Evidence that metformin ameliorates cellular insulin-resistance by potentiating insulin-induced translocation of glucose transporters to the plasma membrane.
To examine the cellular mechanism of the antihyperglycemic action of metformin we studied the effect of metformin on various functional and molecular parameters involved in the pathogenesis of insulin resistance. Isolated rat adipocytes were incubated with or without metformin (1-100 micrograms/ml) for 2 hours at 37 degrees C followed by an incubation with or without insulin (10 ng/ml). Metformin treatment had no significant effect on basal 3-0 methylglucose uptake. In contrast, Metformin increased insulin-stimulated glucose transport in a dose dependent manner up to 43 +/- 7%. This effect was neither associated with a significant effect of Metformin on trace insulin binding, 1.74 +/- .2% (-M) vs. 1.89 +/- .3% (+M), P greater than 0.05, nor with an effect of metformin on in vivo activation of insulin receptor kinase activity as measured by 32P-incorporation into the 95 kDa beta-subunit of the insulin receptor and an exogenous substrate, histone 2B. Determination of glucose transporter numbers in subcellular membrane fractions, plasma membranes and low-density microsomes, using cytochalasin B binding and immunodetection revealed that metformin's effect to increase insulin-stimulated glucose transport is associated with a potentiation (38 +/- 5%) of insulin-induced translocation of glucose transporters from the intracellular pool to the plasma membrane, while the basal state was not significantly affected. Determination of specific glucose transporter mRNA-levels revealed that this metformin effect is not associated with an increase in glucose transporter gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Matthaei
S
S
Department of Medicine, University-Hospital of Hamburg, FRG.
Greten
H
H
D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015152:Blotting, Northern; D002462:Cell Membrane / Q000187:drug effects; D004357:Drug Synergism; D004587:Electrophoresis, Agar Gel; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000378:metabolism
D007328:Insulin; D012313:RNA; D008687:Metformin; D011972:Receptor, Insulin; D005947:Glucose