Metformin interaction with insulin-regulated glucose uptake, using the Xenopus laevis oocyte model expressing the mammalian transporter GLUT4.
The primary goal of this work was to better define, in molecular terms, the impact of metformin on hexose carriers. The methodology consisted of determining the zero-trans kinetics of 2-deoxy-D-glucose uptake for the mammalian insulin-sensitive glucose transporter (GLUT4) expressed in Xenopus laevis oocytes. These cells possessed the specialized protein and, when treated with insulin (2 microM) plus metformin (20 microM), showed a markedly enhanced hexose transport activity (2.4-fold increase over basal) as compared to that of cells incubated in the presence of insulin alone (1.8-fold increase over basal). Kinetic analysis of this process revealed that insulin induced a similar response to that observed for the native carrier, i.e., a higher Vmax. When metformin was added together with insulin, we mainly recorded a significant decrease in apparent Km for the sugar transported, Vmax being only marginally modified. Parathyroid hormone (PTH), which is known to impair the intrinsic activity of GLUT4, prevented the stimulatory effect of metformin in both kinds of oocytes whereas cytochalasin D, which interferes with the translocation of carriers, was without effect. These results suggest that metformin combined with insulin can maintain glucose homeostasis by increasing the catalytic activity of some hexose carriers or by improving the affinity of GLUT4 for glucose.
Detaille
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Laboratory of Comparative Biochemistry and Physiology, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium. dominique.detaille@fundp.ac.be
Wiernsperger
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Devos
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D019325:3-O-Methylglucose / Q000493:pharmacokinetics; D000818:Animals; D015638:Cytochalasin D / Q000494:pharmacology; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D005947:Glucose / Q000493:pharmacokinetics*; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D009004:Monosaccharide Transport Proteins / Q000235:genetics* / Q000502:physiology; D009124:Muscle Proteins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology; D051381:Rats; D014982:Xenopus laevis
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D010281:Parathyroid Hormone; C495694:Slc2a4 protein, rat; D019325:3-O-Methylglucose; D015638:Cytochalasin D; D008687:Metformin; D003847:Deoxyglucose; D005947:Glucose