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 T1DM^4,5. 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 T1DM^4,5,6,7.  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 used^9,10. Mice were then induced to have diabetes by ablating β cells with streptozotoxin or by knocking out Arx gene with shRNA^9,10,11. 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 versa^8,9,11. 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 GABA_A 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 GABA_A 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.

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