Type 1 diabetic akita mouse hearts are insulin sensitive but manifest
structurally abnormal mitochondria that remain coupled despite increased
uncoupling protein 3
Authors Bugger H, Boudina S, Hu XX, Tuinei J, Zaha VG, Theobald HA, Yun UJ, McQueen AP,
Wayment B, Litwin SE, Abel ED
Submitted By E. Dale Abel on 12/19/2008
Status Published
Journal Diabetes
Year 2008
Date Published 11/1/2008
Volume : Pages 57 : 2924 - 2932
PubMed Reference 18678617
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.

Investigators with authorship
E. Dale AbelUniversity of Iowa


Ucp3uncoupling protein 3, mitochondrial