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activator
1 Department of Medical Physiology, University of Tromsø, N-9037 Tromsø, Norway; 2 Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 4N1; and 3 Department of Cardiology and Medicine, University of Edinburgh, Edinburgh EH8 9XF, Scotland
Hearts from diabetic
db/db mice, a model of Type 2 diabetes, exhibit
left ventricular failure and altered metabolism of exogenous substrates. Peroxisome proliferator-activated receptor-
(PPAR-) ligands reduce plasma lipid and glucose concentrations and improve insulin sensitivity in db/db mice. Consequently,
the effect of 4- to 5-wk treatment of db/db mice
with a novel PPAR- ligand (BM 17.0744; 25-38
mg · kg
1 · day1),
commencing at 8 wk of age, on ex vivo cardiac function and metabolism
was determined. Elevated plasma concentrations of glucose, fatty acids,
and triacylglycerol (34.0 ± 3.6, 2.0 ± 0.4, and 0.9 ± 0.1 mM, respectively) were reduced to normal after treatment with BM
17.0744 (10.8 ± 0.6, 1.1 ± 0.1, and 0.6 ± 0.1 mM).
Plasma insulin was also reduced significantly in treated compared with untreated db/db mice. Chronic treatment of
db/db mice with the PPAR- agonist resulted in
a 50% reduction in rates of fatty acid oxidation, with a concomitant
increase in glycolysis (1.7-fold) and glucose oxidation (2.3- fold).
Correction of the diabetes-induced abnormalities in systemic and
cardiac metabolism after BM 17.0744 treatment did not, however, improve
left ventricular contractile function.
substrate oxidation; isolated working mouse hearts
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