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)

(+/-)-5-([4-[2-Methyl-2(pyridylamino)ethoxy]phenyl]methyl) 2,4-thiazolidinedione (BRL 49653) is a new potent antidiabetic agent that improves insulin sensitivity in animal models of NIDDM. In C57BL/6 obese (ob/ob) mice, BRL 49653, included in the diet for 8 days, improved glucose tolerance. The half-maximal effective dose was 3 mumol/kg diet, which is equivalent to approximately 0.1 mg/kg body wt. Improvements in glucose tolerance were accompanied by significant reductions in circulating triacylglycerol, nonesterified fatty acids, and insulin. The insulin receptor number of epididymal white adipocytes prepared from obese mice treated with BRL 49653 (30 mumol/kg diet) for 14 days was increased twofold. The affinity of the receptor for insulin was unchanged. In the absence of added insulin, the rates of glucose transport in adipocytes from untreated and BRL 49653-treated obese mice were similar. Insulin (73 nmol/l) produced only a 1.5-fold increase in glucose transport in adipocytes from control obese mice, whereas after BRL 49653 treatment, insulin stimulated glucose transport 2.8-fold. BRL 49653 did not alter the sensitivity of glucose transport to insulin. The increase in insulin responsiveness was accompanied by a 2.5-fold increase in the total tissue content of the glucose transporter GLUT4. Glucose transport in adipocytes from lean littermates was not altered by BRL 49653. To establish the contribution of changes in glucose transporter trafficking to the BRL 49653-mediated increase in insulin action, the cell-impermeant bis-mannose photolabel 2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis-(D-mannos++ +-4-yloxy) -2-[2-3H]-propylamine was used to measure adipocyte cell-surface-associated glucose transporters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Repeat treatment of obese mice with BRL 49653, a new potent insulin sensitizer, enhances insulin action in white adipocytes. Association with increased insulin binding and cell-surface GLUT4 as measured by photoaffinity labeling. 765 33

A Michelson interferometry apparatus was used for measurement of the displacement of the buccal cusps of premolars after restoration of MOD preparations with composites. The effects of composite type, cavity size, and hydration conditions were examined. Interferometry permitted real-time measurement of cusp movement as it occurred. Contraction occurred very rapidly, about 1/3 of the 60-minute amount within the two-minute period of exposure to the curing light. Cusp movement was smooth rather than interrupted, indicating lack of microfracturing at deformations of 11-46 microns. Contraction, 0.94% for Heliomolar and 1.2% for P-50, was similar to the linear polymerization shrinkage of the resins. Less cusp movement occurred in small cavities than in large cavities. Hydrated teeth had less cusp movement than dehydrated teeth.
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PMID:Interferometric measurements of cusp deformation of teeth restored with composites. 822 5

In subjects with type 2 diabetes, both defects of insulin secretion and insulin resistance contribute to the development of hyperglycaemia. The major goals of treatment are to optimise blood glucose control, and normalise the associated lipid disturbances and elevated blood pressure. Pharmacologic treatment is often necessary. This paper discusses new forms of oral treatment for subjects with type 2 diabetes. These include a new sulphonylurea compound glimepiride (Amaryl), which binds to a different protein of the putative sulphonylurea receptor than glibenclamide, and seems to have a lower risk of hypoglycaemia. A new class of drugs with insulin secretory capacity, of which repaglinide (NovoNorm) is the leading compound, is now in phase III clinical trials. Alpha-glucosidase inhibitors reversibly inhibit alpha-glucosidase enzymes in the small intestine, which delays cleavage of oligo- and disaccharides to monosaccharides. This leads to a delayed and reduced blood glucose rise after a meal. Two compounds are in development or have been marketed, ie, miglitol and acarbose (Glucobay). Another new class of drugs is the thiazolidine-diones, which seem to work by enhancing insulin action. The 'insulin sensitising' effects of the leading compounds, troglitazone and BRL 49653C, do not involve any effect on insulin secretion. These drugs also seem to beneficially influence serum cholesterol and triglyceride levels. Oral antihyperglycaemic agents can be used only during a limited period of time in most patients, after which the diabetic state 'worsens' and insulin therapy has to be started. In this light, two new forms of treatment which require subcutaneous injections are also discussed: the synthetic human amylin analogue AC137 (pramlintide) and glucagon-like peptide-1 (7-36)-amide, a strong glucose-dependent stimulator of insulin secretion. It remains to be seen whether these compounds can be developed further for clinical use in patients with diabetes.
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PMID:New treatments for patients with type 2 diabetes mellitus. 894 6

