Because excess intracellular Ca2+ inhibits insulin signaling by inhibiting PH-domain interactions with membrane PI(3,4)P3 or PI(3,4,5)P3, which abrogates membrane translocation of PH domains and leads to impaired insulin signaling15, we hypothesized that screening for biologically active compounds that restore impaired insulin signaling could identify potential drugs to ameliorate insulin resistance by attenuating intracellular Ca2+ overload (Fig. 1a). The gene discussed is INS; the disease is Insulin resistance.