Overexpression of dominant-negative mutant hepatocyte nuclear fctor-1 alpha in pancreatic beta-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced beta-cell proliferation, and diabetes.
One subtype of maturity-onset diabetes of the young (MODY)-3 results from mutations in the gene encoding hepatocyte nuclear factor (HNF)-1 alpha. We generated transgenic mice expressing a naturally occurring dominant-negative form of human HNF-1 alpha (P291fsinsC) in pancreatic beta-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 beta-cells is associated with impaired insulin secretion. There was also a reduction in beta-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 alpha in normal glucose metabolism, including the regulation of glucose transport, beta-cell growth, and beta-cell-to-beta-cell communication.
Yamagata
Kazuya
K
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. kazu@imed2.osaka-u.ac.jp
Nammo
Takao
T
Moriwaki
Makoto
M
Ihara
Arisa
A
Iizuka
Katsumi
K
Yang
Qin
Q
Satoh
Tomomi
T
Li
Ming
M
Uenaka
Rikako
R
Okita
Kohei
K
Iwahashi
Hiromi
H
Zhu
Qian
Q
Cao
Yang
Y
Imagawa
Akihisa
A
Tochino
Yoshihiro
Y
Hanafusa
Toshiaki
T
Miyagawa
Jun-ichiro
J
Matsuzawa
Yuji
Y
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000276:immunology; D002455:Cell Division; D004268:DNA-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation; D051273:Glucose Transporter Type 2; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
D000906:Antibodies; D001786:Blood Glucose; D015820:Cadherins; D004268:DNA-Binding Proteins; D051273:Glucose Transporter Type 2; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta