Resveratrol enhances GLUT-4 translocation to the caveolar lipid raft fractions through AMPK/Akt/eNOS signalling pathway in diabetic myocardium.
Homeostasis of blood glucose by insulin involves stimulation of glucose uptake by translocation of glucose transporter Glut-4 from intracellular pool to the caveolar membrane system. In this study we examined resveratrol (RSV)-mediated Glut-4 translocation in the streptozotocin (STZ)-induced diabetic myocardium. The rats were randomized into three groups: Control (Con), Diabetes Mellitus (DM) (STZ 65 mg/kg b.w., i.p.) & DM+RSV (2.5 mg/kg b.wt. for 2 weeks orally) (RSV). Isolated rat hearts were used as per the experimental model. RSV induced glucose uptake was observed in vitro with H9c2 cardiac myoblast cells. Decreased blood glucose level was observed after 30 days (375 mg/dl) in RSV-treated rats when compared to DM (587 mg/dl). Treatment with RSV demonstrated increased Adenosine Mono Phosphate Kinase (AMPK) phosphorylation compared to DM. Lipid raft fractions demonstrated decreased expression of Glut-4, Cav-3 (0.4, 0.6-fold) in DM which was increased to 0.75- and 1.1-fold on RSV treatment as compared to control. Increased Cav-1 expression (1.4-fold) in DM was reduced to 0.7-fold on RSV treatment. Increased phosphorylation of endothelial Nitric Oxide Synthase (eNOS) & Akt was also observed in RSV compared to DM (P<0.05). Confocal microscopy and coimmunoprecipitation studies demonstrated decreased association of Glut-4/Cav-3 and increased association of Cav-1/eNOS in DM as compared to control and converse results were obtained on RSV treatment. Our results suggests that the effect of RSV is non-insulin dependent and triggers some of the similar intracellular insulin signalling components in myocardium such as eNOS, Akt through AMPK pathway and also by regulating the caveolin-1 and caveolin-3 status that might play an essential role in Glut-4 translocation and glucose uptake in STZ- induced type-1 diabetic myocardium.
Penumathsa
S Varma
SV
Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030-1110, USA.
Thirunavukkarasu
M
M
Zhan
L
L
Maulik
G
G
Menon
V P
VP
Bagchi
D
D
Maulik
N
N
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D021941:Caveolae / Q000187:drug effects* / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism; D051244:Caveolin 3 / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*
D001786:Blood Glucose; C495537:Cav1 protein, rat; C495549:Cav3 protein, rat; D051242:Caveolin 1; D051244:Caveolin 3; D051275:Glucose Transporter Type 4; C495694:Slc2a4 protein, rat; D013267:Stilbenes; D003847:Deoxyglucose; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol