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

  1. Kazuya Yamagata1,
  2. Takao Nammo1,
  3. Makoto Moriwaki1,
  4. Arisa Ihara1,
  5. Katsumi Iizuka1,
  6. Qin Yang1,
  7. Tomomi Satoh1,
  8. Ming Li1,
  9. Rikako Uenaka1,
  10. Kohei Okita1,
  11. Hiromi Iwahashi1,
  12. Qian Zhu1,
  13. Yang Cao1,
  14. Akihisa Imagawa1,
  15. Yoshihiro Tochino1,
  16. Toshiaki Hanafusa2,
  17. Jun-ichiro Miyagawa1 and
  18. Yuji Matsuzawa1
  1. 1Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
  2. 2First Department of Internal Medicine, Osaka Medical College, Osaka, Japan

    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 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 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.

    Footnotes

    • Address correspondence and reprint requests to Kazuya Yamagata, MD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: kazu{at}imed2.med.osaka-u.ac.jp.

      Received for publication 12 July 2001 and accepted in revised form 17 October 2001.

      K.Y. and T.N. contributed equally to this study.

      BrdU, bromo-2′-deoxyuridine; HKRB, HEPES-balanced Krebs-Ringer bicarbonate; HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young; PCR, polymerase chain reaction; PP, pancreatic polypeptide; RIP, rat insulin promoter; RT, reverse transcription; WT, wild type.

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