INS and type 2 diabetes mellitus: However, in the T2DM model, the IRS_PIK3CA activity depends on both insulin and mTORC1_S6K1 and thus is less active under the same insulin input, validating the driving effect of this functional feedback on insulin resistance (IRS_PIK3CA active 33% of the time for 100% constant insulin activity; Fig. 2, right panel).