Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Bugger, H; Boudina, S; Hu, XX; Tuinei, J; Zaha, VG; Theobald, HA; Yun, UJ; McQueen, AP; Wayment, B; Litwin, SE; Abel, ED.
Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3.
Diabetes. 2008; 57(11): 2924-2932.
Doi: 10.2337/db08-0079
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- Führende Autor*innen der Med Uni Graz
- Bugger Heiko Matthias
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- Abstract:
- Fatty acid-induced mitochondrial uncoupling and oxidative stress have been proposed to reduce cardiac efficiency and contribute to cardiac dysfunction in type 2 diabetes. We hypothesized that mitochondrial uncoupling may also contribute to reduced cardiac efficiency and contractile dysfunction in the type 1 diabetic Akita mouse model (Akita). Cardiac function and substrate utilization were determined in isolated working hearts and in vivo function by echocardiography. Mitochondrial function and coupling were determined in saponin-permeabilized fibers, and proton leak kinetics was determined in isolated mitochondria. Hydrogen peroxide production and aconitase activity were measured in isolated mitochondria, and total reactive oxygen species (ROS) were measured in heart homogenates. Resting cardiac function was normal in Akita mice, and myocardial insulin sensitivity was preserved. Although Akita hearts oxidized more fatty acids, myocardial O(2) consumption was not increased, and cardiac efficiency was not reduced. ADP-stimulated mitochondrial oxygen consumption and ATP synthesis were decreased, and mitochondria showed grossly abnormal morphology in Akita. There was no evidence of oxidative stress, and despite a twofold increase in uncoupling protein 3 (UCP3) content, ATP-to-O ratios and proton leak kinetics were unchanged, even after perfusion of Akita hearts with 1 mmol/l palmitate. Insulin-deficient Akita hearts do not exhibit fatty acid-induced mitochondrial uncoupling, indicating important differences in the basis for mitochondrial dysfunction between insulin-responsive type 1 versus insulin-resistant type 2 diabetic hearts. Increased UCP3 levels do not automatically increase mitochondrial uncoupling in the heart, which supports the hypothesis that fatty acid-induced mitochondrial uncoupling as exists in type 2 diabetic hearts requires a concomitant increase in ROS generation.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Blotting, Western -
- Diabetes Mellitus, Type 1 - genetics
- Diabetes Mellitus, Type 1 - metabolism
- Diabetes Mellitus, Type 1 - pathology
- Echocardiography -
- Insulin - metabolism
- Ion Channels - genetics
- Ion Channels - metabolism
- Male -
- Mice -
- Mice, Inbred C57BL -
- Microscopy, Electron -
- Mitochondria, Heart - metabolism
- Mitochondria, Heart - ultrastructure
- Mitochondrial Proteins - genetics
- Mitochondrial Proteins - metabolism
- Myocardium - metabolism
- Myocardium - ultrastructure
- Oxidative Stress -
- Oxygen Consumption -
- RNA, Messenger - genetics
- RNA, Messenger - metabolism
- Reactive Oxygen Species - metabolism
- Reverse Transcriptase Polymerase Chain Reaction -
- Uncoupling Protein 2 -
- Uncoupling Protein 3 -