Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function

Impaired pancreatic beta-cell function and insulin secretion are hallmarks of type 2 diabetes. miRNAs are short, noncoding RNAs that silence gene expression vital for the development and function of beta cells. We have previously shown that beta cell-specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in beta cells is unclear. We hypothesized that miR-125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycemia in beta cells. Here, we show that islet miR-125b-5p expression is upregulated by glucose in an AMPK-dependent manner and that short-term miR-125b-5p overexpression impairs glucose-stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased, high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human beta-cell line EndoC beta-H1 shortened mitochondria and enhanced GSIS, whereas mice overexpressing miR-125b-5p selectively in beta cells (MIR125B-Tg) were hyperglycemic and glucose intolerant. MIR125B-Tg beta cells contained enlarged lysosomal structures and had reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion.

Automated summary

This study demonstrates that the elevated expression of miR-125b-5p is associated with impaired pancreatic beta-cell function in type 2 diabetes, and overexpression of this miRNA impairs glucose-stimulated insulin secretion. Screening identifies multiple targets of miR-125b-5p, including a transporter and a regulator of organelle dynamics. In human beta cells, silencing miR-125b-5p enhances insulin secretion, while overexpression in a mouse model leads to hyperglycemia and glucose intolerance.