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Contribution of intronic miR-338-3p and its hosting gene AATK to compensatory beta-cell mass expansion

Abstract

The elucidation of the mechanisms directing beta-cell mass regeneration and maintenance is of interest, because the deficit of beta-cell mass contributes to diabetes onset and progression. We previously found that the level of the microRNA (miRNA) miR-338-3p is decreased in pancreatic islets from rodent models displaying insulin resistance and compensatory beta-cell mass expansion, including pregnant rats, diet-induced obese mice, and db/db mice. Transfection of rat islet cells with oligonucleotides that specifically block miR-338-3p activity increased the fraction of proliferating beta-cells in vitro and promoted survival under proapoptotic conditions without affecting the capacity of beta-cells to release insulin in response to glucose. Here, we evaluated the role of miR-338-3p in vivo by injecting mice with an adeno-associated viral vector permitting specific sequestration of this miRNA in beta-cells. We found that the adeno-associated viral construct increased the fraction of proliferating beta-cells confirming the data obtained in vitro. miR-338-3p is generated from an intron of the gene coding for apoptosis-associated tyrosine kinase (AATK). Similarly to miR-338-3p, we found that AATK is down-regulated in rat and human islets and INS832/13 beta-cells in the presence of the cAMP-raising agents exendin-4, estradiol, and a G-protein-coupled Receptor 30 agonist. Moreover, AATK expression is reduced in islets of insulin resistant animal models and selective silencing of AATK in INS832/13 cells by RNA interference promoted beta-cell proliferation. The results point to a coordinated reduction of miR-338-3p and AATK under insulin resistance conditions and provide evidence for a cooperative action of the miRNA and its hosting gene in compensatory beta-cell mass expansion.

Type Journal
ISBN 1944-9917 (Electronic) 0888-8809 (Linking)
Authors Jacovetti, C.; Jimenez, V.; Ayuso, E.; Laybutt, R.; Peyot, M. L.; Prentki, M.; Bosch, F.; Regazzi, R.;
Garvan Authors A/Prof Ross Laybutt
Publisher Name MOL ENDOCRINOL
Published Date 2015-01-01 00:00:00
Published Volume 29
Published Issue 5
Published Pages 693-702
URL http://www.ncbi.nlm.nih.gov/pubmed/25751313
Status Published In-print