Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes.
A number of patients with hyperlipidemia are prescribed 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that are concomitantly used along with the treatment of diabetes mellitus. The effects of atorvastatin and pravastatin on insulin-induced glucose uptake and the related signal transduction in 3T3L1 adipocytes were studied. 3T3L1 fibroblasts were differentiated into adipocytes, pretreated with atorvastatin or pravastatin, and then exposed to insulin. Glucose uptake and the amount of insulin signal proteins were measured. Atorvastatin significantly decreased insulin-stimulated 2-deoxyglucose uptake in 3T3L1 adipocytes associated with the prevention of translocation of GLUT4 into the plasma membrane. The amounts of Rab4 and RhoA that required lipid modification with farnesyl or geranylgeranyl pyrophosphate, in the membrane fraction were decreased by atorvastatin. Insulin-induced tyrosine phosphorylation of IRS-1 and serine/threonine phosphorylation of Akt were reduced by atorvastatin. Pravastatin did not modify these insulin-induced changes in the signal transduction. Inhibitors of the RhoA/Rho kinase system, C3 and Y27632, as well as atorvastatin reduced insulin-induced changes in signal transduction. Atorvastatin and pravastatin did not affect messenger RNA expression, protein level, and tyrosine phosphorylation of insulin receptors. In conclusion, hydrophobic atorvastatin decreases the glucose uptake by 3T3L1 adipocytes since it can enter the cell and prevents lipid modification of some proteins that are involved in the insulin signal transduction process.
Takaguri
Akira
A
Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Japan.
Satoh
Kumi
K
Itagaki
Mai
M
Tokumitsu
Yukiko
Y
Ichihara
Kazuo
K
D041721:3T3-L1 Cells; D036002:ADP Ribose Transferases / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000069059:Atorvastatin; D001905:Botulinum Toxins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D010766:Phosphorylation; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017368:Protein Prenylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020695:rab4 GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D048868:Adaptor Proteins, Signal Transducing; D000577:Amides; D051275:Glucose Transporter Type 4; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D011106:Polyisoprenyl Phosphates; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; C108830:Y 27632; D000069059:Atorvastatin; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; C526380:RhoA protein, mouse; D020695:rab4 GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D005947:Glucose; D017035:Pravastatin; C002963:geranylgeranyl pyrophosphate