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Diabetes 51:1785-1792, 2002
© 2002 by the American Diabetes Association, Inc.

Hepatocyte Nuclear Factor-1{alpha} Modulates Pancreatic ß-Cell Growth by Regulating the Expression of Insulin-Like Growth Factor-1 in INS-1 Cells

Qin Yang1, Kazuya Yamagata1, Kenji Fukui1, Yang Cao1, Takao Nammo1, Hiromi Iwahashi1, Haiyan Wang2, Itaru Matsumura3, Toshiaki Hanafusa4, Richard Bucala5, Claes B. Wollheim2, Jun-ichiro Miyagawa1, and Yuji Matsuzawa1

1 Department of Internal Medicine and Molecular Science, Biomedical Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan
2 Division of Clinical Biochemistry, Department of Internal Medicine, Geneva University Medical Center, Geneva, Switzerland
3 Department of Hematology/Oncology, Biomedical Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan
4 First Department of Internal Medicine, Osaka Medical College, Osaka, Japan
5 Picower Institute for Medical Research, Manhasset, New York

Maturity-onset diabetes of the young type 3 (MODY3) is characterized by impaired insulin secretion. Heterozygous mutations in the gene encoding hepatocyte nuclear factor (HNF)-1{alpha} are the cause of MODY3. Transgenic mice overexpressing dominant-negative HNF-1{alpha} mutant in pancreatic ß-cells and HNF-1{alpha} knockout mice are animal models of MODY3. These mice exhibit defective glucose-stimulated insulin secretion and have reduced ß-cell mass and ß-cell proliferation rate. Here we examined the effect of HNF-1{alpha} on ß-cell proliferation by overexpressing a human naturally occurring dominant- negative mutation P291fsinsC in INS-1 cells under the control of doxycycline-induction system. INS-1 cells overexpressing P291fsinsC showed apparent growth impairment. The proliferation rate estimated by [3H]thymidine incorporation was significantly reduced in P291fsinsC-expressing INS-1 cells compared with noninduced or wild-type HNF-1{alpha}-overexpressing INS-1 cells. Growth inhibition occurred at the transition from G1 to S cell cycle phase, with reduced expression of cyclin E and upregulation of p27. cDNA array analysis revealed that the expression levels of IGF-1, a major growth factor for ß-cells, and macrophage migration inhibitory factor (MIF), a cytokine expressed in pancreatic ß-cells, were reduced in P291fsinsC-HNF-1{alpha}–expressing INS-1 cells. Although MIF seemed to have proliferative function, blockade of MIF action by anti-MIF antibody stimulated INS-1 cell proliferation, excluding its direct role in the growth impairment. However, addition of IGF-1 to P291fsinsC–expressing INS-1 cells rescued the growth inhibition. Our data suggest that HNF-1{alpha} is critical for modulating pancreatic ß-cell growth by regulating IGF-1 expression. IGF-1 might be a potential therapeutic target for the treatment of MODY3.


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