Submitted on April 13, 2009
Revised on November 3, 2009
Accepted on November 3, 2009
Multiple abnormalities of myocardial insulin signaling in a porcine model of diet-induced obesity
Jenny Lee MD, Ya Xu MD, Li Lu, Bryan C Bergman1, J. Wayne Leitner, Clifford Greyson, Boris Draznin, and Gregory G. Schwartz2*
1 University of Colorado H.S.C.
2 VA Medical Center and University of Colorado Denver
* To whom correspondence should be addressed. E-mail: gregory.schwartz{at}va.gov.
Heightened cardiovascular risk among patients with systemic insulin resistance is not fully explained by the extent of atherosclerosis. It is unknown whether myocardial insulin resistance accompanies systemic insulin resistance and contributes to increased cardiovascular risk. This study utilized a porcine model of diet-induced obesity to determine if myocardial insulin resistance develops in parallel with systemic insulin resistance, and investigated potential mechanisms for such changes. Micropigs (n=16) were assigned to control (low-fat, no added sugars) or intervention diet (25% weight/weight coconut oil and 20% high-fructose corn syrup) for 7 months. Intervention diet resulted in obesity, hypertension, dyslipidemia. Systemic insulin resistance was manifest by elevated fasting glucose and insulin, abnormal response to intravenous glucose tolerance testing, and blunted skeletal muscle phosphatidylinositol-3-kinase (PI3K) activation and Akt phosphorylation in response to insulin. In myocardium, insulin-stimulated glucose uptake, PI3K activation and Akt phosphorylation were also blunted in the intervention diet group. These findings were explained by increased myocardial content of p85
(regulatory subunit of PI3K), diminished association of PI3K with insulin receptor substrate (IRS)-1 in response to insulin, and increased serine-307 phosphorylation of IRS-1. Thus, in a porcine model of diet-induced obesity that recapitulates many characteristics of insulin resistant patients, myocardial insulin resistance develops along with systemic insulin resistance and is associated with increased expression of p85 and serine phosphorylation of IRS-1.
