Osthole, a potential antidiabetic agent, alleviates hyperglycemia in db/db mice.
Osthole is an agent isolated from Cnidium monnieri (L.) Cusson and Angelica pubescens and has been used to treat several diseases, including metabolic syndromes. To investigate the hypoglycemic effects of osthole in diabetic db/db mice and the underlying mechanisms of these effects by in vitro assay, diabetic db/db mice and cell experiments were utilized to understand its possible effects. Osthole significantly activated both PPARalpha and PPARgamma in a dose-dependent manner based on the results of the transition transfection assay. The activation of PPARalpha and PPARgamma by osthole also resulted in an increase in the expression of PPAR target genes such as PPAR itself, adipose fatty acid-binding protein 2, acyl-CoA synthetases, and carnitine palmitoyltransferase-1A. In vitro results suggested that osthole might be a dual PPARalpha/gamma activator, but its chemical structure differed from that of the thiazolidinedione class of antidiabetic drugs. In addition, osthole markedly activated the AMP-activated protein kinase and its downstream acetyl CoA carboxylase molecules by increasing their phosphorylation levels. Finally, obese diabetic db/db mice were treated with osthole by different administered routes, and osthole was found to markedly reduce blood glucose level. Interestingly, osthole did not reduce the blood insulin or lipid levels, two phenomena that did occur in animals treated with insulin sensitizers like PPAR agonists. These results suggest that osthole can alleviate hyperglycemia and could be potentially developed into a novel drug for treatment of diabetes mellitus.
Liang
Hong-Jen
HJ
Department of Food Science, Yuanpei University, HsinChu, Taiwan.
Suk
Fat-Moon
FM
Wang
Chung-Kwe
CK
Hung
Ling-Fang
LF
Liu
Der-Zen
DZ
Chen
Nai-Qi
NQ
Chen
Yu-Chien
YC
Chang
Chun-Chao
CC
Liang
Yu-Chih
YC
D041721:3T3-L1 Cells; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology / Q000627:therapeutic use*; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction
D003374:Coumarins; D017931:DNA Primers; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase; C046627:osthol