title: Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy.
abstract: Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) prevent vascular events and are widely prescribed, particularly in persons with type 2 diabetes. However, intolerability because of myopathic symptoms often limits their use. We investigated the effects of simvastatin on parameters of mitochondrial function and muscle gene expression in 11 subjects with type 2 diabetes, none of whom had statin intolerance. After withdrawal of statins for 2 months, we obtained blood samples, performed vastus lateralis muscle biopsies, and assessed whole body resting energy expenditure (REE). We then reinitiated therapy using simvastatin, 20 mg/d, for 1 month before repeating these studies. As expected, simvastatin lowered low-density lipoprotein, but did not induce myalgias or significant increases in serum creatine kinase. However, we found subtle but significant reductions in muscle citrate synthase activity and REE. In addition, quantitative polymerase chain reaction and gene set enrichment analysis of muscle samples revealed significantly repressed gene sets involved in mitochondrial function and induced gene sets involved in remodeling of the extracellular matrix. Furthermore, the effects of simvastatin on muscle gene sets showed some similarities to previously described changes that occur in Duchenne muscular dystrophy, polymyositis, and dermatomyositis. Although statins inhibit an early step in coenzyme Q (CoQ) biosynthesis, we observed no differences in CoQ content within skeletal muscle mitochondria, muscle tissue, or circulating platelets. In summary, we report subtle changes in whole body energetics, mitochondrial citrate synthase activity, and microarray data consistent with subclinical myopathy. Although the benefits of statin therapy are clear, further understanding of muscular perturbations should help guide safety and tolerability.
authors: Division of Nephrology, Department of Internal Medicine, University of Iowa and the Iowa City Veterans Affairs Health Care System, Iowa City VA, Iowa City, Iowa.
authors: Manish
authors: M
authors: Suneja
authors: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa.
authors: Daniel K
authors: DK
authors: Fox
authors: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa and the Iowa City Veterans Affairs Health Care System, Iowa City VA, Iowa City, Iowa.
authors: Brian D
authors: BD
authors: Fink
authors: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa and the Iowa City Veterans Affairs Health Care System, Iowa City VA, Iowa City, Iowa.
authors: Judy A
authors: JA
authors: Herlein
authors: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa; Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa and the Iowa City Veterans Affairs Health Care System, Iowa City VA, Iowa City, Iowa.
authors: Christopher M
authors: CM
authors: Adams
authors: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa and the Iowa City Veterans Affairs Health Care System, Iowa City VA, Iowa City, Iowa. Electronic address: william-sivitz@uiowa.edu.
authors: William I
authors: WI
authors: Sivitz
mesh_terms: D000368:Aged; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D009132:Muscles / Q000187:drug effects / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014451:Ubiquinone; D019821:Simvastatin; D002950:Citrate (si)-Synthase