
PMID:Is diabetic hypercoagulability an acquired annexinopathy? Glycation of annexin II as a putative mechanism for impaired fibrinolysis in diabetic patients. 1220 47

Tissue-type plasminogen activator (tPA) regulates fibrin clot lysis by stimulating the conversion of plasminogen into the active protease plasmin. Fibrin is required for efficient tPA-mediated plasmin generation and thereby stimulates its own proteolysis. Several fibrin regions can bind to tPA, but the structural basis for this interaction is unknown. Amyloid beta (Abeta) is a peptide aggregate that is associated with neurotoxicity in brains afflicted with Alzheimer's disease. Like fibrin, it stimulates tPA-mediated plasmin formation. Intermolecular stacking of peptide backbones in beta sheet conformation underlies cross-beta structure in amyloid peptides. We show here that fibrin-derived peptides adopt cross-beta structure and form amyloid fibers. This correlates with tPA binding and stimulation of tPA-mediated plasminogen activation. Prototype amyloid peptides, including Abeta and islet amyloid polypeptide (IAPP) (associated with pancreatic beta cell toxicity in type II diabetes), have no sequence similarity to the fibrin peptides but also bind to tPA and can substitute for fibrin in plasminogen activation by tPA. Moreover, the induction of cross-beta structure in an otherwise globular protein (endostatin) endows it with tPA-activating potential. Our results classify tPA as a multiligand receptor and show that cross-beta structure is the common denominator in tPA binding ligands.
 ...
PMID:Tissue-type plasminogen activator is a multiligand cross-beta structure receptor. 1241 83

The level of serum sialic acid, which is known to reflect atherosclerotic progress and to be related to the incidence of cardiovascular diseases, is increased in patients with diabetes. To elucidate the mechanism of the relation of serum sialic acid to fibrinogen, the relationship between serum sialic acid and markers of blood coagulation activity was investigated in type 2 diabetic patients. The concentration of serum sialic acid showed significant positive correlations with blood platelet count and with plasma concentrations of fibrinogen, D-dimer, thrombin-antithrombin III complex and plasmin-alpha2 plasmin inhibitor complex. These relationships were still significant after adjustment for age, sex, smoking history, body mass index, hemoglobin A, mean arterial pressure and low-density lipoprotein cholesterol. The correlation coefficient of blood fibrinogen with serum sialic acid was still significant after adjustment for D-dimer, thrombin-antithrombin III complex or plasmin-alpha2 plasmin inhibitor complex. On the contrary, blood fibrinogen showed no significant correlation with D-dimer, thrombin-antithrombin III complex or plasmin-alpha2 plasmin inhibitor complex, although an increase in blood fibrinogen is known to be an atherosclerotic risk factor. These results suggest that the serum sialic acid level reflects blood coagulation activity in type 2 diabetic patients and is related to blood fibrinogen level independently of blood coagulation activity.
 ...
PMID:Relation of serum sialic acid to blood coagulation activity in type 2 diabetes. 1244 7

Decreased degradation of the glomerular extracellular matrix (ECM) is thought to contribute to the accumulation of glomerular ECM that occurs in diabetic nephropathy and other chronic renal diseases. Several lines of evidence indicate a key role for the plasminogen activator/plasminogen/plasmin system in glomerular ECM degradation. However, which of the two plasminogen activators (PAs) present in renal tissue, tissue plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA), is responsible for plasmin generation and those factors that modulate the activity of this system remain unclear. This study utilized mesangial cells isolated from mice with gene deletions for tPA, uPA, and plasminogen activator inhibitor 1 (PAI-1) to further delineate the role of the PA/plasminogen/plasmin system in ECM accumulation. ECM degradation by uPA-null mesangial cells was not significantly different from controls (92% +/- 1%, n = 12). In contrast, ECM degradation by tPA-null mesangial cells was markedly reduced (-78 +/- 1%, n = 12, P < 0.05) compared with controls, whereas tPA/uPA double-null mesangial cells degraded virtually no ECM. Previous studies from this laboratory have established that transforming growth factor-beta1 (TGFbeta1) inhibits ECM degradation by cultured mesangial cells by increasing the production of PAI-1, the major physiological PA inhibitor. In keeping with this observation, TGFbeta1 (1 ng/ml) had no effect on ECM degradation by PAI-1-null MC. High glucose levels (30 mM) in the presence or absence of insulin (0.1 mM) caused a moderate increase in ECM degradation by normal human mesangial cells. In contrast, glycated albumin, whose concentration is known to increase in diabetes, produced a dose-dependent (0.2-0.5 mg/ml) inhibition of ECM degradation by normal human mesangial cells. Taken together, these results document the importance of tPA versus uPA in renal plasmin production and indicate that in contrast to elevated glucose, glycated albumin may contribute to ECM accumulation in diabetic nephropathy.
 ...
PMID:Extracellular matrix degradation by cultured mesangial cells: mediators and modulators. 1453 May 9

