Hepatic translation rewiring in insulin deficiency identifies Reg3α as an insulin-independent glucoregulatory factor [RNA_Ribo_Seq: ID_Healthy]

Insulin deficiency (ID) causes severe metabolic defects and death if untreated. ID affects millions worldwide and insulin therapy remains the only available treatment. However, this approach increases the risk of life-threatening hypoglycemia and does not restore metabolic balance. Thus, insulin therapy is suboptimal. Here, we report that ID reshapes hepatic mRNA translation, characterized by suppression of translation initiation and early elongation, a global reduction in protein synthesis, and extensive remodeling of the hepatic translatome. While ID suppresses anabolic and glucose metabolism pathways, it selectively enhances translation of transcripts involved in lipid metabolism and inflammation. Leptin treatment stimulates the translation of regenerating islet-derived protein 3α (Reg3α) in the liver of ID mice. Notably, increased Reg3α expression alone (i.e., without administered insulin and/or leptin) significantly improves hyperglycemia in ID mice. Mechanistically, Reg3α exerts glucose-lowering effects without altering insulin receptor signaling. These findings identify Reg3α as an insulin-independent regulator of glucose homeostasis and reveal hepatic translational control as a previously unrecognized mechanism contributing to metabolic adaptation in ID, with potential therapeutic implications.