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

Research output: Contribution to journalArticlepeer-review

143 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)114-123
Number of pages10
JournalDiabetes
Volume51
Issue number1
DOIs
Publication statusPublished - 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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