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A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.

Publication ,  Journal Article
Brown, KK; Henke, BR; Blanchard, SG; Cobb, JE; Mook, R; Kaldor, I; Kliewer, SA; Lehmann, JM; Lenhard, JM; Harrington, WW; Novak, PJ; Faison, W ...
Published in: Diabetes
July 1999

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.

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Published In

Diabetes

DOI

ISSN

0012-1797

Publication Date

July 1999

Volume

48

Issue

7

Start / End Page

1415 / 1424

Location

United States

Related Subject Headings

  • Tyrosine
  • Troglitazone
  • Transcription Factors
  • Thiazolidinediones
  • Thiazoles
  • Receptors, Cytoplasmic and Nuclear
  • Rats, Zucker
  • Rats
  • Phenotype
  • Obesity
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Brown, K. K., Henke, B. R., Blanchard, S. G., Cobb, J. E., Mook, R., Kaldor, I., … Willson, T. M. (1999). A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes, 48(7), 1415–1424. https://doi.org/10.2337/diabetes.48.7.1415
Brown, K. K., B. R. Henke, S. G. Blanchard, J. E. Cobb, R. Mook, I. Kaldor, S. A. Kliewer, et al. “A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.Diabetes 48, no. 7 (July 1999): 1415–24. https://doi.org/10.2337/diabetes.48.7.1415.
Brown KK, Henke BR, Blanchard SG, Cobb JE, Mook R, Kaldor I, et al. A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes. 1999 Jul;48(7):1415–24.
Brown, K. K., et al. “A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.Diabetes, vol. 48, no. 7, July 1999, pp. 1415–24. Pubmed, doi:10.2337/diabetes.48.7.1415.
Brown KK, Henke BR, Blanchard SG, Cobb JE, Mook R, Kaldor I, Kliewer SA, Lehmann JM, Lenhard JM, Harrington WW, Novak PJ, Faison W, Binz JG, Hashim MA, Oliver WO, Brown HR, Parks DJ, Plunket KD, Tong WQ, Menius JA, Adkison K, Noble SA, Willson TM. A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes. 1999 Jul;48(7):1415–1424.

Published In

Diabetes

DOI

ISSN

0012-1797

Publication Date

July 1999

Volume

48

Issue

7

Start / End Page

1415 / 1424

Location

United States

Related Subject Headings

  • Tyrosine
  • Troglitazone
  • Transcription Factors
  • Thiazolidinediones
  • Thiazoles
  • Receptors, Cytoplasmic and Nuclear
  • Rats, Zucker
  • Rats
  • Phenotype
  • Obesity