Schematic representation of contribution of lipid emulsion to the treatment of bupivacaine toxicity. (A) On its own IV lipid emulsion (ILE, 10 ml/kg intralipid) rapidly activates insulinergic signaling in cardiac tissue with the phosphorylation of protein kinase B (Akt) at both threonine 308 and serine 473. This leads to feedback phosphorylation of insulin receptor substrate-1 (IRS1). ILE had no observable effect on 5′-adenosine monophosphate protein–activated kinase (AMPK) or downstream targets including acetyl-CoA carboxylase (ACC) or tuberous sclerosis 2 (TSC2) and did not contribute to inhibition or activation of mammalian target of rapamycin complex 1 (mTOR1), p70 s6 kinase (p70s6k), or ribosomal protein s6 (s6). (B) During toxicity, bupivacaine blocks Akt signaling and activate AMPK signaling with the blockade of downstream proteins including p70s6k and s6 via inhibition of mTOR1 by TSC2. Adjuvant lipid emulsion will cause phosphorylation of Akt at threonine 308 and serine 473. AMPK signaling remains activate due to bupivacaine toxicity with continued loss of signaling downstream mTOR1. With persistent activation, IRS1 does not immediately resensitized. PI3K = phosphoinositide-3-kinase.