Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. PPARgamma forms a heterodimer with the retinoid X receptor and upon ligand-activation binds to the PPAR response element in the promoter of genes to allow transcription. The class of insulin-sensitizing drugs known as thiazolidinediones have been identified as specific PPARgamma agonists that have allowed the characterization of many genes regulated by PPARgamma. Thiazolidinediones include rosiglitazone, pioglitazone, troglitazone, and ciglitazone. In addition to these synthetic agonists, cyclopentenone prostaglandins of the J2 series have been identified as natural ligands for PPARgamma. Several in vitro and in vivo studies have demonstrated that pharmacological activation of PPARgamma by 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2) or thiazolidinediones has anti-inflammatory effects. This article provides an overview of the role of PPARgamma in regulating the inflammatory response and emphasizes the potential efficacy of PPARgamma ligands as novel therapeutic approaches beyond diabetes in sepsis, inflammation, and reperfusion injury.
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PMID:Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation. 1583 3

15-Deoxy-Delta(12,14)-prostaglandin J2 (15dPGJ2) is a peroxisome proliferator-activated receptor (3) (PPAR(3)) ligand that regulates lipid homeostasis and has anti-inflammatory properties in many cell types. We postulated that 15dPGJ2 may regulate lipid homeostasis and nitric oxide (NO) levels in term placental tissues and that alterations in these pathways may be involved in diabetes-induced placental derangements. In the present study, we observed that, in term placental tissues from streptozotocin-induced diabetic rats, 15dPGJ2 concentrations were decreased (83%) and immunostaining for nitrotyrosine, indicating peroxynitrite-induced damage, was increased. In the presence of 15dPGJ2, concentrations of nitrates/nitrites (an index of NO production) were diminished (40%) in both control and diabetic rats, an effect that seems to be both dependent on and independent of PPAR(3) activation. Exogenous 15dPGJ2 did not modify lipid mass, but decreased the incorporation of (14)C-acetate into triacylglycerol (35%), cholesteryl ester (55%) and phospholipid (32%) in placenta from control rats, an effect that appears to be dependent on PPAR(3) activation. In contrast, the addition of 15dPGJ2 did not alter de novo lipid synthesis in diabetic rat placenta, which showed decreased levels of PPAR(3). We conclude that 15dPGJ2 modulates placental lipid metabolism and NO production. The concentration and function of 15dPGJ2 and concentrations of PPAR(3) were altered in placentas from diabetic rats, anomalies probably involved in diabetes-induced placental dysfunction.
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PMID:15-Deoxy-Delta12,14-prostaglandin J2 and peroxisome proliferator-activated receptor gamma (PPARgamma) levels in term placental tissues from control and diabetic rats: modulatory effects of a PPARgamma agonist on nitridergic and lipid placental metabolism. 1589 54

Despite lack of scientific evidences to support its therapeutic efficacy, the use of herbal supplements has significantly increased. The purpose of this study was to evaluate the effects of traditional anti-diabetic herbs on the progress of diabetes in db/db mice, a typical non-insulin-dependent model. Five different experimental diets were as follows: control diet, 0.5% mulberry leaf water extract diet, 0.5% Korean red ginseng diet, 0.5% banaba leaf water extract diet, and 0.5% combination diet (mulberry leaf water extract/Korean red ginseng/banaba leaf water extract, 1:1:1). Blood levels of glucose, insulin, HbA1c, and triglyceride were measured every 2 weeks. At 12 weeks of age, animals were sacrificed, and tissue mRNA levels of PPAR-alpha, PPAR-gamma, and LPL were determined. Results indicated that mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, and the combination of above herbs effectively reduced blood glucose, insulin, TG, and percent HbA1c in study animals (p<0.05). We also observed that the increased expressions of liver PPAR-alpha mRNA and adipose tissue PPAR-gamma mRNA in animals fed diets supplemented with test herbs. The expression of liver LPL mRNA was also increased with experimental diets containing herbs. The efficacy was highest in animals fed the combination diet for all of the markers used. These results suggest that mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, and the combination of these herbs fed at the level of 0.5% of the diet significantly increase insulin sensitivity, and improve hyperglycemia possibly through regulating PPAR-mediated lipid metabolism.
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PMID:Effects of dietary mulberry, Korean red ginseng, and banaba on glucose homeostasis in relation to PPAR-alpha, PPAR-gamma, and LPL mRNA expressions. 1597 95

Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion. Considerable evidence implicates altered fat topography and defects in adipocyte metabolism in the pathogenesis of type 2 diabetes. In individuals who develop type 2 diabetes, fat cells tend to be enlarged. Enlarged fat cells are resistant to the antilipolytic effects of insulin, leading to day-long elevated plasma free fatty acid (FFA) levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic and muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. Enlarged fat cells also have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid 'overflows' into muscle and liver, and possibly the beta-cells of the pancreas, exacerbating insulin resistance and further impairing insulin secretion. In addition, dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory and atherosclerosis-provoking cytokines, and fail to secrete normal amounts of insulin-sensitizing cytokines. As more evidence emerges, there is a stronger case for targeting adipose tissue in the treatment of type 2 diabetes. Peroxisome-proliferator activated receptor gamma (PPARgamma) agonists, for example the thiazolidinediones, redistribute fat within the body (decrease visceral and hepatic fat; increase subcutaneous fat) and have been shown to enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA and favourably influence the production of adipocytokines. This article examines in detail the role of adipose tissue in the pathogenesis of type 2 diabetes and highlights the potential of PPAR agonists to improve the management of patients with the condition.
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PMID:Dysfunctional fat cells, lipotoxicity and type 2 diabetes. 1603 92

The metabolic syndrome leads to cardiovascular disease and type 2 diabetes mellitus, through multiple risks, such as insulin resistance, dyslipidemia, hyperinsulinemia, and hypertension. It also represents a disorder of partial genetic background as mutations of the peroxisome proliferator-activated receptor-gamma (PPAR-g). Thiazolidinedione agonists for the PPAR-g system are effective in control of insulin resistance and diabetes. Telmisartan has a molecular structure that imparts partial agonist properties with the PPAR-g molecule, which results in reductions in glucose and lipid metabolism. Administration of telmisartan to rats on a high-fat, high-carbohydrate diet leads to reductions in glucose, insulin, and triglyceride levels. The results imply that the ARB agent, telmisartan, could treat both the hemodynamic and metabolic aberrations seen in subjects with the metabolic syndrome, such as insulin resistance, glucose intolerance, and hypertension.
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PMID:Angiotensin-receptor blocking agents and the peroxisome proliferator-activated receptor-gamma system. 1606 Oct 40

Metabolism, in part, is regulated by the peroxisome proliferator-activated receptors (PPARs). The PPARs act as nutritional lipid sensors and three mammalian PPAR subtypes designated PPARalpha (NR1C1), PPARgamma (NR1C3) and PPARdelta (NR1C2) have been identified. This subgroup of nuclear hormone receptors binds DNA and controls gene expression at the nexus of pathways that regulate lipid and glucose homeostasis, energy storage and expenditure in an organ-specific manner. Recent evidence has demonstrated activation of PPARdelta in the major mass peripheral tissue (ie, adipose and skeletal muscle). It enhances glucose tolerance, insulin-stimulated glucose disposal, lipid catabolism, energy expenditure, cholesterol efflux and oxygen consumption. These effects positively influence the blood-lipid profile. Furthermore, PPARdelta activation produces a predominant type I/slow twitch/oxidative muscle fiber phenotype that leads to increased endurance, insulin sensitivity and resistance to obesity. PPARdelta has rapidly emerged as a potential target in the battle against dyslipidemia, insulin insensitivity, type II diabetes and obesity, with therapeutic efficacy in the treatment of cardiovascular disease risk factors. GW-501516 is currently undergoing phase II safety and efficacy trials in human volunteers for the treatment of dyslipidemia. The outcome of these clinical trials are eagerly awaited against a background of conflicting reports about cancer risks in genetically predisposed animal models. This review focuses on the potential pharmacological utility of selective PPARdelta agonists in the context of risk factors associated with metabolic and cardiovascular disease.
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PMID:Cardiovascular disease and PPARdelta: targeting the risk factors. 1618 88

