Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor that comprises the primary molecular target for thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst expressed in many tissues in humans, its abundant expression in adipose tissue is believed to be the focal point through which TZDs regulate genes involved in glucose and lipid metabolism and via which these agents ultimately improve the hyperglycemia of type 2 diabetes. However, TZDs exhibit many additional properties, not least an array of effects which suggest a broad attack on the inflammatory process. Thus, TZDs have been shown to reduce plasma levels of the chemokine, monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), the endothelial cell adhesion molecules, e-selectin and inter-cellular adhesion molecule-1 (ICAM-1), the leucocyte-activating molecule, CD40L, and the tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further tangible evidence of a reduction by TZDs of systemic inflammation in patients with the classical metabolic syndrome stems from falls in the white blood cell count, P-selectin-positive platelets and in the acute-phase inflammatory proteins, C-reactive protein, serum amyloid A and fibrinogen. At the tissue level, TZDs improve vascular endothelial function, and reduce the rate of progression of intimal-medial thickening of the carotid artery and the microalbuminuria of type 2 diabetes. Further, TZDs have been shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis (NASH). In the case of the latter, a broad spectrum of TZD-related properties is visible. Here, these drugs improve insulin sensitivity for glucose metabolism, reduce hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and lower the circulating levels of liver transaminases (ALT, AST), alkaline phosphatase and gamma glutamyl transferase. These effects in humans are also well-supported by investigative animal and in vitro studies. The ameliorative effects on liver fibrosis are of particular interest since they suggest that TZDs are able to activate a program of corrective tissue-remodeling. The basis for this action may be partly an ability to inhibit matrix protein secretion by hepatic stellate cells. An analogous action has also been seen in kidney mesangial cells. In conclusion, TZDs are important new drugs, presently indicated for the treatment of type 2 diabetes but with a spectrum of properties which suggests their potential for treating a number of degenerative inflammatory diseases, including NASH. However, full-scale, long-term clinical trials are needed with TZDs to test their potential to treat NASH, not least because of the (hepatotoxic) legacy of the prototype TZD, troglitazone, but also in view of the escalating burden of liver disease which is accompanying the increasing global prevalence of clinical obesity and type 2 diabetes.
 ...
PMID:Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection. 1619 19

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.
 ...
PMID:Inhibition of thromboxane biosynthesis by triflusal in type 2 diabetes mellitus. 1628 96

Recent evidence suggests important roles for platelet activation in the progression of atherosclerosis. We have recently shown that P-selectin expression or the presence of platelet-monocyte aggregates, a well-characterized marker of platelet activation, is associated with carotid atherosclerosis in the general population. It is not clear, however, whether platelet activation is also associated with carotid atherosclerosis in patients with type 2 diabetes. In the present study, we measured circulating levels of platelet-monocyte aggregates in 120 patients with type 2 diabetes and 120 age- and gender-matched non-diabetic subjects, and examined their association with carotid atherosclerosis determined by arterial ultrasound. The percentage of platelet-monocyte aggregates was analyzed by CD41-positivity determined by whole-blood flow cytometry. Diabetic subjects (7.73 +/- 4.04%, mean +/- SD) showed significantly higher percentages of platelet-monocyte aggregates than non-diabetic subjects (6.03 +/- 4.38%). The percentage of these aggregates was significantly and positively correlated with HbA(1c) in both diabetic and non-diabetic subjects, with the association independent of other clinical factors. Logistic multiple regression analyses revealed that platelet-monocyte aggregates were significantly associated with the presence of carotid plaques independent of the status of glycemic control in diabetic subjects. Thus, an increase in platelet-monocyte aggregation in type 2 diabetic patients appears to be involved in the pathophysiology of carotid atherosclerosis.
 ...
PMID:Platelet-monocyte aggregates are independently associated with occurrence of carotid plaques in type 2 diabetic patients. 1639 20

