Metformin reverses hexokinase and 6-phosphofructo-1-kinase inhibition in skeletal muscle, liver and adipose tissues from streptozotocin-induced diabetic mouse.
The present work describes the effects of metformin on hexokinase (HK) and phosphofructokinase (PFK) activities and localization in different tissues from streptozotocin-induced diabetic mice. Diabetic mice present lower HK and PFK activities (50%) in skeletal muscle, liver and adipose tissue, as compared with control (P<0.05). Treatment with 250 mg/kg metformin reverses this pattern of enzyme inhibition with concomitant reversal of hyperglycemia and hypolactacidemia. Furthermore, the treatment increases the cytoskeleton-associated PFK activity in skeletal muscle; this activity has been described as an important mechanism for the enzyme activation. This effect might be due to the increased phosphorylation of serine residues in the enzyme, a modification which has been described to increase the interaction of PFK with f-actin. The current work supports the hypothesis that metformin hypoglycemic effects involve the activation of glycolysis through its regulatory enzymes, which may be potential targets for the development of new hypoglycemic drugs.
Da Silva
Daniel
D
Laboratório de Enzimologia e Controle do Metabolismo-LabECoM, Faculdade de Farmácia, UFRJ, Brazil.
Zancan
Patricia
P
Coelho
Wagner Santos
WS
Gomez
Lilian Sales
LS
Sola-Penna
Mauro
M
D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D015195:Drug Design; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000378:metabolism*; D007003:Hypoglycemia / Q000188:drug therapy; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010732:Phosphofructokinase-1 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
D008687:Metformin; D006593:Hexokinase; D010732:Phosphofructokinase-1