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

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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.