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)

Diabetic retinal microangiopathy is characterized by increased permeability, leukostasis, microthrombosis, and apoptosis of capillary cells, all of which could be caused or compounded by activation of complement. In this study, we observed deposition of C5b-9, the terminal product of complement activation, in the wall of retinal vessels of human eye donors with 9 +/- 3 years of type 2 diabetes, but not in the vessels of age-matched nondiabetic donors. C5b-9 often colocalized with von Willebrand factor in luminal endothelium. C1q and C4, the complement components unique to the classical pathway, were not detected in the diabetic retinas, suggesting that C5b-9 was generated via the alternative pathway, the spontaneous activation of which is regulated by complement inhibitors. The diabetic donors showed a prominent reduction in the retinal levels of CD55 and CD59, the two complement inhibitors linked to the plasma membrane by glycosylphosphatidylinositol anchors, but not in the levels of transmembrane CD46. Similar complement activation in retinal vessels and selective reduction in the levels of retinal CD55 and CD59 were observed in rats with a 10-week duration of streptozotocin-induced diabetes. Thus, diabetes causes defective regulation of complement inhibitors and complement activation that precede most other manifestations of diabetic retinal microangiopathy. These are novel clues for probing how diabetes affects and damages vascular cells.
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PMID:Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. 1245 6

Activation of the peroxisome proliferator-activator receptor gamma (PPARgamma) improves insulin resistance and glycemic control in patients with diabetes. As PPARgamma is expressed in the endothelial cell, we have investigated the effect of troglitazone, a PPARgamma activator, on the endothelial function in people with type 2 diabetes in a 12-week, prospective, randomized, double-blinded clinical trial. We studied 87 type 2 diabetic patients who were divided into 3 groups. Group A consisted of 27 patients with recently diagnosed diabetes and no clinical manifestations of macrovascular disease; group B, 29 patients with long-term diabetes and no clinically evident macrovascular disease; and group C, 31 diabetic patients with documented macrovascular disease (cardiovascular, cerebrovascular, or peripheral vascular disease). High-resolution ultrasound images were used to measure the flow-mediated dilation (FMD, endothelium-dependent) and nitroglycerin-induced dilation (NID, endothelium-independent) in the brachial artery. Laser Doppler perfusion imaging was used to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine (Ach, endothelium-dependent) and 1% sodium nitroprusside (NaNP, endothelium-independent). The plasma concentrations of von Willebrand factor (vWF), soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM) were also measured as indicators of endothelial cell activation. The FMD improved in the troglitazone-treated patients in group A (7.72 +/- 3.4 v 5.27 +/- 2.0, P <.05 [exit visit v baseline, percent of increase in brachial artery diameter, mean +/- SD]). The fasting insulin level also improved in this group (15.6 +/- 10 v 19.7 +/- 10, P <.05) and was strongly correlated to changes in FMD (r = -.73, P <.01). No changes were found in the FMD or the fasting insulin levels in the troglitazone-treated patients in groups B or C. The NID was not changed by troglitazone treatment in any of the 3 groups. Also, no differences were found in the microcirculation reactivity measurements or in the biochemical markers of endothelial dysfunction in all 3 groups. A small, but significant, improvement of the FMD was found in placebo-treated patients in group B, probably related to the low FMD levels at baseline in the patients (5.40 +/- 3.0 v 4.36 +/- 2.4, P <.05). We concluded that troglitazone treatment for 12 weeks improved endothelial function in the macrocirculation of patients with recently diagnosed type 2 diabetes and no clinical evidence of macrovascular disease. This improvement was strongly associated with the improvement of fasting plasma insulin concentrations.
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PMID:The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo-controlled randomized clinical trial. 1260 28

