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Molecular and Cellular Biology, June 2005, p. 4969-4976, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.4969-4976.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

MafA Is a Key Regulator of Glucose-Stimulated Insulin Secretion

Chuan Zhang,1 Takashi Moriguchi,1,2 Miwako Kajihara,1 Ritsuko Esaki,1 Ayako Harada,1 Homare Shimohata,1 Hisashi Oishi,1 Michito Hamada,1 Naoki Morito,1 Kazuteru Hasegawa,1 Takashi Kudo,1 James Douglas Engel,2 Masayuki Yamamoto,3 and Satoru Takahashi1*

Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan,1 University of Michigan Medical School, Ann Arbor, Michigan 48109-0616,2 Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan3

Received 1 October 2004/ Returned for modification 9 December 2004/ Accepted 22 March 2005

MafA is a transcription factor that binds to the promoter in the insulin gene and has been postulated to regulate insulin transcription in response to serum glucose levels, but there is no current in vivo evidence to support this hypothesis. To analyze the role of MafA in insulin transcription and glucose homeostasis in vivo, we generated MafA-deficient mice. Here we report that MafA mutant mice display intolerance to glucose and develop diabetes mellitus. Detailed analyses revealed that glucose-, arginine-, or KCl-stimulated insulin secretion from pancreatic ß cells is severely impaired, although insulin content per se is not significantly affected. MafA-deficient mice also display age-dependent pancreatic islet abnormalities. Further analysis revealed that insulin 1, insulin 2, Pdx1, Beta2, and Glut-2 transcripts are diminished in MafA-deficient mice. These results show that MafA is a key regulator of glucose-stimulated insulin secretion in vivo.

* Corresponding author. Mailing address: Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan. Phone: 81-298-53-7516. Fax: 81-298-53-6965. E-mail: satoruta{at}md.tsukuba.ac.jp.

Molecular and Cellular Biology, June 2005, p. 4969-4976, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.4969-4976.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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