Loss-of-function of ALDH3B2 transdifferentiates human pancreatic duct cells into beta-like cells.

Replenishment of pancreatic beta cells is a key to the cure for diabetes. Beta cells regeneration is achieved predominantly by self-replication especially in rodents, but it was also shown that pancreatic duct cells can transdifferentiate into beta cells. How pancreatic duct cells undergo transdifferentiated and whether we could manipulate the transdifferentiation to replenish beta cell mass is not well understood. Using a genome-wide CRISPR screen, we discovered that loss-of-function of ALDH3B2 is sufficient to transdifferentiate human pancreatic duct cells into functional beta-like cells. The transdifferentiated cells have significant increase in beta cell marker genes expression, secrete insulin in response to glucose, and reduce blood glucose when transplanted into diabetic mice. Our study identifies a novel gene that could potentially be targeted in human pancreatic duct cells to replenish beta cell mass for diabetes therapy.

ß Cell Stress and Endocrine Function During T1D: What Is Next to Discover?

Canonically, type 1 diabetes (T1D) is a disease characterized by autoreactive T cells as perpetrators of endocrine dysfunction and ß cell death in the spiral toward loss of ß cell mass, hyperglycemia, and insulin dependence. ß Cells have mostly been considered as bystanders in a flurry of autoimmune processes. More recently, our framework for understanding and investigating T1D has evolved. It appears increasingly likely that intracellular ß cell stress is an important component of T1D etiology/pathology that perpetuates autoimmunity during the progression to T1D. Here we discuss the emerging and complex role of ß cell stress in initiating, provoking, and catalyzing T1D. We outline the bridges between hyperglycemia, endoplasmic reticulum stress, oxidative stress, and autoimmunity from the viewpoint of intrinsic ß cell (dys)function, and we extend this discussion to the potential role for a therapeutic ß cell stress-metabolism axis in T1D. Lastly, we mention research angles that may be pursued to improve ß cell endocrine function during T1D. Biology gleaned from studying T1D will certainly overlap to innovate therapeutic strategies for T2D, and also enhance the pursuit of creating optimized stem cell-derived ß cells as endocrine therapy.