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)

Thiazolidinediones (TZDs) increase peripheral tissue insulin sensitivity in patients with type 2 diabetes mellitus by activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). In bone marrow stromal cell cultures and in vivo, activation of PPARgamma by high doses (20 mg/kg/day) of TZDs has been reported to alter stem cell differentiation by promoting commitment of progenitor cells to the adipocytic lineage while inhibiting osteoblastogenesis. Here, we have examined the in vivo effects of low-dose rosiglitazone (3 mg/kg/day) on bone, administered to mice by gavage for 90 days. Rosiglitazone-treated mice had increased weight when compared with controls, with no significant alterations in serum levels of glucose, calcium or parathyroid hormone (PTH). Bone mineral density (BMD) at the lumbar vertebrae (L1-L4), ilium/sacrum, and total body was diminished by rosiglitazone treatment. Histologically, bone was characterized by decreased trabecular bone volume and increased marrow space with no significant change in bone marrow adipocity. Decreased osteoblast number and activity due to increased apoptotic death of osteoblasts and osteocytes was apparent while osteoclast parameters and serum levels of osteocalcin, alkaline phosphatase activity, and leptin were unaltered by rosiglitazone treatment. Therefore, the imbalance in bone remodeling that follows rosiglitazone administration arises from increased apoptotic death of osteogenic cells and diminished bone formation leading to the observed decrease in trabecular bone volume and BMD. These novel in vivo effects of TZDs on bone are of clinical relevance as patients with type 2 diabetes mellitus and other insulin resistant states treated with these agents may potentially be at increased risk of osteoporosis.
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PMID:Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. 1552 88

The peroxisome proliferator-activated receptor gamma (PPARgamma) is important to adipocyte differentiation and glucose homeostasis, and mutations in the gene have been observed in type 2 diabetes mellitus. The mutated residues, V290 and P467, bind to neither ligands nor a coactivator peptide in the reported crystal structures of the PPARgamma ligand binding domain. To understand the mechanism of type 2 diabetes mellitus caused by germline mutations in the PPARgamma ligand-binding domain, theoretical models of the PPARgamma-ligand-coactivator complex were built at an atomic resolution. In the models, the secondary coactivator peptide was docked next to the conventional coactivator peptide, which both contain the LXXLL motif. The secondary interface in PPARgamma for the secondary coactivator peptide has not been demonstrated by experiments. Binding energy calculations of the complex, considering the solvent effect, revealed that the secondary coactivator peptide, derived from nuclear receptor box 1 of steroid receptor coactivator 1, can be favorably bound to the secondary interface. The secondary coactivator peptide forms hydrogen bonds and a hydrophobic core with PPARgamma and the primary coactivator peptide. Next, we applied mutations to PPARgamma in silico and found that the V290M mutation, observed in type 2 diabetes mellitus, adversely affected the binding of the secondary peptide. Thus, our model provides structural insight into the impairment of PPARgamma function in type 2 diabetes mellitus.
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PMID:Rational discovery of a novel interface for a coactivator in the peroxisome proliferator-activated receptor gamma: theoretical implications of impairment in type 2 diabetes mellitus. 1555 56

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a prototypical member of the nuclear receptor superfamily and integrates the control of energy, lipid, and glucose homeostasis. PPARgamma can bind a variety of small lipophilic compounds derived from metabolism and nutrition. These ligands, in turn, determine cofactor recruitment to PPARgamma, regulating the transcription of genes in a variety of metabolic pathways. PPARgamma is the main target of the thiazolidinedione class of insulin-sensitizing drugs, which are currently a mainstay of therapy for type 2 diabetes. However, this therapy has a number of side effects. Here, we review the clinical consequences of PPARgamma polymorphisms in humans, as well as several studies in mice using general or tissue-specific knockout techniques. We also discuss the recent pharmacological literature describing a variety of new PPARgamma partial agonists and antagonists, as well as pan-PPAR agonists. The results of these studies have added to the understanding of PPARgamma function, allowing us to hypothesize a general mechanism of PPARgamma action and speculate on future trends in the use of PPARgamma as a target in the treatment of type II diabetes.
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PMID:Peroxisome proliferator-activated receptor-gamma calls for activation in moderation: lessons from genetics and pharmacology. 1558 22

Dyslipidemia and gallbladder diseases are two current anomalies observed in patients suffering from the metabolic syndrome and type 2 diabetes. The bile acid-activated nuclear receptor farnesoid X receptor (FXR) controls bile acid as well as lipid metabolism. Recent observations indicate a role for FXR also in carbohydrate metabolism. Hepatic FXR expression is altered in diabetic animal models in vivo and regulated by hormones and nutrients in vitro. At the molecular level, FXR activation modifies the transcriptional activity of different transcription factors controlling gluconeogenesis and lipogenesis, thus affecting in concert bile acid, lipid and carbohydrate metabolism. The present review focuses on recent advances in our understanding of the modulation of carbohydrate metabolism by FXR. These observations raise the intriguing possibility for a modulatory role of this receptor also in the metabolic syndrome.
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PMID:Potential regulatory role of the farnesoid X receptor in the metabolic syndrome. 1573 43