The aim of the study was to determine whether the levels of soluble P-selectin (sP-selectin) and soluble CD40L (sCD40L) are elevated in Asian Indian subjects with impaired glucose tolerance (IGT), diabetes, and metabolic syndrome (MS). Study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), an ongoing population-based study on a representative population of Chennai city in southern India, and were grouped as follows: group 1, normal glucose tolerance (NGT) (n = 60); group 2, IGT (n = 60); and group 3, type 2 diabetes mellitus (n = 60). Normal glucose tolerance, IGT, and diabetes were defined using World Health Organization consulting group criteria. The inclusion criteria were nonsmokers; normal resting 12-lead electrocardiogram; absence of angina, myocardial infarction, or history of any known vascular, infectious, or inflammatory diseases; and subjects not on statins or aspirin. Insulin resistance was calculated using the homeostasis assessment model using the formula: fasting insulin (microIU/mL) x fasting glucose (mmol/L)/22.5. Soluble P-selectin and sCD40L were estimated by enzyme-linked immunosorbent assay. Metabolic syndrome was defined using Adult Treatment Panel III guidelines. Subjects with diabetes and IGT were older (diabetes: 53 +/- 9 years, P < .01; IGT: 51 +/- 10 years, P < .05) compared with the NGT group (48 +/- 10 years). Subjects with diabetes and IGT had higher levels of sP-selectin (diabetes: 162 +/- 79 ng/mL, P < .001; IGT: 102 +/- 37 ng/mL, P < .001) compared with the NGT group (55 +/- 48 ng/mL). Soluble CD40L levels were also higher in those with diabetes and IGT (diabetes: 3.2 +/- 2.0 ng/mL, P < .001; IGT: 2.0 +/- 1.3 ng/mL, P < .001) compared with the NGT group (1.1 +/- 0.9 ng/mL). Subjects with MS had significantly higher levels of sP-selectin (with MS, 118 +/- 76 ng/mL; without MS, 95 +/- 66 ng/mL; P = .028) and sCD40L (with MS, 2.4 +/- 1.8 ng/mL; without MS, 1.9 +/- 1.5 ng/mL; P = .036) compared with subjects without MS. Among subjects with NGT and IGT, the mean levels of sP-selectin (tertile I, 65.0 ng/mL; tertile II, 80.0 ng/mL; tertile III, 91.0 ng/mL) and sCD40L levels (tertile I, 1.2 ng/mL; tertile II, 1.7 ng/mL; tertile III, 1.8 ng/mL) increased with increase in tertiles of homeostasis assessment model-insulin resistance, and the difference reached statistical significance in the last tertile compared with the first tertile (P < .05). This study demonstrates that increased levels of sP-selectin and sCD40L are seen in Asian Indian subjects with IGT, type 2 diabetes mellitus, MS, and insulin resistance.
 ...
PMID:Soluble P-selectin and CD40L levels in subjects with prediabetes, diabetes mellitus, and metabolic syndrome--the Chennai Urban Rural Epidemiology Study. 1642 32

The aim of this study was to investigate the impact of improved metabolic control on platelet reactivity in patients with type 2 diabetes undergoing percutaneous coronary intervention (PCI). Twenty-two patients were randomised to intensive insulin or conventional treatment for diabetes. Platelet P-selectin expression was analysed before and three months after PCI. Metabolic control, as measured by level of glycosylated haemoglobin (HbA1c) and platelet P-selectin expression, was similar in the two treatment groups after three months. However, six of the 12 patients in the intensive group had increased levels of HbA1c after three months and three patients of the 10 in the conventionally treated group showed improved metabolic control. A re-analysis was performed, based on metabolic control. It showed that patients with improved control at three months (HbA1c 6.1% +/- 0.7 at baseline; 5.7% +/- 0.5 at three months; p<0.01; n=9) had lower ADP-induced P-selectin expression (p<0.05) than patients with worsened glycaemic control (HbA1c 5.9% +/- 1.0 at baseline; 6.5% +/- 1.4 at three months; p<0.01; n=13). Levels of HbA1c and fasting glucose were correlated to P-selectin expression (R=0.34 and R=0.31; p<0.05). We conclude from this study that improved glycaemic control reduces platelet reactivity in type 2 diabetes patients following PCI.
 ...
PMID:Effects of improved metabolic control on platelet reactivity in patients with type 2 diabetes mellitus following coronary angioplasty. 1678 82

