Eugenol is a phenylpropanoid with many pharmacological activities, but its anti-hyperglycemic activity is not yet fully explored. For in vitro study, HepG2 cells and primary rat hepatocytes were used, and
glucose production was induced by adding 100 nM of
glucagon in the presence of gluconeogenic substrates. In animal study,
hyperglycemia was induced by high fat diet (HFD) in male C57BL/6J mice, and
eugenol was orally administered at 20 or 40 mg per kg (E20, E40) for 15 weeks.
Eugenol significantly inhibited
glucagon-induced
glucose production and phosphorylated AMPK in the HepG2 and primary rat hepatocytes, and these effects were reversed in the presence of compound C (an AMPK inhibitor) or
STO-609 (a
CAMKK inhibitor). In addition, the
protein and gene expression levels of CREB, CRTC2·CREB complex, PGC-1α, PEPCK and G6Pase were all significantly suppressed. Moreover, inhibition of AMPK by over-expression of dominant negative AMPK prevented
eugenol from suppressions of gluconeogenic gene expression and hepatic
glucose production. In animal study, plasma
glucose and
insulin levels of the E40 group were decreased by 31% and 63%, respectively, when compared to those of HFD control. In
pyruvate tolerance tests,
pyruvate-induced
glucose excursions were decreased, indicating that the anti-hyperglycemic activity of
eugenol is primarily due to the suppression of hepatic gluconeogenesis. In summary,
eugenol effectively ameliorates
hyperglycemia through inhibition of hepatic gluconeogenesis via modulating
CAMKK-AMPK-CREB signaling pathway.
Eugenol or
eugenol-containing medicinal plants could represent a promising therapeutic agent to prevent
type 2 diabetes.