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)

The purpose of this study was to determine the effect of the peroxisome proliferator-activated receptor gamma-(PPAR gamma) ligands troglitazone (TRO), rosiglitazone (RSG), and 15-deoxy-delta prostaglandin J2 (15d-PGJ2) on vascular smooth muscle cell (VSMC) migration directed by multiple chemoattractants. Involvement of mitogen-activated protein kinase (MAPK) in migration also was examined, because TRO was previously shown to inhibit nuclear events stimulated by this pathway during mitogenic signaling in VSMCs. Migration of rat aortic VSMCs was induced 5.4-fold by PDGF, 4.6-fold by thrombin, and 2.3-fold by insulin-like growth factor I (IGF-I; all values of p < 0.05). The PPAR gamma ligands 15d-PGJ2, RSG, or TRO all inhibited VSMC migration with the following order of potency: 15d-PGJ2 > RSG > TRO. Inhibition of MAPK signaling with PD98059 completely blocked PDGF-, thrombin-, and IGF-I-induced migration. All chemoattractants induced MAPK activation. PPAR gamma ligands did not inhibit MAPK activation, suggesting a nuclear effect of these ligands downstream of MAPK. The importance of nuclear events was confirmed because actinomycin D also blocked migration. We conclude that PPAR gamma ligands are potent inhibitors of VSMC migration pathways, dependent on MAPK and nuclear events. PPAR gamma ligands act downstream of the cytoplasmic activation of MAPK and appear to exert their effects in the nucleus. Because VSMC migration plays an important role in the formation of atherosclerotic lesions and restenosis, PPAR gamma ligands like TRO and RSG, which ameliorate insulin resistance in humans, also may protect the vasculature from diabetes-enhanced injury.
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PMID:PPAR gamma-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells. 1022 69

Thiazolidinediones (TZDs) are an exciting new class of insulin-sensitizing drugs being used currently for the treatment of non-insulin-dependent diabetes mellitus. The molecular target of these compounds is thought to be the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is expressed predominantly in adipose tissue, yet a major site of TZD-responsive glucose disposal is skeletal muscle. Potential explanations for this paradox are discussed in this review.
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PMID:Mechanisms by which Thiazolidinediones Enhance Insulin Action. 1032 88

The recently identified uncoupling protein-3 (UCP-3) gene, predicted to encode a new member of the family of uncoupling proteins, is preferentially expressed in skeletal muscle and has been related to phenotypes of obesity and type 2 diabetes. We have established that during mouse ontogeny, the expression of the UCP-3 gene is switched on in skeletal muscle just after birth. The induction of UCP-3 gene expression is dependent on the initiation of suckling and particularly on lipid intake. Treatment of newborn mice with activators of peroxisome proliferator-activated receptors (PPARs), such as clofibrate, bezafibrate, or (4-chloro-6-(2,3-xylidine)-pirimidinylthio)acetic acid (WY 14,643), mimics the action of food intake on UCP-3 gene expression. The specific ligand of PPAR-alpha WY 14,643 induces UCP-3 gene expression in a time- and dose-dependent manner, whereas the thiazolidinedione BRL 49653, specific for PPAR-gamma, has no effect. These treatments act without altering circulating free fatty acids. During development, skeletal muscle expresses constitutive levels of PPAR-delta mRNA, whereas expression of the PPAR-gamma gene is undetectable. PPAR-alpha gene expression is developmentally regulated in muscle as it is first expressed at birth, just before UCP-3 gene induction occurs. The induction of UCP-3 gene expression by WY 14,643 is impaired in skeletal muscle of premature neonates, which do not express PPAR-alpha. It is proposed that the UCP-3 gene is predominantly regulated in neonatal muscle by PPAR-alpha activation.
Diabetes 1999 Jun
PMID:Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. 1034 7

