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Synthetic (+)‐antroquinonol exhibits dual actions against insulin resistance by triggering AMP kinase and inhibiting dipeptidyl peptidase IV activities
Author(s) -
Hsu C Y,
Sulake R S,
Huang PK,
Shih HY,
Sie HW,
Lai YK,
Chen C,
Weng C F
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12828
Subject(s) - glut4 , ampk , endocrinology , medicine , insulin resistance , glucose uptake , insulin , protein kinase b , sitagliptin , glucose transporter , protein kinase a , chemistry , dipeptidyl peptidase 4 , insulin receptor , kinase , biology , biochemistry , phosphorylation , diabetes mellitus , type 2 diabetes , metformin
Background and Purpose The fungal product (+)‐antroquinonol activates AMP kinase (AMPK) activity in cancer cell lines. The present study was conducted to examine whether chemically synthesized (+)‐antroquinonol exhibited beneficial metabolic effects in insulin‐resistant states by activating AMPK and inhibiting dipeptidyl peptidase IV ( DPP IV ) activity. Experimental Approach Effects of (+)‐antroquinonol on DPP IV activity were measured with a DPPIV Assay Kit and effects on GLP ‐1‐induced PKA were measured in AR42J cells. Translocation of the glucose transporter 4, GLUT4, induced either by insulin‐dependent PI3K / AKT signalling or by insulin‐independent AMPK activation, was assayed in differentiated myotubes. Glucose uptake and GLUT4 translocation were assayed in L6 myocytes. Mice with diet‐induced obesity were used to assess effects of acute and chronic treatment with (+)‐antroquinonol on glycaemic control in vivo . Key Results The results showed that of (+)‐antroquinonol (100 μM ) inhibited the DPP IV activity as effectively as the clinically used inhibitor, sitagliptin. The phosphorylation of AMPK Thr 172 in differentiated myotubes was significantly increased by (+)‐antroquinonol. In cells simultaneously treated with S961 (insulin receptor antagonist), insulin and (+)‐antroquinonol, the combination of (+)‐antroquinonol plus insulin still increased both GLUT4 translocation and glucose uptake. Further, (+)‐antroquinonol and sitagliptin reduced blood glucose, when given acutely or chronically to DIO mice. Conclusions and Implications Chemically synthesized (+)‐antroquinonol exhibits dual effects to ameliorate insulin resistance, by increasing AMPK activity and GLUT4 translocation, along with inhibiting DPP IV activity.