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

被引:136
作者
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
机构
[1] Osaka Univ, Grad Sch Med, Dept Internal Med & Mol Sci, Suita, Osaka 5650871, Japan
[2] Osaka Med Coll, Dept Internal Med 1, Osaka, Japan
关键词
D O I
10.2337/diabetes.51.1.114
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
One subtype of maturity-onset diabetes of the young (MODY)-3 results from mutations in the gene encoding hepatocyte nuclear factor (HNF)-1alpha. We generated transgenic mice expressing a naturally occurring dominant-negative form of human HNF-1alpha (P291fsinsC) in pancreatic beta-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 E-cadherin-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 beta-cells is associated with impaired insulin secretion. There was also a reduction in beta-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-1alpha in normal glucose metabolism, including the regulation of glucose transport, beta-cell growth, and beta-cell-to-beta-cell communication.
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页码:114 / 123
页数:10
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