Hepatic Translational Rewiring in Insulin Deficiency Identifies Reg3α as an Insulin-Independent Glucoregulatory Factor

Article Article scientifique Article Hepatic Translational Rewiring in Insulin Deficiency Identifies Reg3α as an Insulin-Independent Glucoregulatory Factor eng 2026-08-31 2026-09-03 author Sousa Teixeira Pryscila Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.,Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. 935446 author Vincent Sarah Mathilda 0009-0008-1053-3982 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.,Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. 877598 Département de physiologie cellulaire et métabolisme (PHYME) author Meurs Romane 0000-0003-3115-2501 Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland. author Ursino Gloria 0000-0002-2703-4417 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.,Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. 909891 author Zahoran Szabolcs Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.,Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. 913585 Département de physiologie cellulaire et métabolisme (PHYME) author Lucibello Giulia 0000-0002-5543-1719 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.,Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. 953475 author Maciel Authiat Marcella 0000-0002-5479-2096 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 982971 author Gavin Perrin Anne-Claude 0000-0003-4917-2340 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 23293 Département de physiologie cellulaire et métabolisme (PHYME) author Ramadori Giorgio 0000-0003-0194-3257 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.,Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. 790895 Département de physiologie cellulaire et métabolisme (PHYME) author Coppari Roberto 0000-0003-1288-6948 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.,Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. 780442 Département de physiologie cellulaire et métabolisme (PHYME) bqag100 10.1210/endocr/bqag100 42673492 0013-7227 PMC13595276 https://academic.oup.com/endo/advance-article/doi/10.1210/endocr/bqag100/8777048 Background: Insulin deficiency (ID) causes severe metabolic defects and death if untreated, while insulin therapy does not fully restore metabolic homeostasis. Leptin therapy corrects metabolic abnormalities and promotes survival in rodents unable to produce insulin, suggesting the existence of insulin-independent glucoregulatory mechanisms. Methods: We use mice with diphtheria toxin-induced pancreatic β-cell ablation, resulting in severe insulin deficiency. We assess hepatic translation by polysome profiling, ribosome profiling (Ribo-seq), and RNA sequencing. To identify leptin-responsive hepatic factors, we compare the hepatic translatome during intracerebroventricular leptin treatment and following leptin withdrawal. Regenerating islet-derived protein 3 alpha (Reg3α) is subsequently overexpressed in the liver of ID mice to assess its metabolic effects. Results: ID suppresses hepatic mechanistic target of rapamycin complex 1 (mTORC1) signaling and global protein synthesis while extensively remodeling the hepatic translatome. Translation of anabolic and glucose-metabolism pathways is reduced, whereas transcripts involved in lipid metabolism are selectively enhanced. Leptin treatment markedly increases hepatic Reg3α translation. Hepatic Reg3α overexpression significantly improves hyperglycemia in ID mice without altering insulin-stimulated AKT phosphorylation in key metabolic tissues. These findings identify hepatic translational rewiring as an important feature of ID and Reg3α as an insulin-independent glucoregulatory factor. Diabetes Insulin MRNA translation Dewey 612 Swiss National Science Foundation To elucidate the pathways promoting survival in insulin deficiency 184767 CH Swiss National Science Foundation To determine the role of FKBP10 in cancer 219229 CH Swiss National Science Foundation To elucidate the pathways improving metabolism in insulin deficiency 214870 CH 134 Département de physiologie cellulaire et métabolisme 21C false 578 La biologie du métabolisme dans la santé et la maladie 921 1276 Métabolisme des lipides 1001 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331248 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331062 https://figshare.com/articles/figure/Supplementary_Material_Figures_and_FigureLegends_docx/33265221 Endocrinology 167 10 bb610c88-6204-4e4f-8be6-724313c18c9c Article (Published version) Public bqag100.pdf 5166349 application/pdf CC BY-4.0 861fa46cb025b1531246bd3b115549e15141f2f53f9ff452d36c02415513406e openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Hepatic Translational Rewiring in Insulin Deficiency Identifies Reg3α as an Insulin-Independent Glucoregulatory Factor	Endocrinology			2026	1	0

Archive ouverte UNIGE

Vincent, Sarah

account_balance UNIGE affiliation entities

UNIGE affiliation entities