In Brief:
Type 2 diabetes and insulin resistance are associated with diastolic heart failure, impaired ventricular function, perimicrovascular fibrosis, and increased expression of PAI-1 in coronary arterial walls. To determine whether these regional manifestations can be induced by loss of IRS-1 mediated signaling we studied IRS-1 knockout (KO) mice at 20 weeks of age. Left ventricular mass/body weight increased; diastolic and systolic LV diameters increased; fractional shortening decreased; and coronary perimicrovascular fibrosis increased associated with increased immunoreactivity of PAI-1 in the tunica media. Thus, loss of IRS-1 signaling is sufficient to induce cardiac and proteo(fibrino)lytic system derangements typical of insulin resistance, and increased PAI-1 expression is not dependent on IRS-1 signaling.
