Reduced Cardiac Efficiency and Altered Substrate Metabolism Precedes the Onset
of Hyperglycemia and Contractile Dysfunction in Two Mouse Models of Insulin
Resistance and Obesity
Authors Jonathan Buchanan, Pradip K. Mazumder, Ping Hu, Gopa Chakrabarti, Matthew W.
Roberts, Ui Jeong Yun, Robert C. Cooksey, Sheldon E. Litwin, and E. Dale Abel
Submitted By E. Dale Abel on 11/9/2005
Status Published
Journal Endocrinology
Year 2005
Date Published 12/1/2005
Volume : Pages 146 : 5341 - 5349
PubMed Reference 16141388
Abstract Hyperglycemia is associated with altered myocardial substrate use, a condition
that has been hypothesized to contribute to impaired cardiac performance. The
goals of this study were to determine whether changes in cardiac metabolism,
gene expression, and function precede or follow the onset of hyperglycemia in
two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db
mice). Ob/ob and db/db mice were studied at 4, 8, and 15wkof age. Four-week-old
mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia
develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and
15 wk. In isolated working hearts, rates of glucose oxidation were reduced by
28–37% at
4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation
rates and myocardial oxygen consumption were increased in 4-wk-old mice of both
strains. Fatty acid oxidation rates progressively increased in db/db mice in
parallel with the earlier onset and greater duration of hyperglycemia. In vivo,
cardiac catheterization revealed significantly increased left ventricular
contractility and relaxation (positive and negative dP/dt) in both strains at 4
wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob
mice at 15 wk of age. Increased -myosin heavy chain isoform expression was
present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression
of peroxisomal proliferator-activated receptor- regulated genes was observed
only at 15 wk in both strains. These data indicate that
altered myocardial substrate use and reduced myocardial efficiency are early
abnormalities in the hearts of obese mice and precede the onset of
hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo,
but loss of the percontractile phenotype of obesity and up-regulation of
peroxisomal proliferator-activated receptor- regulated genes occur later and
are most pronounced in the presence of longstanding hyperglycemia.

Investigators with authorship
E. Dale AbelUniversity of Iowa