Preadipocyte factor 1 induces pancreatic ductal cell differentiation into insulin-producing cells

• Published in: Scientific reports 2016-04, Vol.6 (1), p.23960, Article 23960
• Main Authors: Rhee, Marie, Lee, Seung-Hwan, Kim, Ji-Won, Ham, Dong-Sik, Park, Heon-Seok, Yang, Hae Kyung, Shin, Ju-Young, Cho, Jae-Hyoung, Kim, Young-Bum, Youn, Byung-Soo, Sul, Hei Sook, Yoon, Kun-Ho
• Format: Article
• Language: English
• Subjects: 631/80/86; 692/163/2743/137; 82/80; 96/1; 96/95; AKT protein; Animal models; Animals; Cell Differentiation; Cell Line, Tumor; Cell proliferation; Diabetes mellitus; Enzyme Inhibitors - chemistry; Extracellular Signal-Regulated MAP Kinases - metabolism; Forkhead Box Protein O1 - metabolism; FOXO1 protein; Glucose; Glucose - metabolism; GTP Phosphohydrolases - metabolism; GTPase-activating protein; Guanosine triphosphatases; Homeodomain Proteins - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Insulin; Insulin - metabolism; Insulin secretion; Insulin-Secreting Cells - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Intracellular signalling; MAP kinase; MAP Kinase Signaling System; Membrane Proteins - metabolism; multidisciplinary; Pancreas; Pancreatic Ducts - cytology; Pancreatic Neoplasms - metabolism; Phosphorylation; Preadipocyte factor 1; Proteomics; Proto-Oncogene Proteins c-akt - metabolism; rab GTP-Binding Proteins - metabolism; Rats; Rats, Sprague-Dawley; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Secretion; Signal Transduction; Trans-Activators - metabolism; Translocation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep23960

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.