Simvastatin inhibits glucose uptake activity and GLUT4 translocation through suppression of the IR/IRS-1/Akt signaling in C2C12 myotubes

Li, Weihua; Liang, Xiubo; Zeng, Zhipeng; Yu, Kaizhen; Zhan, Shaopeng; Su, Qiang; Yan, Yinzhi; Mansai, Huseen; Qiao, Weitong; Yang, Qi; Qi, Zhongquan; Huang, Zhengrong

doi:10.1016/j.biopha.2016.06.029

Cited by 45 publications

(36 citation statements)

References 35 publications

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“…Expression of the glucose transporter GLUT1 was not changed, whereas insulin-responsive GLUT4 was significantly reduced following short-term fluvastatin treatment ( Figures S4I and S4J). The inhibitory effect of statins on GLUT4 expression has already been described in different cell types and tissues (Jiang et al, 2016;Li et al, 2016;Nakata et al, 2006). Short-term fluvastatin therapy had no effect on FDG uptake in the supraclavicular BAT depot ( Figure 3W).…”

Section: Statins Reduce Thermogenic Gene Expression In Human Batmentioning

confidence: 90%

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

Baláž¹,

Becker²,

Balážová³

et al. 2019

Cell Metabolism

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Correspondence matthias.betz@usb.ch (M.J.B.), irene.burger@usz.ch (I.A.B.), christian-wolfrum@ethz.ch (C.W.) In Brief Through genetic and pharmacological in vivo and in vitro approaches, Balaz et al. show that the mevalonate pathway is important for adipocyte browning. The importance of this pathway is supported by a retrospective clinical study and a small volunteer trial with fluvastatin. The authors identify geranylgeranyl pyrophosphate as the key mevalonate intermediate driving adipocyte browning. SUMMARYRecent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modu-lating brown adipocyte functionality and systemic metabolism.

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Section: Statins Reduce Thermogenic Gene Expression In Human Batmentioning

confidence: 90%

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

Baláž¹,

Becker²,

Balážová³

et al. 2019

Cell Metabolism

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“…The prominent example is simvastatin, which is commonly used in the prevention and treatment of cardiovascular diseases. Simvastatin reduces the phosphorylation of insulin-induced IR at Tyr, IRS-1 at Tyr, and AKT at Thr [22,23]. Therefore, therapy with simvastatin or other statins might be a risk factor for the development of insulin resistance or diabetes.…”

Section: Irs Protein Nodementioning

confidence: 99%

Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake

Świderska¹,

Strycharz²,

Wróblewski³

et al. 2020

Blood Glucose Levels

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Glucose uptake is regulated by several mechanisms, where insulin plays the most prominent role. This powerful anabolic hormone regulates the transport of glucose into the cell through translocation of glucose transporter from an intracellular pool to the plasma membrane mainly in metabolically active tissues like skeletal muscles, adipose tissue, or liver (GLUT4). This translocation occurs through multiple steps of PI3K/AKT signaling pathway. In this chapter, we will focus on molecular events leading to GLUT4 translocation, starting with activation of insulin receptors through signaling cascade involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) and finally, the action of their effectors. We will present regulatory mechanisms and modulators of insulin-mediated glucose uptake.

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“…There is now a wealth of evidence that IRS-AKT-GLUT4 signal pathway plays an important role in the development of insulin resistance in obese animal models 40,42 . In the present study, we demonstrated that administration with trilobatin alleviated obesity-induced insulin resistance by decreasing the levels of fasting blood glucose and insulin, improving glucose tolerance, and these bene cial effects were associated with trilobatin ameliorating the defects of IRS and AKT phosphorylation, recovering the translocation of GLUT4 in ob/ob mice.…”

Section: Resultsmentioning

confidence: 99%

“…It has been widely reported that GLUT4, mainly expressed in skeletal muscle and white adipose tissue, plays an important role in insulin-induced glucose uptake 38,40 . In these tissues, insulin induced the phosphorylation of IRS by binding to its tyrosine receptor.…”

Section: Discussionmentioning

confidence: 99%

Trilobatin Ameliorates Insulin Resistance through IRS-AKT-GLUT4 Signaling Pathway in C2C12 Myotubes and ob/ob Mice

Liu

Wang

et al. 2020

Preprint

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Background: Trilobatin, a natural compound, has been found to exhibit anti-diabetic properties in high-fat diet (HFD) and streptozotocin (STZ) induced type 2 diabetic mice. But up to now no research has been reported on the effect of trilobatin on insulin resistance in peripheral tissues. Herein, we determined the effects of trilobatin on insulin resistance in palmitate-treated C2C12 myotubes and ob/ob mice.Methods: 8-10 weeks of male ob/ob mice and same background C57BL/6 mice were used to evaluate the role of trilobatin on insulin resistance; Protein expression and phosphorylation were measured by western blot; Glucose uptake was determined a fluorescent test.Results: treatment with trilobatin prevented palmitate-induced insulin resistance by enhancing glucose uptake and the phosphorylation of IRS1 and AKT, recovered the translocation of GLUT4 from cytoplasm to membrane, but preincubation with LY294002, an inhibitor of PI3K, blocked the effects of trilobatin on glucose uptake and the distribution of GLUT4 in C2C12 myotubes. Furthermore, administration with trilobatin for 4 weeks significantly improved insulin resistance by decreasing fasting blood glucose and insulin in serum, enhancing the phosphorylation of IRS1 and AKT, and recovering the expression and translocation of GLUT4 in ob/ob mice.Conclusions: IRS-AKT-GLUT4 signaling pathway might be involved in trilobatin ameliorating insulin resistance in skeletal muscle of obese animal models.

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Simvastatin inhibits glucose uptake activity and GLUT4 translocation through suppression of the IR/IRS-1/Akt signaling in C2C12 myotubes

Cited by 45 publications

References 35 publications

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake

Trilobatin Ameliorates Insulin Resistance through IRS-AKT-GLUT4 Signaling Pathway in C2C12 Myotubes and ob/ob Mice

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