Effects of Atorvastatin and Pravastatin on Signal Transduction Related to Glucose Uptake in 3T3L1 Adipocytes

Abstract

Abstract. 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.

Statins and the Risk of Diabetes: Evidence From a Large Population-Based Cohort Study

“…External adjustment was performed by means of Monte Carlo sensitivity analysis. Adjusted estimates were obtained by means of setting 1) the prevalence of obesity among statin users to 37.5% (12); 2) the risk of diabetes in obese patients to threefold higher than in normal weight patients (25); and 3) the odds of obese patients in the highest PDC category from twofold lower to twofold higher than that of normal weight patients (26,27 Author Contributions. G.C.…”

“…Atorvastatin and simvastatin have been shown to decrease glucose uptake in adipocyte cell lines (26) and insulin sensitivity (27), respectively. Simvastatin and atorvastatin have been shown to decrease insulin secretion in b-cells (28).…”

“…Simvastatin and atorvastatin have been shown to decrease insulin secretion in b-cells (28). The inhibition of isoprenoid synthesis may explain some of the observed dysglycemic effects of statins (26). Finally, it has been hypothesized that statins may influence muscle or liver insulin sensitivity directly, but there is no specific experimental evidence to support this hypothesis (29).…”

Inhibition of the TNF-α^|^ndash;Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR

“…Mouse 3T3L1 fibroblasts were obtained from Health Science Research Resources Bank (Osaka) and were maintained in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS in an atmosphere of 10% CO 2 at 37°C (20). Three days after the fibroblasts had reached confluence, differentiation was induced by treating the cells with DMEM containing 100 mU/mL insulin, 0.5 mM IBMX, and 250 nM dexamethasone and 10% FBS for 3 days.…”

Gene Expression Profile of Dental Pulp Cells During Differentiation Into an Adipocyte Lineage

“…Remarkably, the expression of adiponectin increased by more than 1000-fold at 2 weeks after induction. Insulin is known to promote adipocyte differentiation by activating PI-3-kinase and Akt activity (34), but in our experimental system, insulin was added 1 -2 weeks after starting induction. Therefore, the expression of adiponectin was probably delayed.…”