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

Kathleen K. Brown, Brad R. Henke, Steven G. Blanchard, Jeff E. Cobb, Robert Mook, Istvan Kaldor, Steven A. Kliewer, Jurgen M. Lehmann, James M. Lenhard, Wallace W. Harrington, Paul J. Novak, Walter Faison, Jane G. Binz, Mir A. Hashim, William O. Oliver, H. Roger Brown, Derek J. Parks, Kelli D. Plunket, Wei Qin Tong, J. Alan MeniusKimberly Adkison, Stewart A. Noble, Timothy M. Willson

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

The discovery that peroxisome proliferator-activated receptor (PPAR)-γ was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-γ 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-γ, 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-γ 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-γ. 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.

Original languageEnglish (US)
Pages (from-to)1415-1424
Number of pages10
JournalDiabetes
Volume48
Issue number7
DOIs
StatePublished - 1999

Fingerprint

troglitazone
Peroxisome Proliferator-Activated Receptors
Tyrosine
Phenotype
Pancreas
Insulin
Glucose
Glucose Clamp Technique
Glycosylated Hemoglobin A
Carbohydrate Metabolism
Risk Management
Lipid Metabolism
Nonesterified Fatty Acids
Hypoglycemic Agents
Oral Administration
Meals
Insulin Resistance
GW 1929
Triglycerides
Perfusion

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker diabetic fatty rat. / Brown, Kathleen K.; Henke, Brad R.; Blanchard, Steven G.; Cobb, Jeff E.; Mook, Robert; Kaldor, Istvan; Kliewer, Steven A.; Lehmann, Jurgen M.; Lenhard, James M.; Harrington, Wallace W.; Novak, Paul J.; Faison, Walter; Binz, Jane G.; Hashim, Mir A.; Oliver, William O.; Brown, H. Roger; Parks, Derek J.; Plunket, Kelli D.; Tong, Wei Qin; Menius, J. Alan; Adkison, Kimberly; Noble, Stewart A.; Willson, Timothy M.

In: Diabetes, Vol. 48, No. 7, 1999, p. 1415-1424.

Research output: Contribution to journalArticle

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 1999, 'A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker diabetic fatty rat', Diabetes, vol. 48, no. 7, pp. 1415-1424. https://doi.org/10.2337/diabetes.48.7.1415
Brown, Kathleen K. ; Henke, Brad R. ; Blanchard, Steven G. ; Cobb, Jeff E. ; Mook, Robert ; Kaldor, Istvan ; Kliewer, Steven A. ; Lehmann, Jurgen M. ; Lenhard, James M. ; Harrington, Wallace W. ; Novak, Paul J. ; Faison, Walter ; Binz, Jane G. ; Hashim, Mir A. ; Oliver, William O. ; Brown, H. Roger ; Parks, Derek J. ; Plunket, Kelli D. ; Tong, Wei Qin ; Menius, J. Alan ; Adkison, Kimberly ; Noble, Stewart A. ; Willson, Timothy M. / A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker diabetic fatty rat. In: Diabetes. 1999 ; Vol. 48, No. 7. pp. 1415-1424.
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abstract = "The discovery that peroxisome proliferator-activated receptor (PPAR)-γ was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-γ 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-γ, 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-γ 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-γ. 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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AU - Cobb, Jeff E.

AU - Mook, Robert

AU - Kaldor, Istvan

AU - Kliewer, Steven A.

AU - Lehmann, Jurgen M.

AU - Lenhard, James M.

AU - Harrington, Wallace W.

AU - Novak, Paul J.

AU - Faison, Walter

AU - Binz, Jane G.

AU - Hashim, Mir A.

AU - Oliver, William O.

AU - Brown, H. Roger

AU - Parks, Derek J.

AU - Plunket, Kelli D.

AU - Tong, Wei Qin

AU - Menius, J. Alan

AU - Adkison, Kimberly

AU - Noble, Stewart A.

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