Journal Article

Muraglitazar, a Novel Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves β-Cell Function in db/db Mice

Hao Zhang, Wen-Pin Yang, Cuixia Chu, Dennis Farrelly, Fucheng Qu, Sean Chen, Jimmy Ren, Thomas Harrity, Chunning Shao, Scott Biller, Wei Wang, Ramakrishna Seethala, Kasim A. Mookhtiar, Peter T. Cheng, Denis Ryono, Randolph Ponticiello, Aaron Tieman, Michael Cap, Min Zhou, Richard Gregg, John Wetterau, Pratik Devasthale, Narayanan Hariharan, William Fenderson, Yoon Jeon, Lori Kunselman, Liqun Gu

2006

Overview

Muraglitazar, a Novel Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves β-Cell Function in db/db Mice Thomas Harrity 1 , Dennis Farrelly 1 , Aaron Tieman 1 , Cuixia Chu 1 , Lori Kunselman 1 , Liqun Gu 1 , Randolph Ponticiello 1 , Michael Cap 1 , Fucheng Qu 2 , Chunning Shao 2 , Wei Wang 2 , Hao Zhang 2 , William Fenderson 3 , Sean Chen 2 , Pratik Devasthale 2 , Yoon Jeon 2 , Ramakrishna Seethala 1 , Wen-Pin Yang 3 , Jimmy Ren 1 , Min Zhou 1 , Denis Ryono 2 , Scott Biller 2 , Kasim A. Mookhtiar 1 , John Wetterau 1 , Richard Gregg 1 , Peter T. Cheng 2 and Narayanan Hariharan 1 1 Department of Metabolic Diseases Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 2 Department of Metabolic Diseases Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 3 Department of Applied Genomics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey Address correspondence and reprint requests to Narayanan Hariharan, PhD, Metabolic Diseases, HWP-21-2.02, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543. E-mail: narayanan.hariharan{at}bms.com Abstract Muraglitazar, a novel dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03–50 mg · kg −1 · day −1 for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg · kg −1 · day −1 for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg · kg −1 · day −1 for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high–molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (α/γ) PPAR activator muraglitazar 1 ) exerts potent and efficacious antidiabetic effects, 2 ) preserves pancreatic insulin content, and 3 ) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels. ACO, acyl coenzyme-A oxidase FFA, free fatty acid HMW, high molecular weight LMW, low molecular weight MMW, medium molecular weight PPAR, peroxisome proliferator–activated receptor WAT, white adipose tissue Footnotes S.B. is currently affiliated with Novartis Institute Bio-Med Research, Cambridge, Massachusetts. K.A.M. is currently affiliated with Advinus Therapeutics, Pune, India. J.W. is currently affiliated with the Department of Cardiovascular Pharmaceuticals, Pfizer, Ann Arbor, Michigan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted September 26, 2005. Received May 23, 2005. DIABETES

• Publisher: American Diabetes Association
• Subject: Adiponectin - blood / Animals / Atherosclerosis / Biological and medical sciences / Blood Glucose - drug effects / Care and treatment / Corticosterone - blood / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - pathology / Diabetes. Impaired glucose tolerance / Diagnosis / Diet / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Female / Glycine - analogs & derivatives / Glycine - pharmacology / Glycine - therapeutic use / Health aspects / Hyperlipidemias - drug therapy / Hypoglycemic Agents - pharmacology / Hypoglycemic Agents - therapeutic use / Insulin - blood / Insulin-Secreting Cells - drug effects / Insulin-Secreting Cells - metabolism / Lipid metabolism / Liver / Medical sciences / Mice / Obesity / Oxazoles - pharmacology / Oxazoles - therapeutic use / Peroxisome Proliferator-Activated Receptors - agonists / Peroxisome Proliferator-Activated Receptors - metabolism / Peroxisomes / Risk factors / Thiazolidinediones - therapeutic use