Type 2 diabetes mellitus is frequently accompanied by hypercoagulability and hypofibrinolysis. Both are related to increased cardiovascular risk, but possibly with endothelial injury as well. Studies with nondiabetic persons indicate that unopposed oestrogen replacement therapy (oERT) decreases cardiovascular risk, possibly mediated in part by effects on coagulation and fibrinolysis. In a double-blind, randomised placebo-controlled trial, we assessed the effect of oral 17 beta-oestradiol daily during 6 weeks on indicators of coagulation and of fibrinolysis in postmenopausal women with type 2 diabetes mellitus. We observed significant increases of Factor VII (FVII) and von Willebrand factor (vWF) after oERT and no change in the already high fibrinogen. Prothrombin fragment 1 + 2 (F1 + 2) increased after oERT, whereas thrombin-antithrombin (TAT) complexes was unchanged, but increments of F1 + 2 and TAT correlated. Soluble fibrin (SF) levels remained stable. In fibrinolysis, a clear reduction in plasminogen activator inhibitor 1 (PAI-1) was observed, but no significant change in tissue-type plasminogen activator antigen (t-PA-Ag) or activity was found, although fibrinolytic activity assessed as t-PA activity (t-PA-Act) tended to increase after oERT. Indicators of fibrinolytic activity (plasmin-antiplasmin complexes and fibrin degradation products) however did not change. oERT increased C-reactive protein (CRP) but none of the coagulation or fibrinolysis changes significantly associated with the CRP changes. It is concluded that oERT increases the coagulation potency as well as the fibrinolytic potency raising the question of the net effect in their balance. Increase in F1 + 2 suggests that in diabetic women oERT effectively increases the chronic, continuous activation of coagulation, which appears to be compensated for or not effective in the blood compartment as judged from the unchanged levels of SF. Suspected increased fibrin formation in the vascular wall is at least not followed by increases in fibrinogen degradation products (TDP), which suggests the possibility of accumulation and increased cardiovascular risk. The results indicate that specific attention should be paid to fibrin turnover in studying other categories of women and the effects of the addition of progesterone.
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PMID:The effect of 17 beta-oestradiol on variables of coagulation and fibrinolysis in postmenopausal women with type 2 diabetes mellitus. 1261 82

Diabetes mellitus leads to endothelium dysfunction and an accelerated progression of atherosclerosis. Vascular complications of diabetes mellitus can affect not only large and medium arteries resulting in coronary heart disease and peripheral arteries diseases, but also small vessels leading to retinopathy and nephropathy. Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), E-selectin and von Willebrand factor (vWF) are considered as markers of endothelium dysfunction. The aim of our study was to evaluate plasma levels of ICAM-1, VCAM-1, E-selectin and vWF in patients with type 2 diabetes mellitus receiving insulin therapy and who had diabetic non-proliferative retinopathy, proliferative retinopathy, or did not develop diabetic retinopathy. There were no statistically significant differences between studied groups in any of evaluated endothelium dysfunction markers. There was no statistically significant correlation between measured parameters and a period of diabetic history. None of the studied markers presented a significant correlation with a period of insulin treatment.
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PMID:Endothelium dysfunction markers in patients with diabetic retinopathy. 1570 38

Triflusal is an antiplatelet drug related to aspirin, with different pharmacological properties and a lower haemorrhagic risk. We aimed at comparing their effects on platelet and endothelial activation in type 2 diabetes mellitus (T2DM). In a randomized, double-blind, parallel group study, we compared the effects of three daily regimens (300, 600, and 900 mg) of triflusal, and aspirin (100mg/day) on urinary 11-dehydro-thromboxane (TX)B(2), index of in vivo platelet activation, ex vivo platelet function using the analyzer PFA-100, plasma von Willebrand factor (vWF), P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and serum nitrite and nitrate (NO(2)(-)+NO(3)(-)) in 60 T2DM patients. Triflusal induced a dose-dependent reduction in 11-dehydro-TXB(2) and a prolongation of closure time in the presence of collagen plus epinephrine (Coll/Epi-CT). The effects of the highest triflusal dose were not different from those of aspirin. The closure time in the presence of collagen plus ADP (Coll/ADP-CT), ICAM-1, VCAM-1, and NO(2)(-)+NO(3)(-) were not modified either by triflusal or aspirin. Plasma P-selectin and vWF were reduced by triflusal but not by aspirin. In T2DM triflusal causes a profound inhibition of platelet TXA(2) biosynthesis in vivo, acting on different targets involved in the platelet-endothelial cell interactions.
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PMID:Inhibition of thromboxane biosynthesis by triflusal in type 2 diabetes mellitus. 1628 96

