Metformin-induced regulation of the intestinal D-glucose transporters.
Metformin is an orally administered drug that lowers blood glucose and improves insulin sensitivity in patients with non insulin-dependent diabetes. Although the antihyperglycemic effect of metformin has been extensively studied, its cellular mechanism(s) of action (including the effect on enterocyte) remains to be defined. This study was designed to examine the effect of metformin on glucose transporters in enterocyte. Na(+)-dependent glucose transporter-1 (SGLT-1) activity was followed as glucose-induced short-circuit current (Isc) in Ussing chambers. The effect of metformin (10 micromol/L, 3 min) on transmural glucose transport was studied in isolated rat jejunal loops. Its impact on abundance of transporters SGLT-1 and GLUT2 in jejunal brush border membranes (BBM) and its effect on the phosphorylation of AMP-activated protein kinase (AMPK) alpha2 subunit was studied by western blot. Acute effect of metformin was also measured in vivo by oral glucose tolerance test (OGTT). Metformin markedly inhibited glucose-induced Isc (approximately 77%) after mucosal addition. In addition, metformin reduced the glucose-induced abundance of SGLT-1 in BBM and increased those of GLUT2, concomitantly increasing the phosphorylation of intracellular AMPKalpha2. This effect of metformin was also observed using non-metabolizable sugar alpha3-O-methyl glucose. Transmural glucose transport measured in vitro was increased by 22% under metformin. Finally, oral metformin markedly increased glucose tolerance in OGTT. In conclusion, metformin slightly increases intestinal glucose absorption by inducing a re-distribution of glucose transporters in BBM through AMPK control in enterocyte. In addition to its action to other splanchnic tissues, this could constitute a peripheral signal contributing to the beneficial effect of metformin on glucose tolerance.
Sakar
Y
Y
Institut National de la Sante et de la Recherche Medicale U773, Centre de Recherche Biomedicale Bichat-Beaujon, CRB3, Paris, France.
Meddah
B
B
Faouzi
My A
MA
Cherrah
Y
Y
Bado
A
A
Ducroc
R
R
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2 / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000378:metabolism / Q000494:pharmacology*; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism*
D051273:Glucose Transporter Type 2; D007004:Hypoglycemic Agents; D011720:Pyrazoles; D011743:Pyrimidines; C495683:Slc2a2 protein, rat; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; C516138:dorsomorphin; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005947:Glucose