IRS1 and cardiac hypertrophy: This review establishes the pathological consequences of chronic mTOR activation in the context of T2DM, a major CMVD risk factor. It explains that sustained mTORC1 activity creates a negative feedback loop that suppresses insulin signaling (IRS-1). It connects mTOR to cardiac hypertrophy, ischemia, and fibrosis. This grounds the “over-activation” part of the argument in a highly relevant disease model for CMVD.