title: Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor activator, improves diabetes and other metabolic abnormalities and preserves beta-cell function in db/db mice.
abstract: Muraglitazar, a novel dual (alpha/gamma) 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 (alpha/gamma) 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.
authors.affiliation: Dept. of Metabolic Diseases, HWP-21-2.02, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrity
authors.forename: Dennis
authors.initials: D
authors.lastname: Farrelly
authors.forename: Aaron
authors.initials: A
authors.lastname: Tieman
authors.forename: Cuixia
authors.initials: C
authors.lastname: Chu
authors.forename: Lori
authors.initials: L
authors.lastname: Kunselman
authors.forename: Liqun
authors.initials: L
authors.lastname: Gu
authors.forename: Randolph
authors.initials: R
authors.lastname: Ponticiello
authors.forename: Michael
authors.initials: M
authors.lastname: Cap
authors.forename: Fucheng
authors.initials: F
authors.lastname: Qu
authors.forename: Chunning
authors.initials: C
authors.lastname: Shao
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: William
authors.initials: W
authors.lastname: Fenderson
authors.forename: Sean
authors.initials: S
authors.lastname: Chen
authors.forename: Pratik
authors.initials: P
authors.lastname: Devasthale
authors.forename: Yoon
authors.initials: Y
authors.lastname: Jeon
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Yang
authors.forename: Jimmy
authors.initials: J
authors.lastname: Ren
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.forename: Denis
authors.initials: D
authors.lastname: Ryono
authors.forename: Scott
authors.initials: S
authors.lastname: Biller
authors.forename: Kasim A
authors.initials: KA
authors.lastname: Mookhtiar
authors.forename: John
authors.initials: J
authors.lastname: Wetterau
authors.forename: Richard
authors.initials: R
authors.lastname: Gregg
authors.forename: Peter T
authors.initials: PT
authors.lastname: Cheng
authors.forename: Narayanan
authors.initials: N
authors.lastname: Hariharan
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004032:Diet; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver; D051379:Mice; D009765:Obesity; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010080:Oxazoles; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005998:Glycine; C500085:muraglitazar; D003345:Corticosterone