title: A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.
abstract: 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.
authors.affiliation: Department of Metabolic Diseases, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA. kkb7797@glaxowellcome.com
authors.forename: K K
authors.initials: KK
authors.lastname: Brown
authors.forename: B R
authors.initials: BR
authors.lastname: Henke
authors.forename: S G
authors.initials: SG
authors.lastname: Blanchard
authors.forename: J E
authors.initials: JE
authors.lastname: Cobb
authors.forename: R
authors.initials: R
authors.lastname: Mook
authors.forename: I
authors.initials: I
authors.lastname: Kaldor
authors.forename: S A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: J M
authors.initials: JM
authors.lastname: Lehmann
authors.forename: J M
authors.initials: JM
authors.lastname: Lenhard
authors.forename: W W
authors.initials: WW
authors.lastname: Harrington
authors.forename: P J
authors.initials: PJ
authors.lastname: Novak
authors.forename: W
authors.initials: W
authors.lastname: Faison
authors.forename: J G
authors.initials: JG
authors.lastname: Binz
authors.forename: M A
authors.initials: MA
authors.lastname: Hashim
authors.forename: W O
authors.initials: WO
authors.lastname: Oliver
authors.forename: H R
authors.initials: HR
authors.lastname: Brown
authors.forename: D J
authors.initials: DJ
authors.lastname: Parks
authors.forename: K D
authors.initials: KD
authors.lastname: Plunket
authors.forename: W Q
authors.initials: WQ
authors.lastname: Tong
authors.forename: J A
authors.initials: JA
authors.lastname: Menius
authors.forename: K
authors.initials: K
authors.lastname: Adkison
authors.forename: S A
authors.initials: SA
authors.lastname: Noble
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D002839:Chromans / Q000627:therapeutic use; D002999:Clone Cells; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology*; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007150:Immunohistochemistry; D016015:Logistic Models; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D010641:Phenotype; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D000077288:Troglitazone; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001577:Benzophenones; D002839:Chromans; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014443:Tyrosine; D000077288:Troglitazone; C120099:GW 1929