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

Autor: Tarja Kokkola, Shalem Modi, Nagendra Yaluri
Přispěvatelé: School of Medicine / Clinical Medicine
Rok vydání: 2016
Předmět:
0301 basic medicine
Simvastatin
medicine.medical_specialty
Statin
medicine.drug_class
Glucose uptake
L6 myotubes
Muscle Fibers
Skeletal
Biophysics
030209 endocrinology & metabolism
IR-Dependent IRS-1/PI3K/Akt pathway
Biochemistry
Cell Line
03 medical and health sciences
0302 clinical medicine
Insulin resistance
Glucose transporter 4
Internal medicine
polycyclic compounds
medicine
Animals
Insulin
Phosphorylation
Glycogen synthase
Molecular Biology
Pravastatin
Glucose Transporter Type 4
Glycogen Synthase Kinase 3 beta
biology
nutritional and metabolic diseases
Cell Biology
medicine.disease
Rats
IRS1
Insulin receptor
Cholesterol
Glucose
030104 developmental biology
Endocrinology
biology.protein
lipids (amino acids
peptides
and proteins)
Insulin Resistance
Proto-Oncogene Proteins c-akt
Glycogen
GLUT4
Signal Transduction
medicine.drug
Zdroj: Biochemical and Biophysical Research Communications. 480:194-200
ISSN: 0006-291X
DOI: 10.1016/j.bbrc.2016.10.026
Popis: Article
Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used for the treatment of hypercholesterolemia. Recent data indicates that simvastatin increases the risk of new-onset diabetes by impairing both insulin secretion and insulin sensitivity. However, systematic evaluation of mechanistic pathways is lacking. We aimed to explore the effects of simvastatin on glucose uptake and underlying mechanisms using L6 skeletal muscle myotubes. We performed our experiments at basal and insulin-stimulated conditions, at normal (5.5 mM) and high (16.7 mM) glucose. We showed that simvastatin inhibited glucose uptake at all conditions. We also found out that pravastatin, another widely used statin with different physicochemical properties, did not inhibit glucose uptake. The effect of simvastatin was reversed with geranylgeranyl pyrophosphate but not with farnesyl pyrophosphate, implying that reduced protein geranylgeranylation has a role in simvastatin-induced insulin resistance. Simvastatin also decreased phosphorylation of insulin receptor (IR), insulin receptor substrate 1 (IRS-1), AKT and glycogen synthase kinase 3β (GSK-3β), and downregulated GLUT4. In conclusion, our data indicate that simvastatin decreased both basal and insulin-stimulated glucose uptake through inhibiting the critical steps in IR/IRS-1/AKT signaling cascade, and by hindering GLUT4 function and normal regulation of glycogen synthesis, contributing to insulin resistance.
final draft
http://purl.org/eprint/status/PeerReviewed
Databáze: OpenAIRE
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