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1 Integrative pharmacology, AstraZeneca R&D, Molndal, Sweden
2 Department of Medical Physiology, University of Tromso, Tromso, Norway
3 Diabetes and Obesity Research Program, Garvan Institute, Sydney, Australia
4 Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Canada
* To whom correspondence should be addressed. E-mail: nick.oakes{at}astrazeneca.com.
Studies of cardiac fuel metabolism in mice have been almost exclusively conducted ex vivo. The major aim of this study was to assess in vivo plasma FFA and glucose utilization by the hearts of healthy control (db/+) and diabetic (db/db) mice, based on cardiac uptake of [9,10-3H]-(R)-2-bromopalmitate (3H-R-BrP) and [U-14C]-2-deoxy-D-glucose tracers. To obtain quantitative information about the evaluation of cardiac FFA utilization with 3H-R-BrP, simultaneous comparisons of 3H-R-BrP and 14C-palmitate (14C-P) uptake were first made in isolated perfused working hearts from db/+ mice. It was found that 3H-R-BrP uptake was closely correlated with 14C-P oxidation (r2=0.94, P<0.001). Then, methods for in vivo application of 3H-R-BrP and 14C-2DG previously developed for application in the rat, were specially adapted for use in the mouse. The method yields indices of cardiac FFA utilization (Rf*) and clearance (Kf*), as well as glucose utilization (Rg'). Finally, in the main part of the study, the ability of the heart to switch between FFA and glucose fuels (metabolic flexibility) was investigated by studying anesthetized, 8 hour fasted control and db/db mice in either the basal state, or during glucose infusion. In control mice, glucose infusion raised plasma levels of glucose and insulin, raised Rg' (+58%) and lowered plasma FFA level (-48%), Kf* (-45%) and Rf* (-70%). This apparent reciprocal regulation of glucose and FFA utilization by control hearts illustrates metabolic flexibility for substrate use. By contrast, in the db/db mice, glucose infusion raised glucose levels, with no apparent influence on cardiac FFA or glucose utilization. In conclusion, tracer methodology for assessing in vivo tissue-specific plasma FFA and glucose utilization has been adapted for use in mice and reveals a profound loss of metabolic flexibility in the diabetic db/db heart, suggesting a fixed level of FFA oxidation in fasted and glucose infused states.
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