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 (25% wt/wt
coconut oil and 20%
high-fructose corn syrup) diet for 7 mo. Intervention diet resulted in
obesity,
hypertension, and
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 (PI 3-kinase) activation and
protein kinase B (Akt) phosphorylation in response to
insulin. In myocardium,
insulin-stimulated
glucose uptake,
PI 3-kinase activation, and Akt phosphorylation were also blunted in the intervention diet group. These findings were explained by increased myocardial content of p85alpha (regulatory subunit of
PI 3-kinase), diminished association of
PI 3-kinase 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
multiple abnormalities of
insulin signaling.