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

Cheung, Rebecca; Pizza, Grazia; Chabosseau, Pauline; Rolando, Delphine; Tomas, Alejandra; Burgoyne, Thomas; Wu, Zhiyi; ... Martinez-Sanchez, Aida; + view all (2022) Glucose-Dependent miR-125b is a Negative Regulator of β-Cell Function. Diabetes 10.2337/db21-0803. (In press). Green open access

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Abstract

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 miR125b-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 miR125b-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 overexpressing 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 glucosecontrolled regulator of organelle dynamics that modulates insulin secretion.

Type: Article
Title: Glucose-Dependent miR-125b is a Negative Regulator of β-Cell Function
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.2337/db21-0803
Publisher version: https://doi.org/10.2337/db21-0803
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10148003
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