Enhancement of muscle cell glucose uptake by medicinal plant species of Canada's native populations is mediated by a common, metformin-like mechanism.
OBJECTIVE
The purpose of the present study was to elucidate the mechanisms of action mediating enhancement of basal glucose uptake in skeletal muscle cells by seven medicinal plant products recently identified from the pharmacopeia of native Canadian populations (Spoor et al., 2006).


METHODS
Activity of the major signaling pathways that regulate glucose uptake was assessed by western immunoblot in C2C12 muscle cells treated with extracts from these plant species. Effects of extracts on mitochondrial function were assessed by respirometry in isolated rat liver mitochondria. Metabolic stress induced by extracts was assessed by measuring ATP concentration and rate of cell medium acidification in C2C12 myotubes and H4IIE hepatocytes. Extracts were applied at a dose of 15-100 microg/ml.


RESULTS
The effect of all seven products was achieved through a common mechanism mediated not by the insulin signaling pathway but rather by the AMP-activated protein kinase (AMPK) pathway in response to the disruption of mitochondrial function and ensuing metabolic stress. Disruption of mitochondrial function occurred in the form of uncoupling of oxidative phosphorylation and/or inhibition of ATPsynthase. Activity of the AMPK pathway, in some instances comparable to that stimulated by 4mM of the AMP-mimetic AICAR, was in several cases sustained for at least 18h post-treatment. Duration of metabolic stress, however, was in most cases in the order of 1h.


CONCLUSIONS
The mechanism common to the seven products studied here is analogous to that of the antidiabetic drug Metformin. Of interest is the observation that metabolic stress need not be sustained in order to induce important adaptive responses. The results support the use of these products as culturally adapted treatments for insulin resistance and hyperglycemia in susceptible aboriginal populations where adherence to modern diabetes pharmaceuticals is an issue. The mechanism reported here may be widespread and mediate the antidiabetic activity of traditional remedies from various other cultures.
Martineau
Louis C
LC
Natural Health Products and Metabolic Diseases Laboratory, Dept of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.
Adeyiwola-Spoor
Danielle C A
DC
Vallerand
Diane
D
Afshar
Arvind
A
Arnason
John T
JT
Haddad
Pierre S
PS
D000818:Animals; D002170:Canada; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D024301:Plant Bark; D010946:Plants, Medicinal; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D008687:Metformin; D005947:Glucose