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)

Nuclear receptors function as ligand-inducible transcription factors that regulate various physiological functions such as development, reproduction, and metabolism. Dysregulation of the metabolism of cholesterol, triglyceride, and glucose leads to the metabolic syndrome including type 2 diabetes mellitus, obesity, dyslipidemia, and atherosclerosis. Studies of nuclear receptors promise to provide discoveries of therapeutic agents against the metabolic syndrome. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and is activated by bile acids. FXR regulates the metabolism of not only bile acid but also cholesterol, lipoprotein, triglyceride, and glucose, and is considered a potential therapeutic target for the metabolic syndrome because of these functions. Nuclear receptors have two regions for transactivation, a constitutive activation function (AF-1) and a ligand-dependent activation function (AF-2). AF-1 and AF-2 seem to require interactions with coactivators for the activation function and both work synergistically to give full transactivation of nuclear receptors. However, coactivators for AF-1 activity are poorly understood, whereas coactivators required for AF-2 activity have been well studied. To understand the molecular mechanism of AF-1 in FXR, we isolated proteins associated with AF-1 by GST pull-down assay using the N-terminal region of FXR and nuclear extracts from HeLa cells. This review focuses on the roles of FXR and our new findings regarding FXR-associated factors.
 ...
PMID:[Functional analysis of nuclear receptor FXR controlling metabolism of cholesterol]. 1831 Oct 53

Thiazolidinediones (TZDs) are relatively new agents for the treatment of type 2 diabetes. They act as agonists at the PPAR-gamma nuclear receptor and their therapeutic effects include decreased insulin resistance and hyperglycaemia, an improved plasma lipid, inflammation and pro-coagulant profile, and amelioration of hypertension, microalbuminuria and hepatic steatosis. The most common side effects of TZDs include weight gain and oedema, with occasional reports of congestive heart failure (CHF). This review discusses the benefit-risk profile of TZDs in treating patients with type 2 diabetes, with particular reference to the heart. To provide context, we explore briefly the epidemiology and pathophysiology of heart failure in patients with type 2 diabetes, touch on the association of heart disease and cardiovascular mortality with antihyperglycaemic treatment modalities other than TZDs, and then focus on the effects of TZDs on the heart, cardiovascular risk factors and outcomes. We describe the cluster of host factors, which seems to predispose patients with type 2 diabetes to TZD-induced or TZD-exacerbated oedema and CHF and then provide an overview of the putative mechanisms of these TZD-related side effects. We also propose that certain diuretics (amiloride and spironolactone), by targeting the distal nephron that expresses PPARgamma in collecting duct cells, might be of benefit in ameliorating the fluid retention and oedema associated with TZDs.
 ...
PMID:Thiazolidinedione insulin sensitizers and the heart: a tale of two organs? 1833 90

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily comprising four subtypes designated PPARalpha, PPARgamma1, PPARgamma2, and PPARdelta. These are transcription factors that regulate gene expression, thereby controlling energy metabolism. PPARgamma has widespread distribution in the adipose tissue, skeletal muscle, heart, liver, kidney, gut, macrophages, and vascular tissues. PPARgamma has a key role in adipogenesis, insulin sensitivity, and glucose and lipid metabolism, and also plays a major role in vascular biology, modulating atherosclerosis progression and vascular endothelial function. Thiazolidinediones (TZDs) are the ligands of PPARgamma, and growing evidence suggests that they might both directly and indirectly influence cardiovascular risk in type 2 diabetes patients by favorably altering several pro-atherogenic metabolic processes.
 ...
PMID:PPARgamma agonists and vascular risk factors: potential effects on cardiovascular disease. 1837 Jun 23

