Short-term (4 weeks) HFD as well as acute hyperinsulinemia mediated by systemic insulin resistance in response to S961 treatment did not reveal a marked difference in insulin levels between genotypes (Figs. 2 and 3), suggesting that long-term adaptive mechanisms rather than a primary defect in secretion may be more important in establishing the reduced insulin phenotype observed in HFD-fed M4K4 iKO mice. This evidence concerns the gene INS and Insulin resistance.