Glucose-dependent miR-125b is a negative regulator of β-cell function

Abstract

SUMMARYImpaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. MicroRNAs are short non-coding RNAs that silence gene expression, vital for the development and function of endocrine cells. MiR-125b is a highly conserved miRNA abundant in β-cells, though its role in these cells remains unclear. Here, we show that miR-125b expression in human islets correlates with body mass index (BMI) of the donors and is regulated by glucose in an AMP-activated protein kinase-dependent manner in both mice and humans. Using and unbiased high-throughput approach, we identify dozens of direct gene targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Whereas inactivation of miR-125b in human beta cells led to shorter mitochondria and improved glucose stimulated insulin secretion, mice over-expressing mir-125b selectively in β-cells displayed defective insulin secretion and marked glucose intolerance. Moreover, the β-cells of these transgenic animals showed strongly reduced insulin content and secretion and contained enlarged lysosomal structures. Thus, miR125b provides a glucose-controlled regulator of organelle dynamics that negatively regulates insulin secretion in β-cells.HighlightsIslet miR125b correlates with BMI and is regulated by glucose via AMP-activated protein kinase in β-cellsmiR125b targets dozens of genes including those involved in the regulation of mitochondrial (i.e. Mtfp1) and lysosomal (i.e. M6pr) morphology/functionDeletion of miR125b results in shorten mitochondria and improves glucose stimulated insulin secretion (GSIS)Selective overexpression of miR125b in β-cells causes the appearance of enlarged lysosomes, reduced GSIS and insulin content, loss of β-cell identity and impaired insulin secretion and glucose tolerance in vivoGraphical abstract