Diphenylene iodonium stimulates glucose uptake in skeletal muscle cells through mitochondrial complex I inhibition and activation of AMP-activated protein kinase.
NADPH oxidase inhibitors such as diphenylene iodonium (DPI) and apocynin lower whole body and blood glucose levels and improve diabetes when administered to rodents. Skeletal muscle has an important role in managing glucose homeostasis and we have used L6 cells, C(2)C(12) cells and primary muscle cells as model systems to investigate whether these drugs regulate glucose uptake in skeletal muscle cells. The data presented in this study show that apocynin does not affect glucose uptake in skeletal muscle cells in culture. Tat gp91ds, a chimeric peptide that inhibits NADPH oxidase activity, also failed to affect glucose uptake and we found no significant evidence of NADPH oxidase (subunits tested were Nox4, p22phox, gp91phox and p47phox mRNA) in skeletal muscle cells in culture. However, DPI increases basal and insulin-stimulated glucose uptake in L6 cells, C(2)C(12) cells and primary muscle cells. Detailed studies on L6 cells demonstrate that the increase of glucose uptake is via a mechanism independent of phosphoinositide-3 kinase (PI3K)/Akt but dependent on AMP-activated protein kinase (AMPK). We postulate that DPI through inhibition of mitochondrial complex 1 and decreases in oxygen consumption, leading to decreases of ATP and activation of AMPK, stimulates glucose uptake in skeletal muscle cells.
Hutchinson
Dana S
DS
Department of Physiology, Arrhenius Laboratories F3, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden. dana.hutchinson@med.monash.edu.au
Csikasz
Robert I
RI
Yamamoto
Daniel L
DL
Shabalina
Irina G
IG
Wikström
Per
P
Wilcke
Mona
M
Bengtsson
Tore
T
D055372:AMP-Activated Protein Kinases; D000098:Acetophenones / Q000494:pharmacology; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002454:Cell Differentiation / Q000187:drug effects; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism
D055372:AMP-Activated Protein Kinases; D000098:Acetophenones; D000103:Acetyl-CoA Carboxylase; D000255:Adenosine Triphosphate; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors; D005947:Glucose; D006003:Glycogen; D038362:Glycogen Synthase Kinase 3; D006023:Glycoproteins; D009097:Multienzyme Complexes; D019255:NADPH Oxidases; D009861:Onium Compounds; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D012694:Serine; C473031:gp91ds-tat protein, chimeric; C007517:diphenyleneiodonium; C056165:acetovanillone