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

Kazuya Yamagata, Takao Nammo, Makoto Moriwaki, Arisa Ihara, Katsumi Iizuka, Qin Yang, Tomomi Satoh, Ming Li, Rikako Uenaka, Kohei Okita, Hiromi Iwahashi, Qian Zhu, Yang Cao, Akihisa Imagawa, Yoshihiro Tochino, Toshiaki Hanafusa, Jun Ichiro Miyagawa, Yuji Matsuzawa

研究成果: Article査読

143 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)114-123
ページ数10
ジャーナルDiabetes
51
1
DOI
出版ステータスPublished - 2002
外部発表はい

All Science Journal Classification (ASJC) codes

  • 内科学
  • 内分泌学、糖尿病および代謝内科学

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