The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated receptors which regulate genes involved in lipid metabolism and homeostasis. PPARalpha is preferentially expressed in the liver and PPARgamma preferentially in adipose tissue. Activation of PPARalpha leads to peroxisome proliferation in rodents and increased beta-oxidation of fatty acids. PPARgamma-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both of these PPAR receptors are potential targets for treatment of dyslipidemia in man. Studies by others using a proteomics approach have characterized the effects of PPARalpha agonists in livers from lean healthy mice. However, we wanted to map the effects of a therapeutic dose of a PPARalpha agonist in a disease model of insulin resistance and diabetes, the obese diabetic ob/ob mouse, by proteomics. Therefore, ob/ob mice, which have highly elevated levels of plasma triglycerides, glucose and insulin, were treated for one week with WY14,643 (180 micromol/kg/day), a well-characterized selective PPARalpha agonist. Plasma triglycerides, glucose and insulin levels were determined and we found significant therapeutic effects on triglycerides and glucose levels. The liver protein compositions were investigated by high-resolution two-dimensional gel electrophoresis which showed that WY14,643 produced up-regulation of at least 16 spots. These were identified by mass spectrometry and 14 spots were found to be components of the peroxisomal fatty acid metabolism. Thus, WY14,643 at a therapeutic dose, caused induction of peroxisomal fatty acid beta-oxidation in obese diabetic mice.
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PMID:A proteome analysis of livers from obese (ob/ob) mice treated with the peroxisome proliferator WY14,643. 1034 69

The discovery that peroxisome proliferator-activated receptor (PPAR)-gamma was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-gamma in the regulation of carbohydrate and lipid metabolism. Through the use of high-throughput biochemical assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-gamma, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated hemoglobin. Whole body insulin sensitivity, as determined by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concentrations showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion experiments, animals treated with the PPAR-gamma agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidinedione identified as a high-affinity ligand for human PPAR-gamma. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clinical efficacy when used as monotherapy in type 2 diabetic patients. In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.
Diabetes 1999 Jul
PMID:A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. 1038 47

Peroxisome proliferator-activated receptor (PPAR)-gamma is a major regulator of adipogenesis and insulin sensitivity. The PPAR-gamma gene generates two isoforms through alternative splicing, PPAR-gamma1 and -gamma2, the latter having an additional stretch of 28 amino acids at its NH2-terminus in the ligand-independent activation domain. This extension renders PPAR-gamma2 more sensitive to insulin action. Since there is a Pro12Ala substitution in this domain, we tested whether it is related to type 2 diabetes or insulin resistance. Therefore, 131 type 2 diabetic patients and 312 normoglycemic control subjects were screened for the presence of the mutation and for major clinical and metabolic features. The frequency of the mutation did not differ significantly between diabetic patients and control subjects. BMI, insulin, and other metabolic and anthropometric variables were also not associated with the mutation. Although the study was carried out on a sufficiently large sample, the conclusions do not support a major role for the Pro12Ala substitution of the PPAR-gamma gene in the etiology of type 2 diabetes.
Diabetes 1999 Jul
PMID:Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. 1038 55

The peroxisome proliferator-activated receptor gamma (PPARgamma) quickly evolved over the last decade from a new orphan receptor to one of the best characterized nuclear receptors. This fast pace in PPARgamma research was triggered by two main discoveries. Firstly, that PPARgamma was shown to have a key role in adipogenesis and be a master controller of the "thrifty gene response" leading to efficient energy storage. Secondly, the discovery that its synthetic ligands, the thiazolidinediones, are promising insulin sensitizing drugs, which are currently being developed for the treatment of Type II (non-insulin-dependent) diabetes mellitus. More recently this nuclear receptor emerged from a role limited to metabolism (diabetes and obesity) to a power player in general transcriptional control of numerous cellular processes, with implications in cell cycle control, carcinogenesis, inflammation, atherosclerosis and immunomodulation. This widened role of PPARgamma will certainly initiate a new flurry of research, which will not only refine our current often partial knowledge of PPARgamma but more importantly also establish that this receptor has a definite role as a primary link adapting cellular, tissue and whole body homeostasis to energy stores.
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PMID:PPARgamma, the ultimate thrifty gene. 1044 13

