TY - JOUR

T1 - Simvastatin-Induced Insulin Resistance May Be Linked to Decreased Lipid Uptake and Lipid Synthesis in Human Skeletal Muscle

T2 - the LIFESTAT Study

AU - Larsen, Steen

AU - Vigelsø, Andreas

AU - Dandanell, Sune

AU - Prats, Clara

AU - Dela, Flemming

AU - Helge, Jørn Wulff

PY - 2018

Y1 - 2018

N2 - Background: A prevalent side-effect of simvastatin is attenuated glucose homeostasis. The underlying mechanism is unknown, but impaired lipid metabolism may provide the link. The aim of this study was to investigate whether simvastatin-treated patients had a lower capacity to oxidize lipids and reduced expression of the major proteins regulating lipid uptake, synthesis, lipolysis, and storage in skeletal muscle than matched controls.Materials and Methods: Ten men were treated with simvastatin (HbA1c: 5.7 ± 0.1%), and 10 healthy men (HbA1c: 5.2 ± 0.1%) underwent an oral glucose tolerance test and a muscle biopsy was obtained. Fat oxidation rates were measured at rest and during exercise. Western blotting was used to assess protein content.Results: Patients treated with simvastatin had impaired glucose tolerance compared with control subjects, but fat oxidation at rest and during exercise was compatible. Skeletal muscle protein content of CD36, lipoprotein lipase (LPL), and diacylglycerol acyltransferase (DGAT) 1 were lower, and DGAT 2 tended to be lower in patients treated with simvastatin.Conclusions: Patients treated with simvastatin had a reduced capacity to synthesize FA and diacylglycerol (DAG) into triacylglycerol in skeletal muscle compared to matched controls. Decreased lipid synthesis capacity may lead to accumulation of lipotoxic intermediates (FA and DAG) and hence impair glucose tolerance.

AB - Background: A prevalent side-effect of simvastatin is attenuated glucose homeostasis. The underlying mechanism is unknown, but impaired lipid metabolism may provide the link. The aim of this study was to investigate whether simvastatin-treated patients had a lower capacity to oxidize lipids and reduced expression of the major proteins regulating lipid uptake, synthesis, lipolysis, and storage in skeletal muscle than matched controls.Materials and Methods: Ten men were treated with simvastatin (HbA1c: 5.7 ± 0.1%), and 10 healthy men (HbA1c: 5.2 ± 0.1%) underwent an oral glucose tolerance test and a muscle biopsy was obtained. Fat oxidation rates were measured at rest and during exercise. Western blotting was used to assess protein content.Results: Patients treated with simvastatin had impaired glucose tolerance compared with control subjects, but fat oxidation at rest and during exercise was compatible. Skeletal muscle protein content of CD36, lipoprotein lipase (LPL), and diacylglycerol acyltransferase (DGAT) 1 were lower, and DGAT 2 tended to be lower in patients treated with simvastatin.Conclusions: Patients treated with simvastatin had a reduced capacity to synthesize FA and diacylglycerol (DAG) into triacylglycerol in skeletal muscle compared to matched controls. Decreased lipid synthesis capacity may lead to accumulation of lipotoxic intermediates (FA and DAG) and hence impair glucose tolerance.

KW - Adiponectin/blood

KW - Adult

KW - Blood Glucose/metabolism

KW - Glucose Tolerance Test

KW - Humans

KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology

KW - Hypercholesterolemia/drug therapy

KW - Insulin Resistance/physiology

KW - Leptin/blood

KW - Lipid Metabolism/drug effects

KW - Male

KW - Middle Aged

KW - Muscle, Skeletal/drug effects

KW - Simvastatin/pharmacology

UR - http://www.scopus.com/inward/record.url?scp=85054063208&partnerID=8YFLogxK

U2 - 10.1155/2018/9257874

DO - 10.1155/2018/9257874

M3 - Journal article

C2 - 30276217

AN - SCOPUS:85054063208

VL - 2018

JO - Journal of Diabetes Research

JF - Journal of Diabetes Research

SN - 2314-6745

M1 - 9257874

ER -