Later, at 5–6 months of high‐fat feeding and beyond, in livers of rodents17, 20, 43 (Figure 3) and obese/T2DM humans,18, 19, 43 hepatic IRS‐1/PI3K fails and Akt activation diminishes; nevertheless, conserved activation of hepatic IRS‐2/PI3K and insulin‐stimulated aPKC activation may explain continued lipid and glucose overproduction, even when hepatic IRS‐1/PI3K/Akt activation is reduced. The gene discussed is INS; the disease is type 2 diabetes mellitus.