Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy

Manish Suneja; Daniel K Fox; Brian D Fink; Judy A Herlein; Christopher M Adams; William I Sivitz

doi:10.1016/j.trsl.2015.01.007

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Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy

Journal article

Open access

Peer reviewed

Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy

Manish Suneja, Daniel K Fox, Brian D Fink, Judy A Herlein, Christopher M Adams and William I Sivitz

Translational research : the journal of laboratory and clinical medicine, Vol.166(2), pp.176-187

08/2015

DOI: 10.1016/j.trsl.2015.01.007

PMCID: PMC4509977

PMID: 25683525

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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.

Simvastatin - therapeutic use

Oligonucleotide Array Sequence Analysis

Diabetes Mellitus, Type 2 - genetics

Humans

Middle Aged

Mitochondria, Muscle - metabolism

RNA, Messenger - genetics

Ubiquinone - metabolism

Male

Gene Expression Profiling

Diabetes Mellitus, Type 2 - metabolism

RNA, Messenger - metabolism

Simvastatin - pharmacology

Gene Expression Regulation - drug effects

Muscles - enzymology

Muscles - drug effects

Female

Aged

Citrate (si)-Synthase - metabolism

Mitochondria, Muscle - drug effects

Diabetes Mellitus, Type 2 - drug therapy

Energy Metabolism - drug effects

Details

Title: Subtitle: Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy
Creators: Manish Suneja - 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
Daniel K Fox - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa
Brian D Fink - 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
Judy A Herlein - 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
Christopher M Adams - 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
William I Sivitz - 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
Resource Type: Journal article
Publication Details: Translational research : the journal of laboratory and clinical medicine, Vol.166(2), pp.176-187
DOI: 10.1016/j.trsl.2015.01.007
PMID: 25683525
PMCID: PMC4509977
NLM abbreviation: Transl Res
ISSN: 1931-5244
eISSN: 1878-1810
Publisher: United States
Grant note: I01 BX000976 / BLRD VA R01 HL073166 / NHLBI NIH HHS UL1RR024979 / NCRR NIH HHS T32 GM007337 / NIGMS NIH HHS I01 RX001477 / RRD VA F30 AG043304 / NIA NIH HHS F30AG043304 / NIA NIH HHS I01 BX000285 / BLRD VA AR059115-04 / NIAMS NIH HHS R01 AR059115 / NIAMS NIH HHS
Language: English
Date published: 08/2015
Academic Unit: Molecular Physiology and Biophysics; Nephrology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984025449202771

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