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

Larsen, Steen; Vigelsø, Andreas; Dandanell, Sune; Prats, Clara; Dela, Flemming; Helge, Jørn Wulff

doi:10.1155/2018/9257874

Cited by 20 publications

(20 citation statements)

References 39 publications

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“…Simvastatin-induced insulin resistance has been proposed to result from decreased lipid synthetic capacity in skeletal muscle. This may lead to intracellular accumulation of toxic fatty acid metabolites, which impairs insulin sensitivity ( 13 ). This observation is supported by the finding of larger lipid droplets in muscle cells of patients treated with statins ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Simvastatin profoundly impairs energy metabolism in primary human muscle cells

Mäkinen

Datta

Nguyen

et al. 2020

Endocrine Connections

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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.

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Section: Introductionmentioning

confidence: 99%

Simvastatin profoundly impairs energy metabolism in primary human muscle cells

Mäkinen

Datta

Nguyen

et al. 2020

Endocrine Connections

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“…Statin use may restrain the improvements in mitochondrial oxidative capacity with exercise training . Although this could potentially reduce the capacity to oxidize fat, that effect has not been reported . To our knowledge, there are no studies addressing the acute effect of a bout of exercise on PPTG in individuals chronically treated with statins.…”

Section: Discussionmentioning

confidence: 99%

“…Apparently, statin use reduces skeletal muscle coenzyme Q10 content which could reduce mitochondrial oxidative capacity and potentially fat oxidation. The literature is unclear on the effects of prolonged statin use on fat oxidation during exercise with reports of depressed or unchanged fat oxidation …”

Section: Introductionmentioning

confidence: 99%

Effects of statin therapy and exercise on postprandial triglycerides in overweight individuals with hypercholesterolaemia

Mora-Rodríguez

Ortega

Morales-Palomo

et al. 2020

Brit J Clinical Pharma

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Aims:To determine the effects of statins on postprandial lipaemia (PPL) and to study if exercise could enhance statin actions.Methods: Ten hypercholesteraemic (blood cholesterol 204 ± 36 mg dL −1 ; lowdensity lipoprotein-cholesterol 129 ± 32 36 mg dL −1 ) overweight (body mass index 30 ± 4 kg m −2 ), metabolic syndrome individuals chronically medicated with statins (>6 months) underwent 5-hour PPL tests in 4 occasions in a randomized order:(i) substituting their habitual statin medication by placebo for 96 hours (PLAC trial);(ii) taking their habitual statin medicine (STA trial); (iii) placebo combined with a bout of intense aerobic exercise (EXER+PLAC trial); and (iv) combining exercise and statin medicine (EXER+STA trial).Results: Before the fat meal, statin withdrawal (i.e. PLAC and EXER+PLAC) increased blood triglycerides (TG; 24%), low-density lipoprotein-cholesterol (31%) and total cholesterol (19%; all P < .05) evidencing treatment compliance. After the meal, statin withdrawal increased 5-hour postprandial TG (PPTG) compared to its matched trials (94% higher PLAC vs STA and 45% higher EXER+PLAC vs EXER+STA; P < .05). EXER +PLAC trial did not lower PPTG below PLAC (i.e. incremental AUC of 609 ± 152 vs 826 ± 190 mg dL −1 5 h; P = .09). Adding exercise to statin did not result in larger reductions in PPTG (i.e. EXER+STA vs STA incremental area under the curve of 421 ± 87 vs 421 ± 84 mg dL −1 5 h; P = .99). Conclusion:In hypercholesteraemic metabolic syndrome individuals, chronic statin therapy blunts the elevations in TG after a fat meal (i.e. incremental area under the curve of PPTG) reducing the cardiovascular risk associated to their atherogenic dyslipidaemia. However, a single bout of intense aerobic exercise before the high fat meal, does not reduce PPTG but also does not interfere with the effects of statin treatment. K E Y W O R D S aerobic exercise, hydroxymethylglutaryl-CoA reductase inhibitor, hypercholesterolaemia, metabolic syndrome X, postprandial lipaemia

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“…Muscle symptoms, such as fatigue, pain or weakness, are the most common statin side effects: these symptoms occur in up to 7% of statin users and up to 25% of statin users who participate in vigorous physical exercise [19]. Previous studies have shown that statin-induced muscle dysfunction is related to impaired mitochondrial function [20–22], protein breakdown [23], reduced protein synthesis [24], decreased lipid uptake and synthesis [25] and increased ectopic lipid deposition [26]. Skeletal muscle accounts for the major glucose disposal site in the body, and impaired muscle viability or glucose uptake may result in a risk of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Diabetogenic effect of pravastatin is associated with insulin resistance and myotoxicity in hypercholesterolemic mice

et al. 2019

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Background HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs widely used to treat hypercholesterolemia and prevent cardiovascular disease. Statins are generally well tolerated, but adverse reactions may occur, particularly myopathy and new onset of diabetes. The exact mechanism of statin-induced myopathy and diabetes has not been fully elucidated. We have previously shown that treatment of hypercholesterolemic (LDLr −/− ) mice with pravastatin for 2 months decreased pancreatic islet insulin secretion and increased oxidative stress and cell death, but no glucose intolerance was observed. The purpose of the current work was to study long-term pravastatin effects on glucose homeostasis, insulin sensitivity, muscle protein turnover and cell viability. Methods LDLr −/− mice were treated with pravastatin for 3, 6 and 10 months. Glucose tolerance, insulin resistance and glucose-stimulated insulin secretion were evaluated. The rates of protein synthesis and degradation were determined in gastrocnemius muscle after 10 months of treatment. Insulin signalling, oxidative stress and cell death were analysed in vitro using C2C12 myotubes. Results After 6 and 10 months of treatment, these mice became glucose intolerant, and after 10 months, they exhibited marked insulin resistance. Reduced islet glucose-stimulated insulin secretion was observed after the 3rd month of treatment. Mice treated for 10 months showed significantly decreased body weight and increased muscle protein degradation. In addition, muscle chymotrypsin-like proteasomal activity and lysosomal cathepsin were markedly elevated. C2C12 myotubes exposed to increasing concentrations of pravastatin presented dose-dependent impairment of insulin-induced Akt phosphorylation, increased apoptotic markers (Bax protein and cleaved caspase-3) and augmented superoxide anion production. Conclusions In addition to reduced insulin secretion, long-term pravastatin treatment induces insulin resistance and muscle wasting. These results suggest that the diabetogenic effect of statins is linked to the appearance of myotoxicity induced by oxidative stress, impaired insulin signalling, proteolysis and apoptosis.

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

Cited by 20 publications

References 39 publications

Simvastatin profoundly impairs energy metabolism in primary human muscle cells

Simvastatin profoundly impairs energy metabolism in primary human muscle cells

Effects of statin therapy and exercise on postprandial triglycerides in overweight individuals with hypercholesterolaemia

Diabetogenic effect of pravastatin is associated with insulin resistance and myotoxicity in hypercholesterolemic mice

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