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

Autor:	Cheung R; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Pizza G; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Chabosseau P; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Rolando D; Beta Cell Genome Regulation Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Tomas A; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Burgoyne T; UCL Institute of Ophthalmology, University College London, London, U.K., Wu Z; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Salowka A; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Thapa A; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Macklin A; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Cao Y; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Nguyen-Tu MS; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K., Dickerson MT; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN., Jacobson DA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN., Marchetti P; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy., Shapiro J; Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, Canada., Piemonti L; Vita-Salute San Raffaele University, Milan, Italy., de Koning E; Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands., Leclerc I; CR-CHUM, University of Montreal, Montreal, Quebec, Canada., Bouzakri K; UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France., Sakamoto K; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Smith DM; Emerging Innovations Unit, Discovery Sciences, R&D, AstraZeneca, Cambridge, U.K., Rutter GA; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K.; CR-CHUM, University of Montreal, Montreal, Quebec, Canada.; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore., Martinez-Sanchez A; Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2022 Jul 01; Vol. 71 (7), pp. 1525-1545.
DOI:	10.2337/db21-0803
Abstrakt:	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.)
Databáze:	MEDLINE
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