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.

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

Marchetti, Piero;
2022-01-01

Abstract

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
Cheung, Rebecca; Pizza, Grazia; Chabosseau, Pauline; Rolando, Delphine; Tomas, Alejandra; Burgoyne, Thomas; Wu, Zhiyi; Salowka, Anna; Thapa, Anusha; Macklin, Annabel; Cao, Yufei; Nguyen-Tu, Marie-Sophie; Dickerson, Matthew T; Jacobson, David A; Marchetti, Piero; Shapiro, James; Piemonti, Lorenzo; de Koning, Eelco; Leclerc, Isabelle; Bouzakri, Karim; Sakamoto, Kei; Smith, David M; Rutter, Guy A; Martinez-Sanchez, Aida
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1150582
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