Thiazolidinediones (TZDs) are a novel class of insulin-sensitizing agents used in the treatment of NIDDM and are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). The thiazolidinedione BRL 49653 has been shown to promote the differentiation of the HIB-1B brown preadipocyte cell line and to increase rat interscapular brown adipose tissue (BAT) mass. Given the importance of brown fat in the control of energy metabolism in rodents, this may represent an important therapeutic effect of this class of compound. To date, however, no studies examining the effects of TZDs on human brown fat have been reported. In the present study, we have measured uncoupling protein 1 (UCP-1) mRNA, a specific marker for BAT, in isolated adipocytes and subcultured preadipocytes prepared from different adult human adipose tissue depots. Consistent with previous studies of adult human whole adipose tissue, UCP-1 mRNA was detectable in isolated human adipocytes prepared from all depots studied with a rank order of perirenal, omental, and subcutaneous. BRL 49653 treatment of subcultured human pre-adipocytes prepared from all depots resulted in increased levels of UCP-1 mRNA, compared with those of the vehicle-treated cells. When exposed to BRL 49653 for 5 days, preadipocytes from the human perirenal depot accumulated lipid, and a proportion of cells showed clear mitochondrial staining for UCP-1 protein by confocal microscopy. Thus, cells of the brown fat lineage were detectable in all human adipose depots studied, and cultured human pre-adipocytes, particularly from the perirenal depot, showed a marked increase in UCP-1 expression in response to thiazolidinediones. Given the role of brown adipocytes in the enhancement of energy expenditure, promotion of brown fat adipogenesis by thiazolidinediones could contribute to the beneficial effects of these drugs on insulin resistance in humans.
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PMID:Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes. 942 89

The objective of the study was to quantitatively compare peak strain in buccal & lingual aspects of human molar teeth restored with composite res in polymers as a function of: 1) cavity size, 2) restorative material, 3) restorative technique. Two composite resin materials were investigated: Herculite (sub micron filler particle) & P 50 (supra micron filler particle). Performance was compared to two different types of high copper amalgams. A total of 48 freshly extracted human molar teeth free from cracks or caries were used. MOD cavities were prepared with three different cavity sizes: 1 mm, 2.5 mm & 5 mm. Rectangular rosette strain gauges were applied centrally on the buccal & lingual surfaces of the prepared teeth. Strain measurements were recorded during subsequent cavity restoration procedures and curing cycles. A comparison of peak strains in the amalgam vs composites using bulk-pack technique showed significantly higher strain in the composite series. Highest strains were noted in the largest cavity size (5 mm). Slot preparation following restoration reduced strains in the composite materials. Subsequent re-filling of the slot increased strain, but still less than the initial value.
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PMID:Strain profiles in molars restored with posterior composite resins: effect of cavity size & restorative technique. 949 77

Thiazolidinediones (TZDs) such as BRL 49653 are a class of antidiabetic agents that are agonists for the peroxisome proliferator-activated nuclear receptor (PPAR-gamma2). In vivo, TZDs reduce circulating levels of free fatty acids (FFAs) and ameliorate insulin resistance in individuals with obesity and NIDDM. Adipocyte production of TNF-alpha is proposed to play a role in the development of insulin resistance, and because BRL 49653 has been shown to antagonize some of the effects of TNF-alpha, we examined the effects of TNF-alpha and BRL 49653 on adipocyte lipolysis. After a 24-h incubation of TNF-alpha (10 ng/ml) with 3T3-L1 adipocytes, glycerol release increased by approximately 7-fold, and FFA release increased by approximately 44-fold. BRL 49653 (10 pmol/l) reduced TNF-alpha-induced glycerol release by approximately 50% (P < 0.001) and FFA release by approximately 90% (P < 0.001). BRL 49653 also reduced glycerol release by approximately 50% in adipocytes pretreated for 24 h with TNF-alpha. Prolonged treatment (5 days) with either BRL 49653 or another PPAR-gamma2 agonist, 15-d delta-12,14-prostaglandin J2 (15-d deltaPGJ2), blocked TNF-alpha-induced glycerol release by approximately 100%. Catecholamine (isoproterenol)-stimulated lipolysis was unaffected by BRL 49653 and 15-d deltaPGJ2. BRL 49653 partially blocked the TNF-alpha-mediated reduction in protein levels of hormone-sensitive lipase and perilipin A, two proteins involved in adipocyte lipolysis. These data suggest a novel pathway that may contribute to the ability of the TZDs to reduce serum FFA and increase insulin sensitivity.
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PMID:BRL 49653 blocks the lipolytic actions of tumor necrosis factor-alpha: a potential new insulin-sensitizing mechanism for thiazolidinediones. 956 6

