Abstract
Loss of functional beta cells is the central event of all forms of diabetes. Conventional therapies for type 2 diabetes (T2D) fail to preserve beta cells, leading to worsening glycemia as beta cell function progressively declines. While immunotherapies for type 1 diabetes (T1D) have been unsuccessful, emerging evidence suggests that therapies to revitalize beta cells are essential to reverse T1D. Islet transplantation represents a promising beta cell replacement therapy. However, its widespread application is limited by the scarcity of available islets and post-transplant islet graft loss. Hence, preserving beta cells is fundamental for managing all types of diabetes. Several key beta cell regulators, including pancreatic and duodenal homeobox 1 (PDX1), v-Maf musculoaponeurotic fibrosarcoma oncogene family protein A (MAFA), and paired box 6 (PAX6), are crucial for beta cell function, with their dysregulation tightly linked to beta cell dysfunction. In this commentary, we summarize the roles of PDX1, MAFA, and PAX6 in determining beta cell function and diabetes development. We also explore the potential of gene therapy that delivers these beta cell regulators as therapeutic interventions to rescue beta cell function in diabetes and discuss the strategies of combining gene therapy with cell therapy to enhance islet transplant efficacy.