The contribution of impaired insulin signaling and oxidative stress to myocardial diastolic dysfunction in the obese db/db mouse

Obesity and heart failure (HF) are epidemics in the United States. Obesity related HF is characterized by decreased insulin metabolic signaling and diastolic dysfunction. In a genetic rodent model of obesity, the young db/db mouse, we have investigated the role of mTOR/S6K1 activation and of associated impairment of insulin metabolic signaling and diastolic relaxation. The initial diastolic filling rate, as measured by high resolution MRI, was decreased in 12 week db/db compared to age matched wild type controls. There were contemporaneous increases in reactive oxygen species (ROS), increased small abnormal mitochondria, lipid accumulation and interstitial fibrosis in db/db heart. There was increased Thr 389 phosphorylation (P)/activation of S6K1, enhanced association of S6K1 with IRS1 and Ser307 P of IRS1. This was associated with decreased total IRS1 and a tendency (not significantly) for decreased P/activation of Akt. S6K1 P has been associated with Ser307 P and associated ubiquinization/degradation of IRS1. As NADPH oxidase activity was not increased in db/db heart, suggesting a mitochondrial source of increased ROS. In summary, young db/db manifested diastolic dysfunction possibly due to decreased insulin metabolic signaling, increased mitochondrial generation of ROS, and interstitial fibrosis. Supported by NIH R01‐HL‐63904 and VA Merit (JRS), and VA Career Development Award (AWC).