title: Sox17 regulates insulin secretion in the normal and pathologic mouse β cell.
abstract: SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1β and FOXA2, which are known to regulate postnatal β cell function. Given this, we investigated the role of SOX17 in the developing and postnatal pancreas and found a novel role for SOX17 in regulating insulin secretion. Deletion of the Sox17 gene in the pancreas (Sox17-paLOF) had no observable impact on pancreas development. However, Sox17-paLOF mice had higher islet proinsulin protein content, abnormal trafficking of proinsulin, and dilated secretory organelles suggesting that Sox17-paLOF adult mice are prediabetic. Consistant with this, Sox17-paLOF mice were more susceptible to aged-related and high fat diet-induced hyperglycemia and diabetes. Overexpression of Sox17 in mature β cells using Ins2-rtTA driver mice resulted in precocious secretion of proinsulin. Transcriptionally, SOX17 appears to broadly regulate secretory networks since a 24-hour pulse of SOX17 expression resulted in global transcriptional changes in factors that regulate hormone transport and secretion. Lastly, transient SOX17 overexpression was able to reverse the insulin secretory defects observed in MODY4 animals and restored euglycemia. Together, these data demonstrate a critical new role for SOX17 in regulating insulin trafficking and secretion and that modulation of Sox17-regulated pathways might be used therapeutically to improve cell function in the context of diabetes.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Diva
authors.initials: D
authors.lastname: Jonatan
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, United States of America; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States of America; Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI, United States of America.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Spence
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Method
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kofron
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Katie
authors.initials: K
authors.lastname: Sinagoga
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, MI, United States of America.
authors.forename: Leena
authors.initials: L
authors.lastname: Haataja
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, MI, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.affiliation: Seattle Children's Hospital, Seattle, WA, United States of America.
authors.forename: Gail H
authors.initials: GH
authors.lastname: Deutsch
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Wells
mesh_terms: D000818:Animals; D005260:Female; D005455:Fluorescent Antibody Technique; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D010179:Pancreas / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D060888:Real-Time Polymerase Chain Reaction; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D024002:HMGB Proteins; D007328:Insulin; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse