INS and cardiac hypertrophy: As to the mechanisms by which the TRIB3 R84 variant induces the observed increase in left ventricular mass, we like to hypothesize that it is a consequence of increased TRIB3 function in cardiomyocytes causing a selective insulin resistance resulting in impaired activation of cardioprotective PI3K/Akt-dependent insulin signaling pathway, due to enhanced binding to Akt by the gain-of-function TRIB3 R84 variant, and enhanced activation of the growth-promoting ras/mitogen-activated protein kinase (MAPK)-dependent pathway, which has been associated with cardiac hypertrophy [42].