In last few years, the topic of nuclear receptor has been developed in the field of hepatology allowing envisaging therapeutic strategies for the most frequent chronic liver diseases. Peroxysome proliferator-activated receptors (PPAR) contribute to wide physiological processes within the liver such as lipid/glucid metabolisms, inflammatory response, cell differenciation and cell cycle. In vitro experiments and animal studies showed that PPARalpha discloses anti-inflammatory property and PPARgamma discloses anti-inflammatory, antifibrogenic and antiproliferative properties in the liver. Main available agonists are fibrates (PPARalpha) used for 20 years in cases of lipid metabolism abnormalities and glitazones (PPARgamma) used since 2000 for type 2 diabetes. In terms of therapy, animal studies and human trials have been conducted in steatopathies. However, clinicians have to be aware of potential specific side effects related to glitazones especially on cardiovascular system.
 ...
PMID:[Nuclear receptor PPAR and hepatology: pathophysiological and therapeutical aspects]. 1839 82

Macro- and microvascular disorders currently represent the principal causes of morbidity and mortality in patients with diseases involving the cardiovascular system, such as atherosclerosis, hypertension, stroke, and diabetes. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in a number of vessels in a variety of animal models and in humans with such diseases. Endothelial dysfunction plays a key role in the development of these diseases, yet the genesis of this endothelial dysfunction and its associated vasomotor abnormalities remain poorly understood. Peroxisome proliferator-activated receptor (PPAR)gamma is a nuclear receptor and transcription factor in the steroid superfamily, and PPARgamma agonists (the thiazolidinediones) are used clinically to treat type 2 diabetes. Recent studies have revealed that as well as being involved in adipogenesis and in increased sensitivity to insulin, PPARgamma plays critical roles in the vasculature. In the present review, we discuss the beneficial effects of PPARgamma agonists on vasomotor activities, focusing in particular on endothelium-dependent relaxation in vessels affected by cardiovascular diseases.
 ...
PMID:Relationships among ET-1, PPARgamma, oxidative stress and endothelial dysfunction in diabetic animals. 1855 52

Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor that coordinates carbohydrate and lipid metabolism, and is a therapeutic target for type 2 diabetes. Tanshinone IIA (Tan) is a lipophilic diterpene that is widely used to treat cardiovascular diseases in traditional Chinese medicine, and has recently been found to reduce body weight and lower blood lipids. However, its underlying mechanism of antiadipogenic effects remains unknown. Here, we report that Tan inhibits 3T3-L1 preadipocyte differentiation and transcriptional activities of full-length PPARgamma and PPARgamma ligand-binding domains. The effects of Tan are mediated through its property as a natural antagonist of PPARgamma (dissociation constant of an inhibitor value, 2.562 +/- 0.711 microm). Tan treatment reduced adipose mass and body weight, improved glucose tolerance, and lowered the low-density lipoprotein to high-density lipoprotein ratio without changing the food intake in a high-fat diet-induced obese animal model. Our results suggest that the combined properties of Tan in adipogenesis, glucose tolerance, lipogenesis, and cardiovascular protection are beneficial for treating diabetic patients with complex metabolic conditions, in which modulating a single target is often not sufficient to achieve the desired effect.
 ...
PMID:The role of tanshinone IIA in the treatment of obesity through peroxisome proliferator-activated receptor gamma antagonism. 1881 99

The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be defined as a cluster of cardiovascular disease risk factors including visceral obesity, insulin resistance, dyslipidemia, increased blood pressure, and hypercoagulability. The farnesoid X receptor (FXR) belongs to the superfamily of ligand-activated nuclear receptor transcription factors. FXR is activated by bile acids, and FXR-deficient (FXR(-/-)) mice display elevated serum levels of triglycerides and high-density lipoprotein cholesterol, demonstrating a critical role of FXR in lipid metabolism. In an opposite manner, activation of FXR by bile acids (BAs) or nonsteroidal synthetic FXR agonists lowers plasma triglycerides by a mechanism that may involve the repression of hepatic SREBP-1c expression and/or the modulation of glucose-induced lipogenic genes. A cross-talk between BA and glucose metabolism was recently identified, implicating both FXR-dependent and FXR-independent pathways. The first indication for a potential role of FXR in diabetes came from the observation that hepatic FXR expression is reduced in animal models of diabetes. While FXR(-/-) mice display both impaired glucose tolerance and decreased insulin sensitivity, activation of FXR improves hyperglycemia and dyslipidemia in vivo in diabetic mice. Finally, a recent report also indicates that BA may regulate energy expenditure in a FXR-independent manner in mice, via activation of the G protein-coupled receptor TGR5. Taken together, these findings suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.
 ...
PMID:Role of bile acids and bile acid receptors in metabolic regulation. 1912 57

Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. There are two LXR isoforms termed alpha and beta which upon activation form heterodimers with retinoid X receptor and bind to LXR response element found in the promoter region of the target genes. Their endogenous agonists include a variety of oxidized cholesterol derivatives referred to as oxysterols. In the recent years LXRs have been characterized as key transcriptional regulators of lipid and carbohydrate metabolism. LXRs were shown to function as sterol sensors protecting the cells from cholesterol overload by stimulating reverse cholesterol transport and activating its conversion to bile acids in the liver. This finding led to identification of LXR agonists as potent antiatherogenic agents in rodent models of atherosclerosis. However, first-generation LXR activators were also shown to stimulate lipogenesis via sterol regulatory element binding protein-1c leading to liver steatosis and hypertriglyceridemia. Despite their lipogenic action, LXR agonists possess antidiabetic properties. LXR activation normalizes glycemia and improves insulin sensitivity in rodent models of type 2 diabetes and insulin resistance. Antidiabetic action of LXR agonists is thought to result predominantly from suppression of hepatic gluconeogenesis. However, recent studies suggest that LXR activation may also enhance peripheral glucose uptake. The purpose of this review is to summarize the present state of knowledge on the physiological and pathophysiological implications of LXRs with the special consideration of their role in lipid and carbohydrate metabolism and associated diseases.
 ...
PMID:Biological role of liver X receptors. 1925 56

Cardiovascular disease is the leading cause of morbidity and mortality world-wide. The burden of disease is also increasing as a result of the global epidemics of diabetes and obesity. Peroxisome proliferator-activated receptor alpha (PPARalpha), a member of this nuclear receptor family, has emerged as an important player in this scenario, with evidence supporting a central co-ordinated role in the regulation of fatty acid oxidation, lipid and lipoprotein metabolism and inflammatory and vascular responses, all of which would be predicted to reduce atherosclerotic risk. Additionally, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has indicated the possibility of preventive effects in diabetes-related microvascular complications, although the mechanisms of these effects warrant further study. The multimodal pharmacological profile of PPARalpha has prompted development of selective PPAR modulators (SPPARMs) to maximise therapeutic potential. It is anticipated that PPARalpha will continue to have important clinical application in addressing the major challenge of cardiometabolic risk associated with type 2 diabetes, obesity and metabolic syndrome.
 ...
PMID:Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. 1938 11

The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARalpha, PPARgamma and PPARdelta, encoded by different genes, and they form a subfamily of the nuclear receptor superfamily. The clinical interest in PPARs originates with fibrates and thiazolidinediones, which, respectively, act on PPARalpha and PPARgamma and are used to ameliorate hyperlipidaemia and hyperglycaemia in subjects with type 2 diabetes mellitus (T2DM). PPARs play a central role in these patients due to their ability to regulate the expression of numerous genes involved in glycaemic control, lipid metabolism, vascular tone and inflammation. Abnormal angiogenesis is implicated in several of the long-term complications of diabetes mellitus, characterized by vasculopathy associated with aberrant growth of new blood vessels. This pathological process plays a crucial role in diabetic retinopathy, nephropathy and neuropathy, impaired wound healing and impaired coronary collateral vessel development. In recent years, there has been increasing appreciation of the fact that PPARs might be involved in the molecular mechanisms that regulate angiogenesis through the action of growth factors and cytokines that stimulate migration, proliferation and survival of endothelial cells. During the last few years direct comparative analyses have been performed, using selective PPARs agonists, to clarify the angiogenic properties of the different members of the PPAR family. Lately, the findings provide new information to order to understand the biological, clinical and therapeutic effects of PPARs, and the role of these nuclear receptors in angiogenesis, with potentially important implications for the management of subjects affected by T2DM.
 ...
PMID:Peroxisome proliferator-activated receptors and angiogenesis. 1962 79


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