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PLoS One. 2014 May 16;9(5):e97694. doi: 10.1371/journal.pone.0097694. eCollection 2014.

C-Abl inhibitor imatinib enhances insulin production by β cells: c-Abl negatively regulates insulin production via interfering with the expression of NKx2.2 and GLUT-2.

Author information

1
Department of Hematology, Xuanwu Hospital, Capital Medical University, Bejing, China; Department of Pathology, Immunology and Laboratory Medicine, Diabetes Center of Excellence, University of Florida, Gainesville, Florida, United States of America.
2
Department of Pathology, Immunology and Laboratory Medicine, Diabetes Center of Excellence, University of Florida, Gainesville, Florida, United States of America.

Abstract

Chronic myelogenous leukemia patients treated with tyrosine kinase inhibitor, Imatinib, were shown to have increased serum levels of C-peptide. Imatinib specifically inhibits the tyrosine kinase, c-Abl. However, the mechanism of how Imatinib treatment can lead to increased insulin level is unclear. Specifically, there is little investigation into whether Imatinib directly affects β cells to promote insulin production. In this study, we showed that Imatinib significantly induced insulin expression in both glucose-stimulated and resting β cells. In line with this finding, c-Abl knockdown by siRNA and overexpression of c-Abl markedly enhanced and inhibited insulin expression in β cells, respectively. Unexpectedly, high concentrations of glucose significantly induced c-Abl expression, suggesting c-Abl may play a role in balancing insulin production during glucose stimulation. Further studies demonstrated that c-Abl inhibition did not affect the major insulin gene transcription factor, pancreatic and duodenal homeobox-1 (PDX-1) expression. Of interest, inhibition of c-Abl enhanced NKx2.2 and overexpression of c-Abl in β cells markedly down-regulated NKx2.2, which is a positive regulator for insulin gene expression. Additionally, we found that c-Abl inhibition significantly enhanced the expression of glucose transporter GLUT2 on β cells. Our study demonstrates a previously unrecognized mechanism that controls insulin expression through c-Abl-regulated NKx2.2 and GLUT2. Therapeutic targeting β cell c-Abl could be employed in the treatment of diabetes or β cell tumor, insulinoma.

PMID:
24835010
PMCID:
PMC4023982
DOI:
10.1371/journal.pone.0097694
[Indexed for MEDLINE]
Free PMC Article

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