The miR-203/ZBTB20/MAFA Axis Orchestrates Pancreatic β-Cell Maturation and Identity During Weaning and Diabetes.

Maturation of postnatal β-cells is regulated in a cell-autonomous manner, and metabolically stressed β-cells regress to an immature state, ensuring defective β-cell function and the onset of type 2 diabetes. The molecular mechanisms connecting the nutritional transition to β-cell maturation remain largely unknown. Here, we report a mature form of miRNA (miR-203)/ZBTB20/MAFA regulatory axis that mediates the β-cell maturation process. We show that the level of the mature form of miRNA (miR-203) in β-cells changes during the nutritional transition and that miR-203 inhibits β-cell maturation at the neonatal stage and under high-fat diet conditions. Using single-cell RNA sequencing, we demonstrated that miR-203 elevation promoted the transition of immature β-cells into CgB^Hi endocrine cells while suppressing gene expressions associated with β-cell maturation in a ZBTB20/MAFA-dependent manner. ZBTB20 is an authentic target of miR-203 and transcriptionally upregulates MAFA expression. Manipulating the miR-203/ZBTB20/MAFA axis may therefore offer a novel strategy for boosting functional β-cell numbers to alleviate diabetes. Article Highlights: Nutritional transition from a high-fat diet to carbohydrate-rich diet inhibits expression of the mature form of miRNA (miR-203). Failure to inhibit miR-203 during high-fat diet feeding causes β-cell immaturity and loss of identity. Ablation of miR-203 in β-cells prevents high-fat diet–induced β-cell dysfunction. The miR-203-ZBTB20-MAFA axis mediates β-cell immaturity and is conserved in humans. [ABSTRACT FROM AUTHOR]