A Thr789Ala variant in the von Willebrand Factor (vWF) gene is associated with increased vWF plasma concentrations and might therefore affect the risk of coronary heart disease (CHD) in the general population. Patients with type 2 diabetes have an increased risk for premature atherosclerosis and are characterized by alterations of the coagulation system. However, it is not known whether the Thr789Ala variant in the vWF gene contributes to the increased CHD risk in patients with type 2 diabetes. We therefore investigated the potential relationship between the Thr789Ala variant in the vWF gene and the occurrence of CHD in 356 patients with type 2 diabetes, either with (DM+/CHD+, n = 204) or without evidence for CHD (DM+/CHD-, n = 152). In addition, two control groups without type 2 diabetes, with (DM-/CHD+, n = 22) or without CHD (DM-/CHD-, n = 100), were investigated. Individuals with the vWF Thr789Ala variant have significantly higher von Willebrand factor plasma concentrations (p < 0.001). In addition, ristocetin co-factor was significantly increased in vWF Thr789Ala variant carriers (p < 0.05). Ristocetin co-factor levels and collagen binding capacity were also increased in individuals affected with either type 2 diabetes, CHD or both (DM+/CHD+, DM+/CHD-, DM-/CHD+) as compared to healthy controls (DM-/CHD-) (p < 0.001). However, we did not find an association between the vWF Thr789Ala variant and the occurrence of CHD in patient with type 2 diabetes (p = 0.34). In conclusion, although the Thr789Ala vWF gene variant is associated with increased plasma concentrations of vWF, ristocetin co factor levels and collagen binding capacity in patients with type 2 diabetes and CHD, a direct effect of this variant on the occurrence of CHD in patients with type 2 diabetes, could not be detected.
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PMID:Impact of the Thr789Ala variant of the von Willebrand factor levels, on ristocetin co-factor and collagen binding capacity and its association with coronary heart disease in patients with diabetes mellitus type 2. 1632 Jan 53

Endothelial dysfunction may precede development of type 2 diabetes. We tested the hypothesis that elevated levels of hemostatic markers of endothelial dysfunction, plasminogen activator inhibitor-1 (PAI-1) antigen, and von Willebrand factor (vWF) antigen predicted incident diabetes independent of other diabetes risk factors. We followed 2,924 Framingham Offspring subjects (54% women, mean age 54 years) without diabetes at baseline (defined by treatment, fasting plasma glucose > or =7 or 2-h postchallenge glucose > or =11.1 mmol/l) over 7 years for new cases of diabetes (treatment or fasting plasma glucose > or =7.0 mmol/l). We used a series of regression models to estimate relative risks for diabetes per interquartile range (IQR) increase in PAI-1 (IQR 16.8 ng/ml) and vWF (IQR 66.8% of control) conditioned on baseline characteristics. Over follow-up, there were 153 new cases of diabetes. Age- and sex-adjusted relative risks of diabetes were 1.55 per IQR for PAI-1 (95% CI 1.41-1.70) and 1.49 for vWF (1.21-1.85). These effects remained after further adjustment for diabetes risk factors (including physical activity; HDL cholesterol, triglyceride, and blood pressure levels; smoking; parental history of diabetes; use of alcohol, nonsteroidal anti-inflammatory drugs, exogenous estrogen, or hypertension therapy; and impaired glucose tolerance), waist circumference, homeostasis model assessment of insulin resistance, and inflammation (assessed by levels of C-reactive protein): the adjusted relative risks were 1.18 per IQR for PAI-1 (1.01-1.37) and 1.39 for vWF (1.09-1.77). We conclude that in this community-based sample, plasma markers of endothelial dysfunction increased risk of incident diabetes independent of other diabetes risk factors including obesity, insulin resistance, and inflammation.
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PMID:Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study. 1644 91

