Hepatocyte nuclear factor-1α modulates pancreatic β-cell growth by regulating the expression of insulin-like growth factor-1 in INS-1 cells

Q Yang, K Yamagata, K Fukui, Y Cao, T Nammo… - Diabetes, 2002 - Am Diabetes Assoc
Q Yang, K Yamagata, K Fukui, Y Cao, T Nammo, H Iwahashi, H Wang, I Matsumura…
Diabetes, 2002Am Diabetes Assoc
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 …
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 [3H]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.
Am Diabetes Assoc