Impaired Cardiac Efficiency and Increased Fatty Acid Oxidation in
Insulin-Resistant ob/ob Mouse Hearts.
Authors Mazumder PK, O'Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC, Boudina S,
Abel ED.
Submitted By E. Dale Abel on 8/31/2004
Status Published
Journal Diabetes
Year 2004
Date Published 9/1/2004
Volume : Pages 53 : 2366 - 2374
PubMed Reference 15331547
Abstract Diabetes alters cardiac substrate metabolism. The cardiac phenotype in
insulin-resistant states has not been comprehensively characterized. The goal of
these studies was to determine whether the hearts of leptin-deficient 8-week-old
ob/ob mice were able to modulate cardiac substrate utilization in response to
insulin or to changes in fatty acid delivery. Ob/ob mice were insulin resistant
and glucose intolerant. Insulin signal transduction and insulin-stimulated
glucose uptake were markedly impaired in ob/ob cardiomyocytes.
Insulin-stimulated rates of glycolysis and glucose oxidation were 1.5- and
1.8-fold higher in wild-type hearts, respectively, versus ob/ob, and glucose
metabolism in ob/ob hearts was unresponsive to insulin. Increasing
concentrations of palmitate from 0.4 mmol/l (low) to 1.2 mmol/l (high) led to a
decline in glucose oxidation in wild-type hearts, whereas glucose oxidation
remained depressed and did not change in ob/ob mouse hearts. In contrast, fatty
acid utilization in ob/ob hearts was 1.5- to 2-fold greater in the absence or
presence of 1 nmol/l insulin and rose with increasing palmitate concentrations.
Moreover, the ability of insulin to reduce palmitate oxidation rates was blunted
in the hearts of ob/ob mice. Under low-palmitate and insulin-free conditions,
cardiac performance was significantly greater in wild-type hearts. However, in
the presence of high palmitate and 1 nmol/l insulin, cardiac performance in
ob/ob mouse hearts was relatively preserved, whereas function in wild-type mouse
hearts declined substantially. Under all perfusion conditions, myocardial oxygen
consumption was higher in ob/ob hearts, ranging from 30% higher in low-palmitate
conditions to greater than twofold higher under high-palmitate conditions. These
data indicate that although the hearts of glucose-intolerant ob/ob mice are
capable of maintaining their function under conditions of increased fatty acid
supply and hyperinsulinemia, they are insulin-resistant, metabolically
inefficient, and unable to modulate substrate utilization in response to changes
in insulin and fatty acid supply.

Investigators with authorship
E. Dale AbelUniversity of Iowa