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

Chang-Qing Xia; Pengcheng Zhang; Shiwu Li; Lihui Yuan; Tina Xia; Chao Xie; Michael J Clare-Salzler

doi:10.1371/journal.pone.0097694

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

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

Authors

Chang-Qing Xia¹, Pengcheng Zhang², Shiwu Li², Lihui Yuan², Tina Xia², Chao Xie², Michael J Clare-Salzler²

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzamides / pharmacology*
Cell Line
Gene Expression Regulation
Glucose / metabolism
Glucose Transporter Type 2 / genetics
Glucose Transporter Type 2 / metabolism*
Homeobox Protein Nkx-2.2
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Imatinib Mesylate
Insulin / biosynthesis*
Insulin / genetics
Insulin-Secreting Cells / drug effects*
Leukemia, Myeloid / metabolism
Mice
Peptide Biosynthesis / drug effects
Piperazines / pharmacology*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
Proto-Oncogene Proteins c-abl / genetics
Proto-Oncogene Proteins c-abl / physiology
Pyrimidines / pharmacology*
RNA, Small Interfering / metabolism
Trans-Activators / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism*
Zebrafish Proteins

Substances

Benzamides
Glucose Transporter Type 2
Homeobox Protein Nkx-2.2
Homeodomain Proteins
Insulin
Nkx2-2 protein, mouse
Piperazines
Protein Kinase Inhibitors
Pyrimidines
RNA, Small Interfering
Slc2a2 protein, mouse
Trans-Activators
Transcription Factors
Zebrafish Proteins
nkx2.2b protein, zebrafish
pancreatic and duodenal homeobox 1 protein
Imatinib Mesylate
Proto-Oncogene Proteins c-abl
Glucose

Grants and funding

This work was partially supported by JDRF academic R&D award (17-2008-1036 to CQX) and National Natural Science Foundation of China (81172854 and 81241015 to CQX). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.