Identification of molecular mechanism of pancreatic β-cell development and growth by hepatocyte nuclear factors(HNFs)

• Project/Area Number: 13671190
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Osaka University
• Principal Investigator: YAMAGATA Kazuya Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70324770)
• Co-Investigator(Kenkyū-buntansha): OKITA Kohei Osaka University Graduate School of Medicine, Medical staff, 医学部附属病院, 医員(臨床研究) ; MIYAGAWA Junnichiro Osaka University Graduate school of Medicine, Lecturer, 医学系研究科, 講師 (00127721) ; 上中 理香子 大阪大学, 医学部・附属病院, 医員
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2001: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: diabetes mellitus / maturity-onset diabetes of the young (MODY) / insulin / transcription factor / HNF-1 / growth / development / IGF-1

Research Abstract

Maturity-onset diabetes of the young (MODY) is a monogenic form of type 2 diabetes. We have shown that heterozygous mutations in genes encoding hepatocyte nuclear factor (HNF)-1α, HNF-1β and HNF-4α cause MODY (Nature 1996a, Nature 1996b and Nature Genet. 1997). In the present study, we first examined whether HNF is involved in the development and the gowth of pancreatic β-cells. Immunohistochemical analysis showed that HNF1α is expressed in all kinds of endocrine cells (α-cells, β-cells, δ-cells and Ppcells) in mouse pancreas from the developmental stage. Double staining of pancreas for HNF-1α and various transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2) suggested that HNF-1α expression occurs after the expression of PDX-1, Pax6, Isl1, and Nkx2.2 (Diabetologia 2002).
P291fsinsC-HNF-1α is a most common mutation identified in human MODY3 patients and this mutation functions as dominant negative (Diabetes 1998). Transgenic mice overexpressing P291 fsinsC-HNF-1α mutant in pancreatic β-cells developed diabetes with reduced β-cell number and β-cell growth (Diabetes 2002a). To elucidate the mechanism, we overexpressed the same mutant in INS-1 cells using Tet-On system under the control of doxycyclin (Diabetes 2002b). Cell growth of the INS-1 cells overexpressing P291fsinsC-HNF-1α was impaired with the reduced expression of IGF-1. The addition of IGF-1 rescued the reduced cell growth of P291fsinsC-HNF-1α expressing INS-1 cells.
These data suggest that HNF-1α is involved in the growth and the development of pancreatic β-cells.

Research Products

• [Publications] Kazuya Yamagata et al.: "Overexpression of dominant-negative mutant HNF-1α in pancreatic β-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced β-cell proliferation and diabetes"Diabetes. 51. 114-123 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Issei Yoshiuchi et al.: "Identification of a gain-of-function mutation in the HNF-1β gene in a Japanese family with MODY"Diabetologia. 45. 153-154 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Hiromi Iwahashi et al.: "Thyroid hormone receptor interacting protein 3 (Trip3) is a novel coactivator of hepatocyte nuclear factor-4α"Diabetes. 51. 910-914 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Qin Yang et al.: "Hepatocyte nuclear factor-1α modulates pancreatic β-Cell growth by regulating the expression of insulin-like growth factor-1 in INS-1 cells"Diabetes. 51. 1785-1792 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Takao Nammo et al.: "Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas"Diabetologia. 45. 1142-1153 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yoshiuchi I, Yamagata K, Zhu Q, Tamada I, Takahashi Y, Onigata K, Takeda J, Miyagawa J, Matsuzawa J:: "Identification of a gain-of-function mutation in the HNF-1β gene in a Japanese family with MODY."Diabetologia. 45. 153-154 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yamagata K, Nammo T, Moriwaki M, Ihara A, Iizuka K, Yang Q, Satoh T, Li M, Uenaka R, Okita K, Iwahashi H, Zhu Q, Cao Y, Imagawa A, Tochino Y, Hanafusa T, Miyagawa J, Matsuzawa, Y:: "Overexpression of dominant-negative mutant HNF-1α in pancreatic β-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced β-cell proliferation and diabetes."Diabetes. 51. 114-123 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Iwahashi H, Yamagata K, Yoshiuchi I, Terasaki J, Yang Q, Fukui K, Ihara A, Zhu Q, Asakura T, Cao Y, Imagawa A, Namba M, Hanafusa T, Miyagawa J, Matsuzawa Y:: "Thyroid hormone receptor interacting protein (Trip3) is a novel coactivator of hepatocyte nuclear factor-4α (HNF-4α)"Diabetes. 51. 910-914 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yang Q, Yamagata K, Fukui K, Cao Yang, Nammo T, Iwahashi H, Wang H, Matsumura I, Hanafusa T, Bucala R, Wollheim CB, Miyagawa J, Matsuzawa Y:: "Hepatocyte nuclear factor-1α modulates pancreatic β-cell growth by regulating the expression of insulin-like growth factor-1 in INS-1 cells."Diabetes. 51. 1785-1792 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nammo T, Yamagata K, Hamaoka R, Zhu Q, Akiyama TE, Gonzalez FJ, Miyagawa J, Matsuzawa Y:: "Expression profile of MODY3/HNF-lα protein in the developing mouse pancreas."Diabetologia. 45. 1142-1153 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kazuya Yamagata et al.: "Overexpression of dominant-negative mutant HNF-1α in pancreatic s-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced s-cell proliferation and diabetes"Diabetes. 51. 114-123 (2002)
• [Publications] Issei Yoshiuchi et al.: "Identification of a gain-of-function mutation in the HNF-1β gene in a Japanese family with MODY"Diabetologia. 45. 153-154 (2002)
• [Publications] Hiromi Iwahashi et al.: "Thyroid hormone receptor interacting protein 3 (Trip3) is a novel coactivator of hepatocyte nuclear factor-4α"Diabetes. 51. 910-914 (2002)
• [Publications] Qin Yang et al.: "Hepatocyte nuclear factor-1 modulates pancreatic s-Cell growth by regulating the expression of insulin-like growth factor-1 in INS-1 cells"Diabetes. 51. 1785-1792 (2002)
• [Publications] Takao Nammo: "Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas"Diabetologia. 45. 1142-1153 (2002)
• [Publications] Kazuya Yamagata: "Overexpression of dominant-negative mutant HNF-1α in pancreatic β-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced β-cell proliferation and diabetes"Diabetes. 51. 114-123 (2002)
• [Publications] Issei Yoshiuchi: "Identification of a gain-of-function mutation in the HNF-1β gene in a Japanese family with MODY"Diabetologia. 45. 153-154 (2002)
• [Publications] Issei Yoshiuchi: "A non-functional HNF-1α mutation in Japanese subjects with familial type 1 diabetes"Humman Mutation. 18. 345-351 (2001)