Cross-over Study on Effect of Lipid Lowering by Acipimox on Cardiac and Skeletal Muscle Mitochondrial Function

Summary

Accumulation of lipid in skeletal and cardiac muscle has been associated with insulin resistance and diabetic cardiomyopathy. In skeletal muscle, lipotoxic damage has been suggested to lead to dysfunction of mitochondria. It remains unknown whether lipotoxicity leads to mitochondrial dysfunction in heart as well, and if so, whether this also leads to cardiomyopathy (failure of the heart). Although it has been shown that lipid lowering agents can improve insulin sensitivity, the effect of lowering free fatty acids on cardiac and skeletal muscle mitochondrial function remains unknown. In this study the investigators want to investigate whether lowering cardiac and muscular lipid content will improve mitochondrial and cellular function in type 2 diabetic patients. To this end, type 2 diabetic patients and body mass index (BMI)-matched controls will be included in a blinded cross-over design, in which subjects will receive a lipid lowering agent (Acipimox) or placebo for 2 weeks in random order. During treatment, diabetes medication will be stopped. Baseline measurements will be performed prior to the study and after each treatment to assess cardiac and muscular lipid accumulation, cardiac function, mitochondrial function and insulin sensitivity.

Timeline

Start

2010-03

Primary completion

2012-12

Completion

2012-12

Publications

• Background Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, Jeneson JA, Backes WH, van Echteld CJ, van Engelshoven JM, Mensink M, Schrauwen P. Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia. 2007 Jan;50(1):113-20. doi: 10.1007/s00125-006-0475-1. Epub 2006 Nov 9.
• Background Phielix E, Schrauwen-Hinderling VB, Mensink M, Lenaers E, Meex R, Hoeks J, Kooi ME, Moonen-Kornips E, Sels JP, Hesselink MK, Schrauwen P. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes. 2008 Nov;57(11):2943-9. doi: 10.2337/db08-0391. Epub 2008 Aug 4.
• Background De Feyter HM, Lenaers E, Houten SM, Schrauwen P, Hesselink MK, Wanders RJ, Nicolay K, Prompers JJ. Increased intramyocellular lipid content but normal skeletal muscle mitochondrial oxidative capacity throughout the pathogenesis of type 2 diabetes. FASEB J. 2008 Nov;22(11):3947-55. doi: 10.1096/fj.08-112318. Epub 2008 Jul 24.
• Background Schrauwen-Hinderling VB, Roden M, Kooi ME, Hesselink MK, Schrauwen P. Muscular mitochondrial dysfunction and type 2 diabetes mellitus. Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):698-703. doi: 10.1097/MCO.0b013e3282f0eca9.
• Houzelle A, Jorgensen JA, Schaart G, Daemen S, van Polanen N, Fealy CE, Hesselink MKC, Schrauwen P, Hoeks J. Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity. Diabetologia. 2021 Feb;64(2):424-436. doi: 10.1007/s00125-020-05335-w. Epub 2020 Nov 30.
• Phielix E, Jelenik T, Nowotny P, Szendroedi J, Roden M. Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial. Diabetologia. 2014 Mar;57(3):572-81. doi: 10.1007/s00125-013-3127-2. Epub 2013 Dec 6.

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