Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action.
OBJECTIVE
Berberine (BBR) activates AMP-activated protein kinase (AMPK) and improves insulin sensitivity in rodent models of insulin resistance. We investigated the mechanism of activation of AMPK by BBR and explored whether derivatization of BBR could improve its in vivo efficacy.


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.
Turner
Nigel
N
Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, Sydney, New South Wales 2010, Australia.
Li
Jing-Ya
JY
Gosby
Alison
A
To
Sabrina W C
SW
Cheng
Zhe
Z
Miyoshi
Hiroyuki
H
Taketo
Makoto M
MM
Cooney
Gregory J
GJ
Kraegen
Edward W
EW
James
David E
DE
Hu
Li-Hong
LH
Li
Jia
J
Ye
Ji-Ming
JM
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017867:Cyclic Nucleotide-Regulated Protein Kinases / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar
D007328:Insulin; D001599:Berberine; C039639:dihydroberberine; D017867:Cyclic Nucleotide-Regulated Protein Kinases; D000263:Adenylate Kinase; D042967:Electron Transport Complex I