Abstract
Pancreatic β cells adapt to compensate for increased metabolic demand during insulin resistance. Although the microRNA pathway has an essential role in β cell proliferation, the extent of its contribution is unclear. Here, we report that miR-184 is silenced in the pancreatic islets of insulin-resistant mouse models and type 2 diabetic human subjects. Reduction of miR-184 promotes the expression of its target Argonaute2 (Ago2), a component of the microRNA-induced silencing complex. Moreover, restoration of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory β cell expansion. Loss of Ago2 during insulin resistance blocked β cell growth and relieved the regulation of miR-375-targeted genes, including the growth suppressor Cadm1. Lastly, administration of a ketogenic diet to ob/ob mice rescued insulin sensitivity and miR-184 expression and restored Ago2 and β cell mass. This study identifies the targeting of Ago2 by miR-184 as an essential component of the compensatory response to regulate proliferation according to insulin sensitivity.
Original language | English |
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Pages (from-to) | 122-34 |
Number of pages | 13 |
Journal | Cell Metabolism |
Volume | 19 |
Issue number | 1 |
Early online date | 19 Dec 2013 |
DOIs | |
Publication status | Published - 7 Jan 2014 |
Keywords
- Animals
- Argonaute Proteins
- Cell Proliferation
- Diet, Ketogenic
- Gene Expression Regulation
- Gene Silencing
- Humans
- Insulin Resistance
- Insulin-Secreting Cells
- Mice
- Mice, Obese
- MicroRNAs
- Journal Article
- Research Support, Non-U.S. Gov't