INS and Insulin resistance: Because severe insulin resistance in InsrP1195L/+/HFD mice suggested unsuppressed gluconeogenesis in an otherwise insulin resistant liver, as is found in liver-specific Insr knockout (LIRKO) mice7, mRNA expressions of two key enzymes, phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6pc), were examined (Fig. 1e,f).