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by fatty acids and their derivatives. PPARs consist of three isotypes named PPAR alpha (NR1C1), PPAR beta/delta (NR1C2) and PPAR gamma (NR1C3) in vertebrates. Each of them is encoded in a separate gene and binds fatty acids and eicosanoids. Although each isotype fulfills distinct functions, PPARs function not only as an important fatty acid sensor that regulate lipid, carbohydrate and amino acid metabolism but also play an important role in various signaling pathways (immunity, inflammation, apoptosis and cell differentiation). Dysfunction of PPAR-mediated signals leads to various diseases such as diabetes, obese, hyperlipidemia, inflammation and cancer. Importantly, magnesium appears to play a pivotal role in regulating the PPAR-mediated signaling pathways as a key cofactor in the protein phosphorylation. Therefore, restrict control of magnesium concentration in the body appears to be very important for protection for these diseases. In this review, I focus on emerging knowledge about relationship between PPAR-mediated signals and magnesium.
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PMID:[Nuclear Receptor PPARs and magnesium]. 1627 14

Type 2 diabetes is an important cardiovascular risk factor. A significant component of the risk associated with type 2 diabetes is thought to be because of its characteristic lipid "triad" profile of raised small dense low-density lipoprotein levels, lowered high-density lipoprotein, and elevated triglycerides (TGs). Trials of statins and fibrates have included substantial numbers of patients with diabetes and indicate that lipid lowering reduces cardiovascular event rates in these patients. However, statins alone do not always address all the lipid abnormalities of diabetes. Fibrates, which have low affinity for peroxisome proliferator-activated receptor alpha (PPARalpha), improve most aspects of the atherogenic dyslipidemia of diabetes. Chronic elevations of free fatty acids (FFA) induce insulin resistance and contribute to the lipid triad of diabetes. Therefore, reducing their levels is likely to ameliorate insulin resistance and improve the lipid triad of diabetes. PPARs are intimately involved in the regulation of FFA: PPARalpha modulation increases FFA catabolism and PPARgamma agonism (eg, by thiazolidinediones) increases TG lipolysis, FFA transport, conversion of FFA to TGs, and safe storage of FFA. Integrating potent PPARalpha and PPARgamma activity may deliver greater improvement of the diabetic dyslipidemic profile and its attendant risks than selective PPAR activation.
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PMID:Type 2 diabetes, dyslipidemia, and vascular risk: rationale and evidence for correcting the lipid imbalance. 1629 Sep 51

Two stability challenges were encountered during development of an urine assay for a proliferator-activated receptor (PPAR) agonist, I (2-{[5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}-2-methyl propionic acid), indicated for the treatment of Type II diabetes. First, the analyte was lost in urine samples due to adsorption on container surface which is a common problem during clinical sample handling. Secondly, the acylglucuronide metabolite (III), a major metabolite of I, displayed limited stability and effected the quantitation of parent drug due to the release of I through hydrolysis. Therefore, a clinical collection procedure was carefully established to stabilize I and its acylglucuronide metabolite, III, in human urine. The metabolite was not quantitated with this method. The urine samples are treated with bovine serum albumin (BSA) equal to 1.75% of the urine volume and formic acid equal to 1% of urine volume. Compound (I) and internal standard (II) were extracted from urine with 1 mL ethyl acetate using a fully automated liquid-liquid extraction in 96-well plate format. The analytes are separated by reverse phase high-performance liquid chromatography (HPLC) with tandem mass spectrometry in multiple-reaction-monitoring (MRM) mode used for detection. The urine method has a lower limit of quantitation (LLOQ) of 0.05 ng/mL with a linearity range of 0.05-20 ng/mL using 0.05 mL of urine. The method was validated and used to assay urine clinical samples.
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PMID:Stabilization and determination of a PPAR agonist in human urine using automated 96-well liquid-liquid extraction and liquid chromatography/tandem mass spectrometry. 1676 56

Treatment with statins reduces coronary risk In all people but do not remove the risk associated with a low HDL-C or with other features of the metabolic syndrome such as an elevated level of plasma triglyceride or with a high BMI. Treatment with a fibrate such as gemfibrozil (a PPAR alpha agonist) has been shown to be especially effective in people with low HDL-C and other features of the metabolic syndrome. Potential beneficial effects of the combination of a statin and an agent with PPAR alpha activity in patients with type 2 diabetes is currently being addressed in the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.
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PMID:Managing diabetic dyslipidaemia--beyond LDL-C:HDL-C and triglycerides. 1682 46


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