Abstract | OBJECTIVE: RESEARCH DESIGN AND METHODS: AMPK phosphorylation was examined in L6 myotubes and LKB1(-/-) cells, with or without the Ca(2+)/calmodulin-dependent protein kinase kinase ( CAMKK) inhibitor STO-609. Oxygen consumption was measured in L6 myotubes and isolated muscle mitochondria. The effect of a BBR derivative, dihydroberberine (dhBBR), on adiposity and glucose metabolism was examined in rodents fed a high-fat diet. RESULTS; We have made the following novel observations: 1) BBR dose-dependently inhibited respiration in L6 myotubes and muscle mitochondria, through a specific effect on respiratory complex I, similar to that observed with metformin and rosiglitazone; 2) activation of AMPK by BBR did not rely on the activity of either LKB1 or CAMKKbeta, consistent with major regulation at the level of the AMPK phosphatase; and 3) a novel BBR derivative, dhBBR, was identified that displayed improved in vivo efficacy in terms of counteracting increased adiposity, tissue triglyceride accumulation, and insulin resistance in high-fat-fed rodents. This effect is likely due to enhanced oral bioavailability. CONCLUSIONS: Complex I of the respiratory chain represents a major target for compounds that improve whole-body insulin sensitivity through increased AMPK activity. The identification of a novel derivative of BBR with improved in vivo efficacy highlights the potential importance of BBR as a novel therapy for the treatment of type 2 diabetes.
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Authors | Nigel Turner, Jing-Ya Li, Alison Gosby, Sabrina W C To, Zhe Cheng, Hiroyuki Miyoshi, Makoto M Taketo, Gregory J Cooney, Edward W Kraegen, David E James, Li-Hong Hu, Jia Li, Ji-Ming Ye |
Journal | Diabetes
(Diabetes)
Vol. 57
Issue 5
Pg. 1414-8
(May 2008)
ISSN: 1939-327X [Electronic] United States |
PMID | 18285556
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Insulin
- Berberine
- dihydroberberine
- Cyclic Nucleotide-Regulated Protein Kinases
- Adenylate Kinase
- Electron Transport Complex I
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Topics |
- Adenylate Kinase
(metabolism)
- Animals
- Berberine
(analogs & derivatives, pharmacology)
- Cyclic Nucleotide-Regulated Protein Kinases
(metabolism)
- Electron Transport Complex I
(antagonists & inhibitors)
- Enzyme Activation
- Insulin
(pharmacology, physiology)
- Male
- Mice
- Mice, Inbred C57BL
- Mitochondria, Muscle
(drug effects, enzymology)
- Phosphorylation
- Rats
- Rats, Wistar
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