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

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. © 2022 by the American Diabetes Association.

Citation

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, Kei Sakamoto, David M Smith, Guy A Rutter, Aida Martinez-Sanchez. Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function. Diabetes. 2022 Jul 01;71(7):1525-1545

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PMID: 35476777

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