Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3

Heiko Bugger, Sihem Boudina, Xiao Xuan Hu, Joseph Tuinei, Vlad G. Zaha, Heather A. Theobald, Ui Jeong Yun, Alfred P. McQueen, Benjamin Wayment, Sheldon E. Litwin, E. Dale Abel

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE-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). RESEARCH DESIGN AND METHODS-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. RESULTS-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. CONCLUSIONS-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.

Original languageEnglish (US)
Pages (from-to)2924-2932
Number of pages9
JournalDiabetes
Volume57
Issue number11
DOIs
StatePublished - Nov 1 2008

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Mitochondria
Insulin
Fatty Acids
Protons
Reactive Oxygen Species
Oxidative Stress
Aconitate Hydratase
Uncoupling Protein 3
Palmitates
Saponins
Oxygen Consumption
Adenosine Diphosphate
Type 2 Diabetes Mellitus
Hydrogen Peroxide
Echocardiography
Insulin Resistance
Research Design
Perfusion
Adenosine Triphosphate

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. / Bugger, Heiko; Boudina, Sihem; Hu, Xiao Xuan; Tuinei, Joseph; Zaha, Vlad G.; Theobald, Heather A.; Yun, Ui Jeong; McQueen, Alfred P.; Wayment, Benjamin; Litwin, Sheldon E.; Abel, E. Dale.

In: Diabetes, Vol. 57, No. 11, 01.11.2008, p. 2924-2932.

Research output: Contribution to journalArticle

Bugger, H, Boudina, S, Hu, XX, Tuinei, J, Zaha, VG, Theobald, HA, Yun, UJ, McQueen, AP, Wayment, B, Litwin, SE & Abel, ED 2008, 'Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3', Diabetes, vol. 57, no. 11, pp. 2924-2932. https://doi.org/10.2337/db08-0079
Bugger, Heiko ; Boudina, Sihem ; Hu, Xiao Xuan ; Tuinei, Joseph ; Zaha, Vlad G. ; Theobald, Heather A. ; Yun, Ui Jeong ; McQueen, Alfred P. ; Wayment, Benjamin ; Litwin, Sheldon E. ; Abel, E. Dale. / Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. In: Diabetes. 2008 ; Vol. 57, No. 11. pp. 2924-2932.
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abstract = "OBJECTIVE-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). RESEARCH DESIGN AND METHODS-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. RESULTS-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. CONCLUSIONS-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.",
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T1 - Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3

AU - Bugger, Heiko

AU - Boudina, Sihem

AU - Hu, Xiao Xuan

AU - Tuinei, Joseph

AU - Zaha, Vlad G.

AU - Theobald, Heather A.

AU - Yun, Ui Jeong

AU - McQueen, Alfred P.

AU - Wayment, Benjamin

AU - Litwin, Sheldon E.

AU - Abel, E. Dale

PY - 2008/11/1

Y1 - 2008/11/1

N2 - OBJECTIVE-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). RESEARCH DESIGN AND METHODS-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. RESULTS-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. CONCLUSIONS-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.

AB - OBJECTIVE-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). RESEARCH DESIGN AND METHODS-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. RESULTS-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. CONCLUSIONS-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.

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DO - 10.2337/db08-0079

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