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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Rebecca Cheung
  • Grazia Pizza
  • Pauline Chabosseau
  • Delphine Rolando
  • Alejandra Tomas
  • Thomas Burgoyne
  • Zhiyi Wu
  • Anna Salowka
  • Anusha Thapa
  • 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
  • David M. Smith
  • Guy A. Rutter
  • Aida Martinez-Sanchez

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.

Original languageEnglish
Issue number7
Pages (from-to)1525-1545
Number of pages21
Publication statusPublished - 2022

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© 2022 by the American Diabetes Association.

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