Thiazolidinediones (TDZs, glitazones) form a new substance group in the treatment of diabetes mellitus. As a result of influences on insulin signalling, glucose transport, hepatic glucose metabolism and modulation of the peroxisome proliferator activating receptor (PPAR-gamma), TZDs augment the effect of insulin in insulin-sensitive target tissues. Pioglitazone (CAS 111025-46-8 resp. 112529-15-4; Actos) is a member of the group of glitazones. According to existing clinical data, pioglitazone at a once daily oral dose of 15 to 45 mg, as monotherapy or in combination with sulphonylureas, metformin or exogenous insulin, has a pronounced and reproducible blood sugar-lowering effect. As well as improving glucose metabolism, pioglitazone has a beneficial effect on insulin resistance and the plasma levels of free fatty acids, triglycerides and HDL-cholesterol which is clinically relevant. Pioglitazone is well tolerated: treatment of 4300 type 2 diabetics worldwide has not revealed any evidence of hepatotoxic potential. Owing to their pathophysiological mode of action, glitazones have the potential to reduce the incidence of long-term diabetic complications in addition to their blood sugar-reducing effect.
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PMID:[Mechanisms and clinical effects of pioglatizone as a new agent for the treatment of type-2 diabetes]. 1055 61

Peroxisome proliferator-activated receptors (PPARs) are implicated in several metabolic disorders with altered glucose and lipid metabolism, including atherosclerosis and diabetes. In the present study, we evaluated the in vitro and ex vivo effects of high glucose concentrations on macrophage PPAR mRNA expression. Exposition of monocyte-derived macrophages isolated from healthy donors to a high glucose environment led to an increase in PPARalpha and PPARbeta mRNA expression. In contrast, this treatment significantly decreased human macrophage PPARgamma mRNA expression. Overexpression of PPARalpha and PPARbeta mRNA and inhibition of PPARgamma mRNA expression were also observed in monocyte-derived macrophages isolated from patients with type 2 diabetes. Because high glucose and PPARalpha agonists increase lipoprotein lipase (LPL) gene expression, the role of PPARalpha in the glucose-mediated upregulation of macrophage LPL gene expression was next evaluated. Incubation of murine J774 macrophages with high glucose concentrations increased the expression of PPARalpha at the mRNA and protein levels and enhanced nuclear protein binding to the peroxisome proliferator responsive element of the LPL promoter. Incubation of nuclear extracts in the presence of anti-PPARalpha and anti-PPARbeta antibodies decreased glucose-stimulated nuclear protein binding to the peroxisome proliferator responsive element. These results demonstrate that glucose is an important regulator of macrophage PPAR expression and suggest a role of PPARalpha and PPARbeta in the upregulation of macrophage LPL by glucose. Dysregulation of macrophage PPAR expression in type 2 diabetes may contribute, by altering arterial lipid metabolism and inflammatory response, to the accelerated atherosclerosis associated with diabetes.
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PMID:Differential regulation of macrophage peroxisome proliferator-activated receptor expression by glucose : role of peroxisome proliferator-activated receptors in lipoprotein lipase gene expression. 1063 6

The thiazolidinedione class of insulin-sensitizing, antidiabetic drugs interacts with peroxisome proliferator-activated receptor gamma (PPAR-gamma). To gain insight into the role of this nuclear receptor in insulin resistance and diabetes, we conducted metabolic studies in the PPAR-gamma gene knockout mouse model. Because homozygous PPAR-gamma-null mice die in development, we studied glucose metabolism in mice heterozygous for the mutation (PPAR-gamma(+/-) mice). We identified no statistically significant differences in body weight, basal glucose, insulin, or FFA levels between the wild-type (WT) and PPAR-gamma(+/-) groups. Nor was there a difference in glucose excursion between the groups of mice during oral glucose tolerance test, but insulin concentrations of the WT group were greater than those of the PPAR-gamma(+/-) group, and insulin-induced increase in glucose disposal rate was significantly increased in PPAR-gamma(+/-) mice. Likewise, the insulin-induced suppression of hepatic glucose production was significantly greater in the PPAR-gamma(+/-) mice than in the WT mice. Taken together, these results indicate that - counterintuitively - although pharmacological activation of PPAR-gamma improves insulin sensitivity, a similar effect is obtained by genetically reducing the expression levels of the receptor.
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PMID:Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. 1067 54


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