BRL 49653 (rosiglitazone) and troglitazone are thiazolidinedione insulin-sensitizing agents, which are undergoing clinical evaluation as treatments for NIDDM. Potential side effects of thiazolidinediones include edema and hemodilution. Although the underlying mechanisms are presently unclear, animal and human studies have demonstrated a vasodilator action of troglitazone, which could in theory cause fluid retention. This in vitro study compared the direct vasodilator effects of troglitazone and BRL 49653 in small arteries (n = 44) from human subcutaneous fat. In arterial rings with a functioning endothelium and preconstricted with norepinephrine (NE; 6 micromol/l), troglitazone (n = 22 vessels), but not BRL 49653 (1-100 micromol/l), caused a concentration-related relaxation (69.4 +/- 5.2% at 100 micromol/l; P < 0.01). In the presence of indomethacin (IM; 10 micromol/l; n = 12), this vasorelaxant effect of troglitazone was abolished (P < 0.01 vs. troglitazone alone) and replaced by enhanced vasoconstriction (58.5 +/- 39.5% over the NE baseline) similar in magnitude to that produced by troglitazone vehicle (ethanol) alone (n = 16; NS vs. ethanol vehicle). By contrast, BRL 49653 (100 micromol/l; n = 22) and an equivalent volume of ethanol alone (n = 12) caused similar degrees of vasoconstriction (18.7 +/- 14.6 and 22.5 +/- 8.0%, respectively; NS). In the presence of IM (10 micromol/l; n = 10), the vasoconstrictor effect of BRL 49653 was enhanced (41.5 +/- 14.4%), although not significantly (NS vs. BRL 49653 alone or ethanol alone). Additional studies in Wistar rat arteries showed a similar vasodilator effect of troglitazone that was not inhibited by L-NAME (100 micromol/l). The alpha-tocopherol moiety alone had no vasorelaxant effect at concentrations up to 300 micromol/l. Thus, in human arterial resistance vessels in vitro, BRL 49653 does not possess the direct, IM-sensitive vasorelaxant action of troglitazone. This vasodilation could, in theory, permit transmission of systemic pressure to the capillary bed.
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PMID:Differential vasoactive effects of the insulin sensitizers rosiglitazone (BRL 49653) and troglitazone on human small arteries in vitro. 958 54

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.
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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

Thiazolidinediones (TZDs) reduce insulin resistance in type 2 diabetes by increasing peripheral uptake of glucose, and they bind to and activate the transcriptional factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have suggested that TZD-induced activation of PPAR-gamma correlates with antidiabetic action, but the mechanism by which the activated PPAR-gamma is involved in reducing insulin resistance is not known. To examine whether activation of PPAR-gamma directly correlates with antidiabetic activities, we compared the effects of 4 TZDs (troglitazone, pioglitazone, BRL-49653, and a new derivative, NC-2100) on the activation of PPAR-gamma in a reporter assay, transcription of the target genes, adipogenesis, plasma glucose and triglyceride levels, and body weight using obese KKAy mice. There were 10- to 30-fold higher concentrations of NC-2100 required for maximal activation of PPAR-gamma in a reporter assay system, and only high concentrations of NC-2100 weakly induced transcription of the PPAR-gamma but not PPAR-alpha target genes in a whole mouse and adipogenesis of cultured 3T3L1 cells, which indicates that NC-2100 is a weak PPAR-gamma activator. However, low concentrations of NC-2100 efficiently lowered plasma glucose levels in KKAy obese mice. These results strongly suggest that TZD-induced activation of PPAR-gamma does not directly correlate with antidiabetic (glucose-lowering) action. Furthermore, NC-2100 caused the smallest body weight increase of the 4 TZDs, which may be partly explained by the finding that NC-2100 efficiently induces uncoupling protein (UCP)-2 mRNA and significantly induces UCP1 mRNA in white adipose tissue (WAT). NC-2100 induced UCP1 efficiently in mesenteric WAT and less efficiently in subcutaneous WAT, although pioglitazone and troglitazone also slightly induced UCP1 only in mesenteric WAT. These characteristics of NC-2100 should be beneficial for humans with limited amounts of brown adipose tissue.
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PMID:A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice. 1090 84

Studies of pioglitazone, troglitazone, BRL 49653 and other thiazolidinediones in preclinical animal models of non-insulin dependent diabetes mellitus (NIDDM) and obesity led to the observation that these compounds were effective in reducing hyperglycaemia and hyperlipidaemia. In these models, animals treated with thiazolidinediones had notable improvements in blood glucose levels, hepatic glucose output, peripheral insulin resistance, and serum lipid levels. Mechanistic studies indicate that thiazolidinediones act at many intracellular sites and can influence several processes to increase cell sensitivity to insulin. These include influence on insulin receptor kinase activity, control of insulin receptor phosphorylation, change in number of insulin receptors, quantity and activity of GLUT-4, modulation of tumour necrosis factor (TNF) activity, activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and alteration of hepatic glucose metabolism. Available data on pioglitazone and troglitazone from clinical studies support the efficacy and safety of this class of compounds in reducing hyperglycaemia, hypertriglyceridaemia and insulin resistance associated with NIDDM. Currently, only troglitazone is approved for use in the United States and only in combination with insulin. This new pharmacological class of drugs has great promise for the treatment of NIDDM and also as a valuable research tool to further the understanding of the mechanisms that underlie NIDDM and insulin resistance syndrome.
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PMID:Mechanisms and clinical effects of thiazolidinediones. 1598 61


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