CREB1 and Insulin resistance: Loss of aortic CREB is found in rodent models of hypertension, atherosclerosis and insulin resistance,25 while murine cardiac-specific expression of dominant-negative CREB increases oxidative stress, mitochondrial dysfunction and mortality.38 Although CREBSer133 is a direct target of AMPK,24 CREB activation by MTX might also occur via adenosine binding of G protein-coupled receptors, leading to protein kinase A activation via cAMP.