Transgenic overexpression of microRNA-30d in pancreatic beta-cells progressively regulates beta-cell function and identity

Abnormal microRNA functions are closely associated with pancreatic beta-cell loss and dysfunction in type 2 diabetes. Dysregulation of miR-30d has been reported in the individuals with diabetes. To study how miR-30d affects pancreatic beta-cell functions, we generated two transgenic mouse lines that specifically overexpressed miR-30d in beta-cells at distinct low and high levels. Transgenic overexpressed miR-30d systemically affected beta-cell function. Elevated miR-30d at low-level (TgL, 2-fold) had mild effects on signaling pathways and displayed no significant changes to metabolic homeostasis. In contrast, transgenic mice with high-level of miR-30d expression (TgH, 12-fold) exhibited significant diet-induced hyperglycemia and beta-cell dysfunction. In addition, loss of beta-cell identity was invariably accompanied with increased insulin/glucagon-double positive bihormonal cells and excess plasma glucagon levels. The transcriptomic analysis revealed that miR-30d overexpression inhibited beta-cell-enriched gene expression and induced alpha-cell-enriched gene expression. These findings implicate that an appropriate miR-30d level is essential in maintaining normal beta-cell identity and function.