Effects of metformin on glucose metabolism of perfused rat livers.
Although metformin has been used to treat type 2 diabetes for several decades, the mechanism of its action on glucose metabolism remains controversial. To further assess the effect of metformin on glucose metabolism this work was undertaken to investigate the acute actions of metformin on glycogenolysis, glycolysis, gluconeogenesis, and ureogenesis in perfused rat livers. Metformin (5 mM) inhibited oxygen consumption and increased glycolysis and glycogenolysis in livers from fed rats. In perfused livers of fasted rats, the drug (concentrations higher than 1.0 mM) inhibited oxygen consumption and glucose production from lactate and pyruvate. Gluconeogenesis and ureogenesis from alanine were also inhibited. The cellular levels of ATP were decreased by metformin whereas the AMP levels of livers from fasted rats were increased. Taken together our results indicate that the energy status of the cell is probably compromised by metformin. The antihyperglycemic effect of metformin seems to be the result of a reduced oxidative phosphorylation without direct inhibition of key enzymatic activities of the gluconeogenic pathway. The AMP-activated protein kinase cascade could also be a probable target for metformin, which switches on catabolic pathways such as glycogenolysis and glycolysis, while switches off ATP consuming processes.
Silva
Francielli Maria de Souza
FM
Faculdade Integrado de Campo Mourão, Campo Mourão, Brazil.
da Silva
Mário Henrique Rocha Alves
MH
Bracht
Adelar
A
Eller
Gabrielle Jacklin
GJ
Constantin
Rodrigo Polimeni
RP
Yamamoto
Nair Seiko
NS
D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005215:Fasting; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D050261:Glycogenolysis / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D019518:Postprandial Period; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014508:Urea / Q000378:metabolism
D007004:Hypoglycemic Agents; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D014508:Urea; D008687:Metformin; D005947:Glucose