Hypertension commonly occurs as part of a genetically complex disorder of carbohydrate and lipid metabolism known as the metabolic syndrome. Most current antihypertensive drugs appear ineffective against the metabolic syndrome, which is a strong predictor of cardiovascular disease and death in affected patients. Angiotensin II can influence the activity of certain genes and cellular and biochemical pathways that may contribute to the pathogenesis of the metabolic syndrome. However, as a class, angiotensin II receptor blockers (ARBs) have proven only minimally to modestly effective in ameliorating the disturbances in carbohydrate and lipid metabolism that characterise the metabolic syndrome. Recent preclinical studies indicate that the ARB telmisartan acts as a selective peroxisome proliferators-activated receptor-gamma (PPARgamma) modulator when tested at concentrations that might be achievable with oral doses recommended for treatment of hypertension; this property does not appear to be shared by other ARBs. PPARgamma is a nuclear receptor that influences the expression of multiple genes involved in carbohydrate and lipid metabolism and is an attractive therapeutic target for the prevention and control of insulin resistance, type 2 diabetes and atherosclerosis. In cellular transactivation assays, telmisartan functioned as a partial agonist of PPARgamma and achieved 25-30% of maximal receptor activation attained with conventional PPARgamma ligands. Preclinical and clinical studies indicate that administration of telmisartan can improve carbohydrate and lipid metabolism without causing the side effects that accompany full PPARgamma activators. If the preliminary data are supported by the results of ongoing large-scale clinical studies, telmisartan could have a central role in the prevention and treatment of metabolic syndrome, diabetes and atherosclerosis.
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PMID:Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator. 1586 21

PPARg (peroxisome proliferator-activated receptor gamma) is a nuclear receptor that regulates the transcription of numerous genes involved in the differentiation, proliferation and apoptosis of various cell types. It was initially discovered in adipocytes as a differentiation agent, then was characterized in vascular endothelium and recently in choroidal and retinal endothelial cells. Agonists that bind to PPARgamma and stimulate its transcriptional activity are endogenous lipids such as lysophosphatidic acid and 15-d-PGJ2 as well as the synthetic pharmacological compounds, thiazolidinediones, used for treating type 2 diabetes. These ligands prevent choroidal and retinal neovascularization in several experimental animal models, notably through the inhibition of vascular endothelial growth factor (VEGF) receptor expression. Because of the high affinity and the low molecular weight of agonists, suitable for good bioavailability, PPARgamma could potentially be a novel pharmacological target of angiostatic agents, particularly useful to treat age-related macular degeneration and diabetic retinopathy.
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PMID:[PPAR gamma: a novel pharmacological target against retinal and choroidal neovascularization]. 1588

PPARgamma nuclear receptors are mainly expressed in adipose tissue. However, they are also expressed in renal glomerular tissue and in vascular walls, thus participating through various and complex mechanisms, to glomerular and vascular sclerosis and to nephropathy development and progression. Studies carried out with glitazones, pharmacological agonists of nuclear receptor PPARgamma, in experimental models, either in vitro, or in vivo in animal models, have demonstrated their favourable effects on arterial blood pressure and on prevention and/or progression of diabetic nephropathy. The few clinical studies conducted in type 2 diabetic patients to assess these effects, are also in favor of a beneficial effect of glitazones on blood pressure and nephropathy in these patients. Thus, it appears extremely important and fully justified to conduct specific studies in patients with type 2 diabetes, with the aim to establish and to better characterize these effects in various clinical conditions (antihypertensive effect in treated hypertensive patients according to the class of antihypertensive agents used, prevention of diabetic nephropathy and/or effect on its progression, renal protection, etc.). Some adverse events, although with a low incidence, may be associated with glitazone use (weight gain, peripheral oedema, fluid retention, etc.), and may limit their use in some patients. It is clearly important to better understand the pathophysiological mechanisms of these effects and their possible long term consequences. Finally, it is important to emphasize the easiness to use glitazones in patients with renal insufficiency, without the need to adjust the drug regimen.
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PMID:[Kidney and glitazones]. 1595 7

Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-alpha, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-alpha mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-alpha luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-alpha antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-alpha activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity.
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PMID:Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: activation of PPAR-alpha. 1597 14

Cardiovascular disease (CVD) remains the leading cause of mortality in developed countries. Several risk factors are associated with CVD, including type 2 diabetes, obesity, insulin resistance, dyslipidaemia and hypertension. Different pharmacological therapies have been developed to control these risk factors. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily that controls lipid and glucose metabolism as well as inflammatory risk factors for CVD. PPARalpha agonists, such as the fibrates, correct dyslipidaemia, thus decreasing CVD risk. PPARgamma agonists, such as the glitazones, increase insulin sensitivity and decrease plasma glucose levels in patients with diabetes. Moreover, both PPARalpha and PPARgamma agonists exert anti-inflammatory activities in liver, adipose and vascular tissues. In this review, we focus on the mode of action of PPARalpha and PPARalpha agonists, illustrating the potential of the newly developed dual PPAR agonists for the treatment of global risk in patients with the metabolic syndrome or type 2 diabetes.
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PMID:Inflammation, dyslipidaemia, diabetes and PPars: pharmacological interest of dual PPARalpha and PPARgamma agonists. 1603 93

A complex network of interacting transcription factors plays a critical role in normal pancreatic beta cell function, with mutations in certain transcription factor genes known to cause diabetes. In a recent issue of Cell, Gunton et al.(2005) demonstrate a role for the transcription factor ARNT/HIF1beta (hydrocarbon nuclear receptor translocator/hypoxia-inducible factor 1 beta) in normal beta cell function. ARNT expression is reduced in diabetic human islets and beta cell-specific ARNT knockout mice show the impaired glucose tolerance and abnormal insulin secretion that are characteristic of type 2 diabetes.
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PMID:Diabetic pancreatic beta cells ARNT all they should be. 1609 23


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