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

Authors

Cheung R Rebecca , Pizza G Grazia , Chabosseau P Pauline , Rolando D Delphine , Tomas A Alejandra , Burgoyne T Thomas , Wu Z Zhiyi , Salowka A Anna , Tapa A Anusha , Macklin A Annabel , Cao Y Yufei , Nguyen-Tu MS Marie-Sophie , Dickerson MT Matthew T , Jacobson DA David A , Marchetti P Piero , Shapiro J James , Piemonti L Lorenzo , de Koning E Eelco , Leclerc I Isabelle , Bouzakri K Karim , Sakamoto K Kei , Smith DM David M , Rutter GA Guy A , Martinez-Sanchez A Aida .
Diabetes. 2022 04 27; ().

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.