Vascular dysfunction, low-grade inflammation, insulin resistance, and impaired fibrinolysis have each been reported to be present in type 2 diabetes, but their relationships, and the role of obesity, have not been investigated. We measured insulin sensitivity (euglycemic clamp), forearm blood flow responses to graded local acetylcholine (Ach) and sodium nitroprusside (SNP) infusions, plasma concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, von Willebrand factor (vWF), plasminogen activator inhibitor (PAI)-1, tissue plasminogen activator (tPA), and high-sensitivity C-reactive protein (hs-CRP) in 81 diabetic patients. When patients were stratified by insulin resistance, more severe insulin resistance was associated (P < 0.05) with overweight, central fat distribution, hypertension, and dyslipidemia (with similar sex distribution, age, fasting plasma glucose, and HbA1c). With regard to vascular function, both endothelium-dependent (Ach) (-22, -40, and -52%; P < 0.0001) and -independent (SNP) (-3, -7, and -27%; P < 0.02) vasodilatation were progressively reduced across insulin resistance tertiles. In multivariate analysis, inflammatory markers (IL-6, hs-CRP, and TNF-alpha) were independently associated with insulin resistance and fasting glycemia, fibrinolytic markers PAI-1 and tPA with insulin resistance and central fat distribution, and vascular indexes (vWF, Ach, and SNP vasodilation) with insulin resistance and obesity or cytokines (TNF-alpha or IL-6). In type 2 diabetes, insulin resistance is associated with vascular dysfunction/damage, impaired fibrinolysis, and low-grade inflammation independently of obesity and poor glycemic control.
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PMID:Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. 1656 39

The molecular pathways leading to islet fibrosis in diabetes are unknown. Therefore, we studied gene expression in islets of 4-month-old Goto-Kakizaki (GK) and Wistar control rats. Of 71 genes found to be overexpressed in GK islets, 24% belong to extracellular matrix (ECM)/cell adhesion and 34% to inflammatory/immune response families. Based on gene data, we selected several antibodies to study fibrosis development during progression of hyperglycemia by immunohistochemistry. One-month-old GK and Wistar islets appeared to be similar. Two-month-old GK islets were strongly heterogenous in terms of ECM accumulation compared with Wistar islets. GK islet vascularization, labeled by von Willebrand factor, was altered after 1 month of mild hyperglycemia. Numerous macrophages (major histocompatibility complex class II(+) and CD68(+)) and granulocytes were found in/around GK islets. These data demonstrate that marked inflammatory reaction accompanies GK islet fibrosis and suggest that islet alterations in this nonobese model of type 2 diabetes develop in a way reminiscent of microangiopathy.
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PMID:Islet inflammation and fibrosis in a spontaneous model of type 2 diabetes, the GK rat. 1673 24

Patients with type 2 diabetes and abdominal fat patterning displayed higher plasma activities of clotting factors VII and VIII as well as increased plasma levels of fibrinogen and von Willebrand factor antigen, when compared with not only healthy normal weight controls, but also with diabetic patients at normal body weight. Mechanisms associating abdominal obesity with the above mentioned prothrombotic changes are only partially elucidated and may differ according to the individual haemostatic variable. Actually, according to data in the literature and authors' observations increased plasma factor VII activity is mainly associated with increased plasma triglyceride level, while the hepatic synthesis of fibrinogen as well as the synthesis and release of endothelia-derived von Willebrand factor are stimulated by cytokines originating in the visceral adipose tissue. The relationship between the presently investigated hemostatic variables and features of the metabolic syndrome are less obvious than in the previously recorded association of metabolic risk factors with plasma levels of plasminogen activator inhibitor.
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PMID:Effect of abdominal obesity on prothrombotic tendency in type 2 diabetes. Behavior of clotting factors VII and VIII, fibrinogen and von Willebrand Factor. 1673 71


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