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Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
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Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
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Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
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Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
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Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
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Objectives
Simvastatin use is associated with muscular side effects, and increased risk for type 2 diabetes (T2D). In clinical use, simvastatin is administered in inactive lipophilic lactone-form, which is then converted to active acid-form in the body. Here, we have investigated if lactone- and acid-form simvastatin differentially affect glucose metabolism and mitochondrial respiration in primary human skeletal muscle cells.
Methods
Muscle cells were exposed separately to lactone- and acid-form simvastatin for 48 h. After pre-exposure, glucose uptake and glycogen synthesis were measured using radioactive tracers; insulin signalling was detected with Western blotting; and glycolysis, mitochondrial oxygen consumption and ATP production were measured with Seahorse XFe96 analyzer.
Results
Lactone-form simvastatin increased glucose uptake and glycogen synthesis, whereas acid-form simvastatin did not affect glucose uptake and decreased glycogen synthesis. Phosphorylation of insulin signalling targets Akt substrate 160 kDa (AS160) and glycogen synthase kinase 3β (GSK3β) was upregulated with lactone-, but not with acid-form simvastatin. Exposure to both forms of simvastatin led to a decrease in glycolysis and glycolytic capacity, as well as to a decrease in mitochondrial respiration and ATP production.
Conclusions
These data suggest that lactone- and acid-forms of simvastatin exhibit differential effects on non-oxidative glucose metabolism as lactone-form increases and acid-form impairs glucose storage into glycogen, suggesting impaired insulin sensitivity in response to acid-form simvastatin. Both forms profoundly impair oxidative glucose metabolism and energy production in human skeletal muscle cells. These effects may contribute to muscular side effects and risk for T2D observed with simvastatin use.
Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
Search for other papers by Selina Mäkinen in
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PubMed
Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
Search for other papers by Neeta Datta in
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PubMed
Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
Search for other papers by Yen H Nguyen in
Google Scholar
PubMed
Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
Search for other papers by Petro Kyrylenko in
Google Scholar
PubMed
Search for other papers by Markku Laakso in
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PubMed
Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
Search for other papers by Heikki A Koistinen in
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PubMed
