Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells.
Mutations in the hepatocyte nuclear factor (HNF)-4alpha gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of glucose-stimulated insulin secretion by pancreatic beta-cells. HNF-4alpha, a transcription factor belonging to the nuclear receptor superfamily, is expressed in pancreatic islets as well as in the liver, kidney, and intestine. However, the role of HNF-4alpha in pancreatic beta-cell is unclear. To clarify the role of HNF-4alpha in beta-cells, we generated beta-cell-specific HNF-4alpha knock-out (betaHNF-4alphaKO) mice using the Cre-LoxP system. The betaHNF-4alphaKO mice exhibited impairment of glucose-stimulated insulin secretion, which is a characteristic of MODY1. Pancreatic islet morphology, beta-cell mass, and insulin content were normal in the HNF-4alpha mutant mice. Insulin secretion by betaHNF-4alphaKO islets and the intracellular calcium response were impaired after stimulation by glucose or sulfonylurea but were normal after stimulation with KCl or arginine. Both NAD(P)H generation and ATP content at high glucose concentrations were normal in the betaHNF-4alphaKO mice. Expression levels of Kir6.2 and SUR1 proteins in the betaHNF-4alphaKO mice were unchanged as compared with control mice. Patch clamp experiments revealed that the current density was significantly increased in betaHNF-4alphaKO mice compared with control mice. These results are suggestive of the dysfunction of K(ATP) channel activity in the pancreatic beta-cells of HNF-4alpha-deficient mice. Because the K(ATP) channel is important for proper insulin secretion in beta-cells, altered K(ATP) channel activity could be related to the impaired insulin secretion in the betaHNF-4alphaKO mice.
Miura
Atsuko
A
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.
Yamagata
Kazuya
K
Kakei
Masafumi
M
Hatakeyama
Hiroyasu
H
Takahashi
Noriko
N
Fukui
Kenji
K
Nammo
Takao
T
Yoneda
Kazue
K
Inoue
Yusuke
Y
Sladek
Frances M
FM
Magnuson
Mark A
MA
Kasai
Haruo
H
Miyagawa
Junichiro
J
Gonzalez
Frank J
FJ
Shimomura
Iichiro
I
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001120:Arginine / Q000737:chemistry; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005091:Exons; D005260:Female; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism / Q000502:physiology*; D006579:Heterozygote; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000737:chemistry; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011189:Potassium Chloride / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D011955:Receptors, Drug; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013453:Sulfonylurea Compounds / Q000737:chemistry; D064233:Sulfonylurea Receptors; D014018:Tissue Distribution; D019076:Transgenes; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D001120:Arginine; D001786:Blood Glucose; D002118:Calcium; D005947:Glucose; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011188:Potassium; D024661:Potassium Channels, Inwardly Rectifying; D011189:Potassium Chloride; D012333:RNA, Messenger; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577508:Abcc8 protein, mouse