title: Effects of eugenol on hepatic glucose production and AMPK signaling pathway in hepatocytes and C57BL/6J mice.
abstract: 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.
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Kyong Ju
authors.initials: KJ
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Do Yeon
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Quan
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Jo
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Go Woon
authors.initials: GW
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: suchung@khu.ac.kr.
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Chung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005054:Eugenol / Q000494:pharmacology / Q000627:therapeutic use*; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D019289:Pyruvic Acid / Q000378:metabolism; D011897:Random Allocation
chemical_list: D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D010936:Plant Extracts; D005054:Eugenol; D019289:Pyruvic Acid; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; CREB; Eugenol; Hepatic glucose production; Type 2 diabetes