Thyroid hormone action, widely recognized on cell proliferation and metabolism, has recently been related to the phosphoinositide 3 kinase (PI3K), an upstream regulator of the Akt kinase and the involvement of the thyroid hormone receptor β1 has been hypothesized. The serine-threonine kinase Akt can regulate various substrates that drive cell mass, proliferation and survival. Its action has also been characterized in pancreatic β-cells. We previously demonstrated that Akt activity and its activation in the insulinoma cell line hCM can be considered a specific target of the non genomic action of T3. In this study, we analyzed the molecular pathways involved in the regulation of cell proliferation, survival, size and protein synthesis by T3 in a stable TRβ1 interfered insulinoma cell line, derived from the hCM, and evidenced a strong regulation of both physiological and molecular events by T3 mediated by the thyroid hormone receptor β1. We showed that the thyroid receptor β1 mediates the T3 regulation of the cdk4·cyc D1·p21CIP1·p27KIP1 complex formation and activity. In addition TRβ1 is essential for the T3 upregulation of the Akt targets β-catenin, p70S6K and for the phosphorylation of Bad and mTOR. We demonstrated that the β1 receptor mediates the T3 upregulation of protein synthesis and cell size, together with the cell proliferation and survival, playing a crucial role in the T3 regulation of the PI3K/Akt pathway.