Patients with end-stage renal disease dialyzed due to diabetic nephropathy are at higher risk of death due to cardiovascular complications than dialyzed non-diabetic patients. Disturbances in hemostasis may play a role in the vascular complications of diabetes mellitus. It has been postulated that TAFI-Thrombin Activatable Fibrinolysis Inhibitor, newly described glycoprotein, couples two opposite systems: coagulation and fibrinolysis. The aim of the work was to study TAFI concentration in hemodialyzed and peritoneally dialyzed diabetic and non-diabetic patients. We assessed: TAFI concentration, markers of ongoing coagulation: thrombin-antithrombin complexes, prothrombin fragments 1 + 2 (markers of TAFI activation), a marker of ongoing fibrinolysis: plasmin-antiplasmin complexes, a marker of TAFI cataliser to TAFIa-thrombomodulin using commercially available kits. All four groups studied did not differ in regard to fibrinogen, thrombomodulin, plasmin-antiplasmin complexes, and TAFI concentration. Both groups of dialyzed diabetic patients have higher concentration of markers of ongoing coagulation when compared to dialyzed non-diabetic patients. Hypercoagulable state observed in dialyzed diabetic patients may contribute to the higher cardiovascular mortality in these population.
 ...
PMID:[Thrombin activatable fibrinolysis o inhibitor-TAFI- in dialyzed patients with diabetic nephropathy]. 1468 22

Patients dialyzed due to diabetic nephropathy are at a higher risk of death due to cardiovascular complications than dialyzed non-diabetic patients. Disturbances in hemostasis may play a role in the vascular complications of diabetes mellitus. It has been postulated that TAFI-thrombin activatable fibrinolysis inhibitor, which couples two opposite systems: coagulation and fibrinolysis, may be involved in the mechanism of vascular endothelial damage in diabetic patients. We assessed: TAFI and TAFIa, markers of ongoing coagulation: thrombin-antithrombin complexes, prothrombin fragments 1+2, a marker of ongoing fibrinolysis: plasmin-antiplasmin complexes in diabetic and non-diabetic patients on hemodialyses-HD, peritoneal dialyses-CAPD, patients with chronic renal failure with and without diabetic nephropathy on conservative treatment. Both groups of dialyzed diabetic patients have a higher concentration of markers of ongoing coagulation and TAFI activity when compared to dialyzed non-diabetic patients. Linear regression analysis showed that TAFI concentration was directly related to albumin in HD and CAPD patients without diabetic nephropathy, whereas TAFIa correlated with triglycerides, fibrinogen and leukocytes count in this group. When evaluated separately (HD, CAPD), significant correlations between TAFIa and triglycerides and fibrinogen were found only in diabetic CAPD patients. Multivariate analysis showed no correlation between TAFI and other parameters studied. In conclusion, elevated circulating TAFI and TAFIa might be a new link in the pathogenesis of impaired fibrinolysis in diabetic nephropathy, and thus atherosclerosis progression, particularly in CAPD patients. Hypercoagulable state observed in diabetic patients on conservative treatment and maintained on dialyses may contribute to the higher cardiovascular mortality in this population. In these patients there is also evidence of endothelial injury, and probably secondary activation of the coagulation cascade.
 ...
PMID:Thrombin activatable fibrinolysis inhibitor (TAFI) and markers of endothelial cell injury in dialyzed patients with diabetic nephropathy. 1498 23