A direct consequence of increased platelet sensitivity in diabetes mellitus might be augmented release of platelet granule contents, which, in turn, may lead to the formation of a platelet volume gradient, increased platelet turnover and reduced survival of platelets from diabetic individuals. In this study we addressed the question whether diabetes-induced and lipid fluidity-mediated changes in platelet receptor exposure and accessibility might be part of a general mechanism underlying the increased rate of platelet ageing and reduced platelet survival in diabetes. Diabetic individuals showed higher numbers of platelets of extreme dimensions: very small platelets and larger platelets were more frequent compared to controls ( P(chi(2))< 0.03). The shifts in platelet volume distributions were paralleled by decreased expression of the alpha subunit of glycoprotein Ib (by up to 17%, P < 0.01) in platelet membranes from diabetic patients, increased expression of P-selectin in thrombin-stimulated diabetic platelets (P< 0.02), an increased number of platelet microparticles in diabetic individuals (P< 0.05 or P< 0.03 for resting or stimulated platelets, respectively), and reduced platelet membrane fluidity (by 5.2 +/- 0.6%, P< 0.01). We suggest that the distinct bimodality of platelet distribution in diabetic patients might arise from accelerated thrombopoiesis in diabetic subjects, and this is supported by the demonstration of elevated fractions of reticulated (rich with residual RNA) platelets in diabetic patients (14.6 +/- 5.6% vs 8.1 + 2.1% p(u) < 0.025). Overall, our results point to a fluidity-mediated platelet hypersensitivity and accelerated rate of platelet production in subjects with type 2 diabetes mellitus, which results in a greater number of very large and hypersensitive younger platelets and a more abundant fraction of small exhausted platelets.
 ...
PMID:Possible mechanisms of the altered platelet volume distribution in type 2 diabetes: does increased platelet activation contribute to platelet size heterogeneity? 1680 Oct 71

Nifedipine, a dihydropyridine calcium antagonist, improves endothelial function in patients with hypercholesterolaemia by enhancing nitric oxide (NO) activity, and increases endothelial NO bioavailability by antioxidant mechanisms. We administered a long-acting nifedipine formulation (controlled release (CR) nifedipine: 20 mg/day) to hypertensive patients for 6 months. There were no other changes of drug treatment during therapy with CR nifedipine. Clinical and biochemical data obtained before and after CR nifedipine administration were compared. All markers were measured by enzyme-linked immunosorbant assay. The levels of soluble markers (soluble CD40 ligand, soluble P-selectin, and soluble E-selectin), microparticles (MP) (platelet-derived MP, monocyte-derived MP, and endothelial cell-derived MP), and adiponectin differed between the control group and the hypertension group. The levels of these markers were also different in hypertensive patients with and without type 2 diabetes compared with the control group. In the hypertensive patients with type 2 diabetes, all markers except adiponectin decreased significantly after 3 months of CR nifedipine treatment. In contrast, markers were unchanged in the hypertensive patients without type 2 diabetes. Adiponectin was increased after 6 months of CR nifedipine treatment in hypertensive patients with type 2 diabetes. The effects of CR nifedipine on platelet/monocyte activation and adiponectin levels demonstrated in the present study indicate the potential effectiveness of calcium antagonist therapy for hypertensive patients with type 2 diabetes.
 ...
PMID:Effect of nifedipine on adiponectin in hypertensive patients with type 2 diabetes mellitus. 1706 83

