Targeting Pax4 for α- to β-cell Transdifferentiation: a Promising Therapy for Diabetes Mellitus Type 1

Victor H. Rodríguez

Introduction. Type 1 diabetes mellitus (T1DM) is an autoimmune disease causing chronic inflammation of the pancreatic islets of Langerhans affecting β cells and insulin production and yields hyperglycemic states in individuals1. T1DM affects U.S. 3 million people2. Untreated individuals develop retinopathy, kidney disease, cardiovascular disease, and neuropathy3. Current insulin and pancreatic transplant treatments provide limited relief3. Although studies have been directed on the autoimmune mediated process for future therapies, new studies have focused Pax4 due to polymorphs associated development of T1DM4,5. Moreover, expression of Pax4 has been noted to be necessary and sufficient to promote β-cell differentiation in pancreas morphogenesis in mice, suggesting a possible therapy to treat T1DM4,5,6,7.  Methods. RIP-B7.1 with tetracycline response element to promote Pax4 was used to induce T1DM in mice and observe the protective role of Pax4 in diabetes8. To identify the potential of a to β cell transdifferentiation, aTC1.9 and Glu-Cre::ROSA transgenic mice were used9,10. Mice were then induced to have diabetes by ablating β cells with streptozotoxin or by knocking out Arx gene with shRNA9,10,11. Future treatment for T1DM assays involved the use of Artemisinins and an Adenovirus vector with the Pax4 genome (Ad5.Pax4)10,12. Data was analyzed through immunohistochemistry, electron microscopy, and RNA microarrays techniques. Results. The induced overexpression of Pax4 upregulates genes involved in the cell cycle and ER homeostasis in RIP-B7.1 mice in comparison to mutated Pax4 gene8. Pax4 promotes β cell proliferation while also down-regulating Arx, a gene involved in a cell expression, and vice versa8,9,11. Long-term gamma-Aminobutyric acid (GABA) treatment in T1DM induced mice reveal upregulation of Pax4 gene expression9. Glu-Cre::ROSA transgenic mice confirm a to β cell conversion when Pax4 is overexpressed9. Antimalaria drug, artemisinins, binds GABAA receptors and reveals increased insulin secretion and a to β cell transdifferentiation in zebra fish, rodent, and human cell models10. Pax4 can be transferred into a cells with Ad5.Pax412. Ad5.Pax4 treated human a cells can be injected intraperitoneally into T1DM-induced mice and decrease hyperglycemic conditions12. Conclusion. Studies reveal the important role of Pax4 in protecting against β cell survival, but also its potential role in transdifferentiating a to β cells. Additionally, these studies elucidate the role of GABAA in upregulating Pax4 to help identify target treatment options, such as Artemisinins, for T1DM patients. Lastly, Pax4 research has identified a possible injectable vector treatment for T1DM that promotes a to β cell conversion.


  1. Clark M, Kroger CJ, Tisch RM. Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response. Frontiers in Immunology. 2017;8:1898. doi:10.3389/fimmu.2017.01898.
  2. Chiang JL, Kirkman MS, Laffel LM, Peters AL. Type 1 Diabetes Through the Life Span: A Position Statement of the American Diabetes Association. Diabetes Care. 2014;37(7):2034-2054. doi:10.2337/dc14-1140.
  3. Lu J, Xia Q, Zhou Q. How to make insulin-producing pancreatic β cells for diabetes treatment. Science China Life Sciences. 2017;60(3):239-248.
  4. Napolitano T, Avolio F, Courtney M, et al. Pax4 acts as a key player in pancreas development and plasticity. Seminars in Cell & Developmental Biology. 2015;44:107–
  5. Lorenzo PI, Juárez-Vicente F, Cobo-Vuilleumier N, García-Domínguez M, Guathier BR. The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consecuences. Genes. 2017;101(8):1–
  6. Bouwens L, Houbracken I, Mfopou JK. The use of stem cells for pancreatic regeneration in diabetes mellitus. Nature Reviews Endocrinology. 2013;9:598–
  7. Vetere A, Choudhary A, Burns SM, Wagner BK. Targeting the pancreatic β-cells to treat diabetes. Nature Reviews Drug Discovery. 2014;13:278–
  8. Mellado-Gil JM, Jiménez-Moreno CM, Martin-Montalvo A, et al. PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus. Diabetologia. 2016;59:755–765.
  9. Ben-Othman N, Vieira A, Courtney M, et al. Long-Term GABA Administration Induces Aplha Cell-Mediated Beta-like Cell Neogenesis. Cell. 2017;168:73–85.
  10. Li J, Casteels T, Frogne T, et al. Artemisinins Target GABAA Receptor Signaling and Impair a Cell Identity. Cell. 2017;168:86–100.
  11. Friedman-Mazursky O, Elkon R, Efrat S. Redifferentiation of expanded human islet β cells by inhibition of ARX. Nature Scientific Reports. 2016;6:20698.
  12. Zhang Y, Fava GE, Wang H, Mauvais-Jarivs F, Fonseca VA, Wu H. PAX4 Gene Transfer Induces a-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Molecular Therapy. 2016;24(2):251–260.