Although multiple pathological mechanisms have been proposed for hepatic insulin resistance in NAFLD (as reviewed above), hepatic insulin resistance is almost universally associated with intrahepatic accumulation of triglyceride and DAGs, with the latter activation of PKCε and subsequent inhibition of insulin-stimulated insulin receptor kinase activity in a variety of experimental and clinical models (Jornayvaz and Shulman, 2012; Birkenfeld and Shulman, 2014; Perry et al., 2014; Figure 1). The gene discussed is INS; the disease is metabolic dysfunction-associated steatotic liver disease.