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

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posted on 27.04.2022, 20:01 by Rebecca Cheung, Grazia Pizza, Pauline Chabosseau, Delphine Rolando, Alejandra Tomas, Thomas Burgoyne, Zhiyi Wu, Anna Salowka, Anusha Tapa, Annabel Macklin, Yufei Cao, Marie-Sophie Nguyen-Tu, Matthew T. Dickerson, David A. Jacobson, Piero Marchetti, James Shapiro, Lorenzo Piemonti, Eelco de Koning, Isabelle Leclerc, Karim Bouzakri, Kei Sakamoto, David M. Smith, Guy A. Rutter, Aida Martinez-Sanchez

Impaired 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 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 hyperglycaemia in β-cells. Here we show that islet miR-125b-5p expression is up-regulated 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, whilst mice over-expressing miR-125b-5p selectively in β-cells (MIR125B-Tg) were hyperglycaemic and glucose intolerant. MIR125B-Tg β-cells contained enlarged lysosomal structures and showed reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion.

Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 115881 (RHAPSODY) to G.R. and P.M. Human islet preparations (Milan, Italy) were obtained from the European Consortium for Islet Transplantation; the Human Islet Distribution program was supported by Juvenile Diabetes Research Foundation Grant 3-RSC-2016-160-I-X.

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