This study compared lipids, the product of lipid peroxidation malondialdehyde (MDA), the acute phase reactant high-sensitive C-reactive protein (hsCRP), endothelin-1 (ET-1), P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) between healthy controls, subjects with ischemic heart disease (IHD) and type 2 diabetes mellitus (DM) subjects who did not perform coronary artery bypass graft (CABG) surgery as well as type 2 DM subjects who performed CABG. HbA1c, lipids, MDA, hsCRP, ET-1, P-selectin, ICAM-1, and VCAM-1 levels were significantly higher in the diabetic groups than in either healthy controls or IHD subjects. In the diabetic groups, there was a negative association among hsCRP and HDL-C. ET-1, ICAM-1 levels, and TAG were positively correlated, as do the association between P-selectin, VCAM-1, and HbA1c%. Also a positive relation was found among hsCRP levels and ICAM-1, as well as MDA and ET-1. P-selectin and ICAM-1 were significantly positively correlated. This study indicates that increased level of oxidative stress marker, proinflammatory markers, and their downstream effectors adhesion molecules occur in type 2 DM.
 ...
PMID:Evaluation of C-reactive protein, endothelin-1, adhesion molecule(s), and lipids as inflammatory markers in type 2 diabetes mellitus patients. 1749 38

The primary target receptor for thiazolidinediones (TZDs) or peroxisome proliferator-activated receptor gamma (PPARgamma) agonists is a transcription factor in the nucleus of adipocytes and other metabolically active cells, where they improve insulin sensitivity and glucose utilization. TZDs are also able to modify gene expression in macrophages, smooth muscle cells, and endothelial cells. Although PPARgamma is considered to be a nuclear receptor, enucleate platelets also highly express this receptor. The aim of this review is to present the current understanding of a direct or indirect effect of TZDs on platelet function. By means of a comprehensive literature search (January 1990-June 2006), publications were obtained that contained specific information about in vitro and in vivo effects of TZDs on platelet function. The effects were studied for different risk biochemical markers, i.e., proteins found to be elevated in the state of procoagulant inflammation and endothelial dysfunction. Improvement of platelet function was reported for all TZDs-troglitazone, pioglitazone, and rosiglitazone. The described effects included reduction of platelet aggregation, suppression of thrombin-induced protein kinase C-alpha and -beta activation, decrease in plasma P-selectin and platelet P-selectin expression, increase in nitric oxide production, inhibition of the Rho/Rho kinase pathway, and inhibition of tissue factor- and platelet-activating factor-induced morphological changes in macrophages. These findings appeared in parallel with reduction of the plasma concentrations of pro-inflammatory risk markers. TZDs seem to have a direct pleiotropic positive influence on platelet function and coagulation and may be helpful in treating the prothrombotic state observed in patients with type 2 diabetes and metabolic syndrome.
 ...
PMID:Review of the pleiotropic effects of peroxisome proliferator-activated receptor gamma agonists on platelet function. 1793 Oct 49

The effects of treatment with pitavastatin on inflammatory and platelet activation markers and adiponectin in 117 patients with hyperlipidemia were investigated to determine whether pitavastatin may prevent the progression of atherosclerotic changes in hyperlipidemic patients. Adiponectin levels prior to pitavastatin treatment in hyperlipidemic patients with and without diabetes were lower than levels in normolipidemic controls. Both total cholesterol and the low-density lipoprotein cholesterol decreased significantly after pitavastatin administration. Additionally, hyperlipidemic patients with or without type 2 diabetes exhibited a significant increase in adiponectin levels 6 months after pitavastatin treatment (diabetes: 3.52 +/- 0.80 vs. 4.52 +/- 0.71 microg/ml, p < 0.001; no diabetes: 3.48 +/- 0.71 vs. 4.23 +/- 0.82 microg/ml, p < 0.05). However, high-sensitivity C-reactive protein, platelet-derived microparticle and soluble P-selectin did not exhibit any differences before or after pitavastatin administration. Levels of adiponectin significantly increased after pitavastatin administration in the group of lower soluble P-selectin (soluble P-selectin before pitavastatin treatment <200 ng/ml). These results suggest that pitavastatin possesses an adiponectin-increasing effect in patients with hyperlipidemia and this effect is influenced by intensive platelet activation.
 ...
PMID:Effects of pitavastatin on adiponectin in patients with hyperlipidemia. 1833 8


<< Previous 1 2 3 4 5 Next >>