Anti-diabetic effects of a phenolic-rich extract from Hypericum attenuatum Choisy in KK-Ay mice mediated through AMPK /PI3K/Akt/GSK3β signaling and GLUT4, PPARγ, and PPARα expression

Abstract In this study, we investigated anti-diabetic activities of a phenolic-rich extract from Hypericum attenuatum Choisy (HA-PRE). In vivo, 4-week treatment of HA-PRE improved hyperglycemia, obesity, glucose tolerance, and hyperinsulinism. Western blot analysis revealed that HA-PRE increased AMPKα and Akt phosphorylation in skeletal muscle, liver and white adipose tissue (WAT); increased GSK3β phosphorylation in skeletal muscle and liver; and enhanced GLUT4 expression in WAT and skeletal muscle. HA-PRE reduced PPARγ expression, increased PPARα expression, and enhanced ACC phosphorylation in liver and WAT. In vitro, HA-PRE enhanced glucose uptake. Mechanisms analysis revealed that HA-PRE increased GLUT4, p-AMPKα, p-Akt, and p-GSK3β expression in L6 myotubes. Moreover, Compound C, an AMPK inhibitor, partly inhibited these effects. Wortmannin, a PI3K inhibitor, inhibited HA-PRE-stimulated Akt phosphorylation and GSK3β phosphorylation, but had no effects on AMPKα phosphorylation. Taken together, these findings indicate that HA-PRE alleviate diabetes through AMPK/PI3K/Akt/GSK3β and regulating GLUT4, PPARα, and PPARγ expression.