Hepatocyte Nuclear Factor-1α Modulates Pancreatic β-Cell Growth by Regulating the Expression of Insulin-Like Growth Factor-1 in INS-1 Cells

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 6; pp. 1785 - 1792
• Main Authors: YANG, Qin, YAMAGATA, Kazuya, WOLLHEIM, Claes B, MIYAGAWA, Jun-Ichiro, MATSUZAWA, Yuji, FUKUI, Kenji, CAO, Yang, NAMMO, Takao, IWAHASHI, Hiromi, WANG, Haiyan, MATSUMURA, Itaru, HANAFUSA, Toshiaki, BUCALA, Richard
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2002
• Subjects: Biological and medical sciences; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Insulin-like growth factor 1; Medical sciences; Physiological aspects; United States; Japan; Endocrinopathy; Maturity onset diabetes young; Transcription factor HNF1; Cell line; β Cell; Gene expression; Insulin like growth factor 1; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.6.1785

Hepatocyte Nuclear Factor-1α Modulates Pancreatic β-Cell Growth by Regulating the Expression of Insulin-Like Growth Factor-1 in INS-1 Cells Qin Yang 1 , Kazuya Yamagata 1 , Kenji Fukui 1 , Yang Cao 1 , Takao Nammo 1 , Hiromi Iwahashi 1 , Haiyan Wang 2 , Itaru Matsumura 3 , Toshiaki Hanafusa 4 , Richard Bucala 5 , Claes B. Wollheim 2 , Jun-ichiro Miyagawa 1 and Yuji Matsuzawa 1 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 Abstract 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)-1α are the cause of MODY3. Transgenic mice overexpressing dominant-negative HNF-1α mutant in pancreatic β-cells and HNF-1α knockout mice are animal models of MODY3. These mice exhibit defective glucose-stimulated insulin secretion and have reduced β-cell mass and β-cell proliferation rate. Here we examined the effect of HNF-1α on β-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 [ 3 H]thymidine incorporation was significantly reduced in P291fsinsC-expressing INS-1 cells compared with noninduced or wild-type HNF-1α-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 β-cells, and macrophage migration inhibitory factor (MIF), a cytokine expressed in pancreatic β-cells, were reduced in P291fsinsC-HNF-1α–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-1α is critical for modulating pancreatic β-cell growth by regulating IGF-1 expression. IGF-1 might be a potential therapeutic target for the treatment of MODY3. Footnotes Address correspondence and reprint requests to Kazuya Yamagata, MD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: kazu{at}imed2.med.osaka-u.ac.jp . Received for publication 10 December 2001 and accepted in revised form 26 February 2002. CDK, cyclin-dependent kinase; FACS, fluorescence-activated cell sorter; HGF, hepatocyte growth factor; HNF, hepatocyte nuclear factor; IGFBP, IGF binding protein; MIF, migration inhibitory factor; MODY, maturity-onset diabetes of the young; PI, phosphatidylinositol; PL, placental lactogen; WT, wild-type. DIABETES