Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function
Rebecca Cheung, Grazia Pizza, Pauline Chabosseau, Delphine Rolando, Alejandra Tomás, Thomas Burgoyne, Zhiyi Wu, Anna Sałówka, Anusha Thapa, Annabel Macklin, Yufei Cao, Marie‐Sophie Nguyen‐Tu, Matthew T. Dickerson, David A. Jacobson, Piero Marchetti, James Shapiro, Lorenzo Piemonti, Eelco J.P. de Koning, Isabelle Leclerc, Karim Bouzakri, Kei Sakamoto, David M. Smith, Guy A. Rutter, Aida Martínez-Sánchez
Abstract
Impaired pancreatic β-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 β cells. We have previously shown that β 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 β 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 β 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 β-cell line EndoCβ-H1 shortened mitochondria and enhanced GSIS, whereas mice overexpressing miR-125b-5p selectively in β cells (MIR125B-Tg) were hyperglycemic and glucose intolerant. MIR125B-Tg β 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.