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

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 1 , Takao Nammo 1 , Makoto Moriwaki 1 , Arisa Ihara 1 , Katsumi Iizuka 1 , Qin Yang 1 , Tomomi Satoh 1 , Ming Li 1 , Rikako Uenaka 1 , Kohei Okita 1 , Hiromi Iwahashi 1 , Qian Zhu 1 , Yang Cao 1 , Akihisa Imagawa 1 , Yoshihiro Tochino 1 , Toshiaki Hanafusa 2 , Jun-ichiro Miyagawa 1 and Yuji Matsuzawa 1 1 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan 2 First 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 Ca 2+ 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 reacti