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© 2002 by the American Diabetes Association, Inc.
Overexpression of Dominant-Negative Mutant Hepatocyte Nuclear Factor-1
in Pancreatic ß-Cells Causes Abnormal Islet Architecture With Decreased Expression of E-Cadherin, Reduced ß-cell Proliferation, and Diabetes
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
One subtype of maturity-onset diabetes of the young (MODY)-3 results from mutations in the gene encoding hepatocyte nuclear factor (HNF)-1
. We generated transgenic mice expressing a naturally occurring dominant-negative form of human HNF-1 (P291fsinsC) in pancreatic ß-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 ß-cells is associated with impaired insulin secretion. There was also a reduction in ß-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-1 in normal glucose metabolism, including the regulation of glucose transport, ß-cell growth, and ß-cell–to–ß-cell communication.
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