Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function
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Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function. / 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.
In: Diabetes, Vol. 71, No. 7, 2022, p. 1525-1545.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function
AU - Cheung, Rebecca
AU - Pizza, Grazia
AU - Chabosseau, Pauline
AU - Rolando, Delphine
AU - Tomas, Alejandra
AU - Burgoyne, Thomas
AU - Wu, Zhiyi
AU - Salowka, Anna
AU - Thapa, Anusha
AU - Macklin, Annabel
AU - Cao, Yufei
AU - Nguyen-Tu, Marie Sophie
AU - Dickerson, Matthew T.
AU - Jacobson, David A.
AU - Marchetti, Piero
AU - Shapiro, James
AU - Piemonti, Lorenzo
AU - de Koning, Eelco
AU - Leclerc, Isabelle
AU - Bouzakri, Karim
AU - Sakamoto, Kei
AU - Smith, David M.
AU - Rutter, Guy A.
AU - Martinez-Sanchez, Aida
N1 - Publisher Copyright: © 2022 by the American Diabetes Association.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.2337/db21-0803
DO - 10.2337/db21-0803
M3 - Journal article
C2 - 35476777
AN - SCOPUS:85133102872
VL - 71
SP - 1525
EP - 1545
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 7
ER -
ID: 313707027