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.
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.
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.
Chang-Qing
CQ
Xia
Department of Pathology, Immunology and Laboratory Medicine, Diabetes Center of Excellence, University of Florida, Gainesville, Florida, United States of America.
Pengcheng
P
Zhang
Department of Pathology, Immunology and Laboratory Medicine, Diabetes Center of Excellence, University of Florida, Gainesville, Florida, United States of America.
Shiwu
S
Li
Department of Pathology, Immunology and Laboratory Medicine, Diabetes Center of Excellence, University of Florida, Gainesville, Florida, United States of America.
Lihui
L
Yuan
Department of Pathology, Immunology and Laboratory Medicine, Diabetes Center of Excellence, University of Florida, Gainesville, Florida, United States of America.
Tina
T
Xia
Department of Pathology, Immunology and Laboratory Medicine, Diabetes Center of Excellence, University of Florida, Gainesville, Florida, United States of America.
Chao
C
Xie
Department of Pathology, Immunology and Laboratory Medicine, Diabetes Center of Excellence, University of Florida, Gainesville, Florida, United States of America.
Michael J
MJ
Clare-Salzler
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D000068877:Imatinib Mesylate; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007951:Leukemia, Myeloid / Q000378:metabolism; D051379:Mice; D010452:Peptide Biosynthesis / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
D001549:Benzamides; D051273:Glucose Transporter Type 2; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D007328:Insulin; C000715627:Nkx2-2 protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; C495682:Slc2a2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; C084010:pancreatic and duodenal homeobox 1 protein; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D005947:Glucose