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: Soo Jung Kim, Hai Yan Quan, Kyong Ju Jeong, Do Yeon Kim, Go woon Kim, Hee Kyung Jo, Sung Hyun Chung
• Journal: Journal of agricultural and food chemistry (J Agric Food Chem) Vol. 62 Issue 2 Pg. 434-42 (Jan 15 2014) ISSN: 1520-5118 [Electronic] United States
• PMID: 24354358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CREB1 protein, human
• Cyclic AMP Response Element-Binding Protein
• Enzyme Inhibitors
• Hypoglycemic Agents
• Pentacyclic Triterpenes
• Triterpenes
• Calcium-Calmodulin-Dependent Protein Kinase Kinase
• AMP-Activated Protein Kinases
• Glucose
• Betulinic Acid

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (antagonists & inhibitors, metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Diabetes Mellitus, Type 2 (drug therapy)
• Diet, High-Fat
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Gluconeogenesis (drug effects, genetics)
• Glucose (biosynthesis)
• Hep G2 Cells
• Humans
• Hyperglycemia (drug therapy)
• Hypoglycemic Agents (pharmacology)
• Liver (drug effects, metabolism)
• Mice
• Mice, Inbred ICR
• Pentacyclic Triterpenes
• Phosphorylation (drug effects)
• Signal Transduction (drug effects)
• Triterpenes (pharmacology)
• Betulinic Acid