Synthetic (+)-antroquinonol exhibits dual actions against insulin resistance by triggering AMP kinase and inhibiting dipeptidyl peptidase IV activities.

Abstract

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.

• Authors: C Y Hsu, R S Sulake, P-K Huang, H-Y Shih, H-W Sie, Y-K Lai, C Chen, C F Weng
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 1 Pg. 38-49 (Jan 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 24977411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Glucose Transporter Type 4
• Slc2a4 protein, mouse
• Ubiquinone
• Glucagon-Like Peptide 1
• antroquinonol
• Cyclic AMP-Dependent Protein Kinases
• AMP-Activated Protein Kinases
• Dipeptidyl Peptidase 4
• Glucose

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Caco-2 Cells
• Cell Line
• Cell Line, Tumor
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Dipeptidyl Peptidase 4 (metabolism)
• Dipeptidyl-Peptidase IV Inhibitors (chemical synthesis, pharmacology)
• Glucagon-Like Peptide 1 (pharmacology)
• Glucose (metabolism)
• Glucose Tolerance Test
• Glucose Transporter Type 4 (metabolism)
• Humans
• Insulin Resistance
• Mice
• Obesity (metabolism)
• Rats
• Ubiquinone (analogs & derivatives, chemical synthesis, pharmacology)