TY - JOUR
T1 - Overexpression of dominant-negative mutant hepatocyte nuclear factor-1α in pancreatic β-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced β-cell proliferation, and diabetes
AU - Yamagata, Kazuya
AU - Nammo, Takao
AU - Moriwaki, Makoto
AU - Ihara, Arisa
AU - Iizuka, Katsumi
AU - Yang, Qin
AU - Satoh, Tomomi
AU - Li, Ming
AU - Uenaka, Rikako
AU - Okita, Kohei
AU - Iwahashi, Hiromi
AU - Zhu, Qian
AU - Cao, Yang
AU - Imagawa, Akihisa
AU - Tochino, Yoshihiro
AU - Hanafusa, Toshiaki
AU - Miyagawa, Jun Ichiro
AU - Matsuzawa, Yuji
PY - 2002
Y1 - 2002
N2 - One subtype of maturity-onset diabetes of the young (MODY)-3 results from mutations in the gene encoding hepatocyte nuclear factor (HNF)-1α. We generated transgenic mice expressing a naturally occurring dominant-negative form of human HNF-1α (P291fsinsC) in pancreatic β-cells. A progressive hyperglycemia with age was seen in these transgenic mice, and the mice developed diabetes with impaired glucose-stimulated insulin secretion. The pancreatic islets exhibited abnormal architecture with reduced expression of glucose transporter (GLUT2) and E-cadherin. Blockade of Ecadherin-mediated cell adhesion in pancreatic islets abolished the glucose-stimulated increases in intracellular Ca2+ levels and insulin secretion, suggesting that loss of E-cadherin in β-cells is associated with impaired insulin secretion. There was also a reduction in β-cell number (50%), proliferation rate (15%), and pancreatic insulin content (45%) in 2-day-old transgenic mice and a further reduction in 4-week-old animals. Our findings suggest various roles for HNF-1α in normal glucose metabolism, including the regulation of glucose transport, β-cell growth, and β-cell-to-β-cell communication.
AB - One subtype of maturity-onset diabetes of the young (MODY)-3 results from mutations in the gene encoding hepatocyte nuclear factor (HNF)-1α. We generated transgenic mice expressing a naturally occurring dominant-negative form of human HNF-1α (P291fsinsC) in pancreatic β-cells. A progressive hyperglycemia with age was seen in these transgenic mice, and the mice developed diabetes with impaired glucose-stimulated insulin secretion. The pancreatic islets exhibited abnormal architecture with reduced expression of glucose transporter (GLUT2) and E-cadherin. Blockade of Ecadherin-mediated cell adhesion in pancreatic islets abolished the glucose-stimulated increases in intracellular Ca2+ levels and insulin secretion, suggesting that loss of E-cadherin in β-cells is associated with impaired insulin secretion. There was also a reduction in β-cell number (50%), proliferation rate (15%), and pancreatic insulin content (45%) in 2-day-old transgenic mice and a further reduction in 4-week-old animals. Our findings suggest various roles for HNF-1α in normal glucose metabolism, including the regulation of glucose transport, β-cell growth, and β-cell-to-β-cell communication.
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U2 - 10.2337/diabetes.51.1.114
DO - 10.2337/diabetes.51.1.114
M3 - Article
C2 - 11756330
AN - SCOPUS:0036091921
SN - 0012-1797
VL - 51
SP - 114
EP - 123
JO - Diabetes
JF - Diabetes
IS - 1
ER -