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

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

Abbreviations: 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

Muraglitazar, a novel dual (/) 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 (/) 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.

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