The goals of this article were (1) to identify cell surface proteins whose expression was regulated by diabetes and (2) to assess their contribution to diabetic complications. We purified heat shock protein 90alpha (Hsp90alpha) from the membrane fraction of high glucose-treated endothelial cells (ECs) as a binding partner for a diabetes-specific phage. Further investigation revealed that high glucose elevated cell surface Hsp90alpha in cultured cells, and that diabetes increased the amount of Hsp90alpha on the luminal surface of the aorta. We also found that high glucose or diabetes promoted the association of Hsp90alpha with annexin II and increased the expression of annexin II on the surface of aortic ECs. Finally, plasmin activity was increased by high glucose or diabetes, and this change was partially reversed with an annexin II antibody. These findings reveal a novel glucose-regulated interaction between Hsp90alpha and annexin II, and raise the possibility that increased expression of annexin II, which promotes the generation of plasmin, is linked to clotting abnormalities associated with the diabetic state.
 ...
PMID:Heat shock protein 90alpha-dependent translocation of annexin II to the surface of endothelial cells modulates plasmin activity in the diabetic rat aorta. 1500 30

Impaired fibrinolysis in type 2 diabetes may be caused by an increased plasma concentration of plasminogen activator inhibitor 1 (PAI-1), although the effects of short-term hypoglycemic therapy on fibrinolytic activity are poorly understood. This study investigated the effects of metabolic improvement on fibrinolysis activity and plasma concentrations of PAI-1 in poorly controlled, hospitalized type 2 diabetic patients. Forty-eight poorly controlled type 2 diabetic patients were studied; 26 were subsequently treated with sulfonylurea (SU) and 22 with insulin. The plasma concentrations of plasmin-alpha2-antiplasmin (PAP), a measure of fibrinolytic activity, plasma PAI-1, and fasting triglycerides and glucoses were measured at the beginning and the end of hospitalization. The body mass index and fasting triglyceride decreased significantly after treatment (p < 0.0001). The plasma concentration of PAP increased significantly (p < 0.01), and the plasma PAI-1 decreased by 50% after treatment. There was an inverse correlation between the changes in the plasma concentrations of PAP and PAI-1 (r= - 0.36, p = 0.023). Treatment with SU or insulin showed an increase in plasma PAP with a concomitant decrease in the plasma PAI-1 with equivalent glycemic control. In poorly controlled type 2 diabetic patients, the plasma PAP concentration can be significantly increased and the plasma PAI-1 antigen significantly reduced, even with short-term metabolic improvements including weight reduction, a better lipid profile, and tighter glycemic control with either SU or insulin therapy, and that enhanced fibrinolysis may be mediated partly through a decrease in the plasma PAI-1 after metabolic control.
Exp Clin Endocrinol Diabetes 2004 Apr
PMID:Enhancement of fibrinolysis in poorly controlled, hospitalized type 2 diabetic patients by short-term metabolic control: association with a decrease in plasminogen activator inhibitor 1. 1512 20

The importance of obtaining insight in the structure/function relationship in the serpin plasminogen activator inhibitor type-1 can be understood from the major role PAI-1 plays in different (patho)physiological processes, mainly because of its involvement in the plasminogen/plasmin system. Moreover, during the past years, studies indicated a contribution of PAI-1 to the development of cardiovascular disease in common syndromes such as atherosclerosis, diabetes and hypertension. Furthermore, PAI-1 also inhibits u-PA, attributing a role in phenomena such as cell migration and tissue remodelling. Considering the role of PAI-1 in such various pathogenic path-ways, detailed insight into the structure/function relationship in PAI-1 might provide a means of interfering with a given pathological situation without disturbing other physiological processes. Therefore, since the discovery of PAI-1 and the cloning of its cDNA 20 years ago, over 600 PAI-1 variants have been constructed, elucidating the most important structural features of PAI-1. This review gives an overview of the contribution of the different PAI-1 variants to the understanding of the structure/function relationship in PAI-1, based on the different functional features of PAI-1.
 ...
PMID:The story of the serpin plasminogen activator inhibitor 1: is there any need for another mutant? 1554 16


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