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. 2018 Sep 12:2018:9257874.
doi: 10.1155/2018/9257874. eCollection 2018.

Simvastatin-Induced Insulin Resistance May Be Linked to Decreased Lipid Uptake and Lipid Synthesis in Human Skeletal Muscle: the LIFESTAT Study

Steen Larsen  1   2 , Andreas Vigelsø  1 , Sune Dandanell  1   3 , Clara Prats  1 , Flemming Dela  1   4 , Jørn Wulff Helge  1
Affiliations

Simvastatin-Induced Insulin Resistance May Be Linked to Decreased Lipid Uptake and Lipid Synthesis in Human Skeletal Muscle: the LIFESTAT Study

Steen Larsen et al. J Diabetes Res. .

Abstract

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.

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Figures

Figure 1
Figure 1
Protein expression of major proteins in skeletal muscle from patients in treatment with simvastatin (yellow squares) and matched controls (grey circles). (a) Lipid uptake-related proteins EL (endothelial lipase), LPL (lipoprotein lipase), FAPBpm (plasma membrane-bound fatty acid-binding protein), and CD36. (b) Lipid synthesis-related protein DGAT 1 and 2 (diacylglycerol acyltransferase). (c) Lipid droplet regulation, perilipins 2, 3, and 5. (d) Lipolysis: ATGL (adipose triacylglycerol lipase) and HSL (hormone-sensitive lipase). Data are mean ± SE, ∗P < 0.05. Data are presented as relative to mean of the control. Representative blots are shown in Figure 2.
Figure 2
Figure 2
Representative Western blots for Figure 1 for patients in simvastatin treatment (SIM) and matched controls (CON). ATGL: adipose triglyceride lipase; DGAT: diacylglycerol acyltransferase; EL: endothelial lipase; FABPpm: plasma membrane-bound fatty acid-binding protein; HSL: hormone-sensitive lipase; LPL: lipoprotein lipase; perilipins 2, 3, and 5. Representative picture of a coomassie staining that visualizes equal protein loading.
See this image and copyright information in PMC

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