title: Beneficial effect of betulinic acid on hyperglycemia via suppression of hepatic glucose production.
abstract: The inhibitory effect of betulinic acid (BA) on hepatic glucose production was examined in HepG2 cells and high fat diet (HFD)-fed ICR mice. BA significantly inhibited the hepatic glucose production (HGP) and gene expression levels of PGC-1α, PEPCK, and G6Pase. BA activated AMPK and suppressed the expression level of phosphorylated CREB. These effects were all abolished in the presence of compound C (an AMPK inhibitor). Moreover, inhibition of AMPK by overexpression of dominant negative AMPK prevented BA from suppression of HGP, indicating that the inhibitory effect of BA on HGP is AMPK-dependent. In addition, BA markedly phosphorylated CAMKK, and phosphorylation of AMPK and ACC, and suppression of HGP were all reversed in the presence of STO-609 (a CAMKK inhibitor), suggesting that CAMKK is an upstream kinase for AMPK. In an animal study, HFD-fed ICR mice were orally administered with 5 or 10 mg of BA per kg (B5 and B10) for three weeks. Plasma glucose, triglyceride, and the insulin resistance index of the B10 group were decreased by 34%, 59%, and 38%, respectively. In a pyruvate tolerance test, pyruvate-induced glucose excursion was decreased by 27% when mice were pretreated with 10 mg/kg of BA. In summary, BA effectively ameliorates hyperglycemia through inhibition of hepatic gluconeogenesis via modulating the CAMKK-AMPK-CREB signaling pathway.
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University , 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hai Yan
authors.initials: HY
authors.lastname: Quan
authors.forename: Kyong Ju
authors.initials: KJ
authors.lastname: Jeong
authors.forename: Do Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Go woon
authors.initials: Gw
authors.lastname: Kim
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Jo
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Chung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D059305:Diet, High-Fat; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000096:biosynthesis*; D056945:Hep G2 Cells; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000094062:Betulinic Acid
keywords: AMPK; CREB; betulinic acid; hepatic glucose production; type 2 diabetes