Mechanisms of metformin action on glucose transport and metabolism in human adipocytes.
The mechanisms of metformin effects on glucose transport and metabolism were investigated in human adipocytes. Human preadipocytes obtained from surgical biopsies were differentiated in vitro into adipocytes and the effects of metformin on glucose uptake, glucose oxidation and the involved signaling pathways were analyzed. Metformin (1mM, 24h) increased glucose uptake 2.3±0.2-fold (p<0.001 vs. basal) in human adipocytes, without altering cell viability and oxygen consumption. Metformin did not alter GLUT-1 mRNA expression and protein content but increased GLUT-4 mRNA expression and cellular protein content, leading to increased GLUT-4 protein content in the plasma membrane. Neither basal nor insulin-induced phosphorylation of Akt at Ser-473 and AS160 (Akt substrate of 160kDa) at Thr-642 were enhanced by metformin. Suppression of metformin-induced AMP-activated protein kinase (AMPK) activity by AMPKα1 silencing, however, reduced metformin-associated GLUT-4 expression and stimulation of glucose uptake. In addition, metformin induced glucose oxidation. In conclusion, activation of AMPKα1 without impairment of cell respiration is crucial for metformin-mediated increase in GLUT-4 protein content and glucose uptake in human adipocytes.
Grisouard
Jean
J
Department of Biomedicine, Metabolism Group, Div. of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Basel, CH-4031 Basel, Switzerland. jean.grisouard@unibas.ch
Timper
Katharina
K
Radimerski
Tanja M
TM
Frey
Daniel M
DM
Peterli
Ralph
R
Kola
Blerina
B
Korbonits
Márta
M
Herrmann
Paul
P
Krähenbühl
Stephan
S
Zulewski
Henryk
H
Keller
Ulrich
U
Müller
Beat
B
Christ-Crain
Mirjam
M
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008875:Middle Aged; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D051275:Glucose Transporter Type 4; D008687:Metformin; D005947:Glucose