Impaired pyruvate oxidation but normal glucose uptake in diabetic
swine myocardium during dobutamine-induced work .
Hall, Jennifer L., William C. Stanley, Gary D. Lopaschuk, Judith A.
Wisneski, Robert D. Pizzurro, C. Dawn Hamilton* and James G.
McCormack.
Syntex Discovery Research, Palo Alto, CA, 94303; Syntex Research,
Edinburgh, Scotland, EH14 4AP; Department of Human Biodynamics,
University of California Berkeley, Berkeley, CA, 94720;
Cardiovascular Disease Research Group and Departments of Pediatrics
and Pharmacology, University of Alberta, Edmonton, Canada, 76G 2S2;
Department of Medicine, University of California, San Francisco, and
the Veterans Affairs Medical Center, San Francisco, CA, 94121
APStracts 3:0267H, 1996.
We tested the hypothesis that diabetes impairs myocardial glucose
uptake and pyruvate oxidation under normal conditions and during a
dobutamine-induced increase in work. We also tested the hypothesis
that an increase in work would result in a decrease in the levels of
malonyl CoA, a potent inhibitor of carnitine palmitoyltransferase I
(CPT I). Streptozotocin-diabetic micro-pigs were compared to a
nondiabetic control group (n=8 per group). Triglyceride emulsion,
glucose, and somatostatin were infused into the nondiabetic group to
create an acute diabetic-like state. In accord with our hypothesis,
malonyl CoA decreased significantly with dobutamine in both groups,
providing a possible mechanism for increased fatty acid oxidation
through relieved inhibition on CPT I. In the absence of dobutamine,
glucose uptake and tracer-measured lactate uptake were decreased by
57% and 80%, respectively, in the diabetic group. Dobutamine infusion
resulted in similar increases in cardiac contractility, oxygen
consumption and glucose uptake in both groups despite reductions of
50 to 65% in GLUT 4 and GLUT 1 protein in the diabetic group.
Diabetic animals possessed a defect in myocardial pyruvate oxidation,
as reflected in increased lactate production, and depressed lactate
uptake and PDH activity under control and dobutamine conditions. In
conclusion, the major derangement in carbohydrate metabolism in
diabetic myocardium was not in glycolysis, but rather in pyruvate
oxidation.
Received 1 November 1995; accepted in final form 20 May 1996.
APS Manuscript Number H1025-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 4 July 96