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.
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.
Harrity
Thomas
T
Dept. of Metabolic Diseases, HWP-21-2.02, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Farrelly
Dennis
D
Tieman
Aaron
A
Chu
Cuixia
C
Kunselman
Lori
L
Gu
Liqun
L
Ponticiello
Randolph
R
Cap
Michael
M
Qu
Fucheng
F
Shao
Chunning
C
Wang
Wei
W
Zhang
Hao
H
Fenderson
William
W
Chen
Sean
S
Devasthale
Pratik
P
Jeon
Yoon
Y
Seethala
Ramakrishna
R
Yang
Wen-Pin
WP
Ren
Jimmy
J
Zhou
Min
M
Ryono
Denis
D
Biller
Scott
S
Mookhtiar
Kasim A
KA
Wetterau
John
J
Gregg
Richard
R
Cheng
Peter T
PT
Hariharan
Narayanan
N
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
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