4.7 Article

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

Journal

DIABETES
Volume 71, Issue 7, Pages 1525-1545

Publisher

AMER DIABETES ASSOC
DOI: 10.2337/db21-0803

Keywords

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Funding

  1. MRC New Investigator Research Grant [MR/P023223/1]
  2. Wellcome Trust Senior Investigator Award [WT098424AIA, 212625/Z/18/Z]
  3. MRC Programme grants [MR/R022259/1, MR/J0003042/1, MR/L020149/1]
  4. MRC [MR/R010676/1]
  5. Diabetes UK project grant [16/0005485]
  6. European Union [115881]
  7. Juvenile Diabetes Research Foundation Grant [3-RSC-2016-160-I-X]
  8. Wellcome Trust [212625/Z/18/Z] Funding Source: Wellcome Trust

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This study demonstrates that the elevated expression of miR-125b-5p is associated with impaired pancreatic beta-cell function in type 2 diabetes, and overexpression of this miRNA impairs glucose-stimulated insulin secretion. Screening identifies multiple targets of miR-125b-5p, including a transporter and a regulator of organelle dynamics. In human beta cells, silencing miR-125b-5p enhances insulin secretion, while overexpression in a mouse model leads to hyperglycemia and glucose intolerance.
Impaired pancreatic beta-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 beta cells. We have previously shown that beta 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 beta 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 beta 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 beta-cell line EndoC beta-H1 shortened mitochondria and enhanced GSIS, whereas mice overexpressing miR-125b-5p selectively in beta cells (MIR125B-Tg) were hyperglycemic and glucose intolerant. MIR125B-Tg beta 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.

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