title: Preadipocyte factor 1 induces pancreatic ductal cell differentiation into insulin-producing cells.
abstract: The preadipocyte factor 1 (Pref-1) is involved in the proliferation and differentiation of various precursor cells. However, the intracellular signaling pathways that control these processes and the role of Pref-1 in the pancreas remain poorly understood. Here, we showed that Pref-1 induces insulin synthesis and secretion via two independent pathways. The overexpression of Pref-1 activated MAPK signaling, which induced nucleocytoplasmic translocation of FOXO1 and PDX1 and led to the differentiation of human pancreatic ductal cells into β-like cells and an increase in insulin synthesis. Concurrently, Pref-1 activated Akt signaling and facilitated insulin secretion. A proteomics analysis identified the Rab43 GTPase-activating protein as a downstream target of Akt. A serial activation of both proteins induced various granular protein syntheses which led to enhanced glucose-stimulated insulin secretion. In a pancreatectomised diabetic animal model, exogenous Pref-1 improved glucose homeostasis by accelerating pancreatic ductal and β-cell regeneration after injury. These data establish a novel role for Pref-1, opening the possibility of applying this molecule to the treatment of diabetes.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Marie
authors.initials: M
authors.lastname: Rhee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Dong-Sik
authors.initials: DS
authors.lastname: Ham
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Heon-Seok
authors.initials: HS
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Yang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jae-Hyoung
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Youn
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, CA, USA.
authors.forename: Hei Sook
authors.initials: HS
authors.lastname: Sul
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Kun-Ho
authors.initials: KH
authors.lastname: Yoon
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D010183:Pancreatic Ducts / Q000166:cytology*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D000071161:Forkhead Box Protein O1; D020558:GTP Phosphohydrolases; D005947:Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D015534:Trans-Activators; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C512941:DLK1 protein, human; C085126:FOXO1 protein, human; C084010:pancreatic and duodenal homeobox 1 protein; C494918:AKT1 protein, human