IRS1 and Insulin resistance: Increased circulating levels of FFAs facilitate the development of insulin resistance and concomitant impairment of insulin signaling via reduced content and phosphorylation of insulin receptor substrate 1 (IRS-1).100–102 Finally, in the rat heart, GCs significantly decrease AMPK activity, suggesting that the observed detrimental effects of GC excess on the heart (i.e., left ventricular hypertrophy and myocardial ischemia), as is observed in patients with chronic exposure to excess GCs, could be, at least in part, mediated by the decrease in AMPK activity.98