Simvastatin induces insulin resistance in L6 skeletal muscle myotubes by suppressing insulin signaling, GLUT4 expression and GSK-3β phosphorylation

Yaluri, Nagendra; Modi, Shalem; Kokkola, Tarja

doi:10.1016/j.bbrc.2016.10.026

Cited by 33 publications

(22 citation statements)

References 28 publications

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“…In vitro studies have shown that treatment of rat skeletal muscle myotubes with simvastatin can reduce the expression of GLUT4. 25 Here, we report similar protein levels of both GLUT4 and HKII in all three groups suggesting no connection between statin-induced myalgia and the expression of these proteins.…”

Section: Discussionsupporting

confidence: 47%

Glucose homeostasis in statin users—The LIFESTAT study

Morville

Dohlmann

Kuhlman

et al. 2018

Diabetes Metabolism Res

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Background Statins are widely used to lower cholesterol concentrations in both primary and secondary prevention of cardiovascular disease. The treatment increases the risk of muscle pain (myalgia) and of type 2 diabetes. However, the underlying mechanisms remain disputed. Methods We investigated whether statin induced myalgia is coupled to impaired glucose homeostasis using oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), and the hyperinsulinemic euglycemic clamp. We performed a cross‐sectional study of statin users without CVD (primary prevention) stratified into a statin myalgic (M; n = 25) and a non‐myalgic (NM; n = 39) group as well as a control group (C; n = 20) consisting of non‐statin users. Results A reduction in the insulin secretion rate during the OGTT was observed in the myalgic group compared with the non‐myalgic group (AUC ISROGTT, C: 1032 (683 ‐ 1500); M: 922 (678 ‐ 1091); NM: 1089 (933 ‐ 1391) pmol·L−1·min (median with 25%‐75% percentiles), but no other measurements indicated impaired β‐cell function. We found no other differences between the three groups for other measurements in the OGTT, IVGTT, and euglycemic clamp. Muscle protein content of GLUT4 and hexokinase II was similar between the three groups. Conclusions We conclude that statin users in primary prevention experiencing myalgia do not have impaired glucose homeostasis compared with other statin users or non‐users. We consider this an important aspect in the dialogue between physician and patient regarding statin treatment and adverse effects.

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Section: Discussionsupporting

confidence: 47%

Glucose homeostasis in statin users—The LIFESTAT study

Morville

Dohlmann

Kuhlman

et al. 2018

Diabetes Metabolism Res

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“…In support of a role for a statin-induced insulin resistance in skeletal muscle, a decreased GLUT-4 expression has been found in L6 myotubes after simvastatin treatment [107]. Alternatively, it has been more recently shown that atorvastatin diminishes GLUT-4 translocation to the plasma membrane without affecting total GLUT-4 protein expression in C2C12 myotubes [108].…”

Section: Skeletal Musclementioning

confidence: 99%

Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

Galicia-García

Jebari

Larrea-Sebal

et al. 2020

IJMS

101

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Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.

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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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Simvastatin induces insulin resistance in L6 skeletal muscle myotubes by suppressing insulin signaling, GLUT4 expression and GSK-3β phosphorylation

Cited by 33 publications

References 28 publications

Glucose homeostasis in statin users—The LIFESTAT study

Glucose homeostasis in statin users—The LIFESTAT study

Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

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

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