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Diabetes 53:1475-1481, 2004
© 2004 by the American Diabetes Association, Inc.

The Role of Calcium/Calmodulin-Dependent Protein Kinase Cascade in Glucose Upregulation of Insulin Gene Expression

Xiao Yu1, Koji Murao1, Yoshitaka Sayo1, Hitomi Imachi1, Wen M. Cao1, Shouji Ohtsuka1, Michio Niimi1, Hiroshi Tokumitsu2, Hiroyuki Inuzuka2, Norman C.W. Wong3,4, Ryoji Kobayashi2, and Toshihiko Ishida1

1 First Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan
2 Department of Signal Transduction Sciences, Kagawa Medical University, Kagawa, Japan
3 Department of Medicine, Faculty of Medicine, University of Calgary, Health Sciences Center, Calgary, Alberta, Canada
4 Department of Biochemistry & Molecular Biology, Faculty of Medicine, University of Calgary, Health Sciences Center, Calgary, Alberta, Canada

A number of factors have been reported to affect insulin synthesis in ß-cells. Although glucose is the most important regulator of insulin gene expression in pancreatic ß-cells, the mechanisms whereby glucose stimulates insulin gene transcription in response to changes in glucose concentration have not been clarified yet. In this study, we examined the role of the Ca2+/calmodulin (CaM)-dependent protein kinase (CaM-K) cascade in transcriptional activation of insulin. RT-PCR, Western blotting, and immunohistochemical staining analysis revealed that CaM-K kinase-{alpha} (CaM-KK{alpha}) and CaM-KIV were localized in rat pancreatic ß-cells and their cell line, INS-1. Exposure of INS-1 cells to 11.2 mmol/l glucose elicited an increase of insulin promoter activity as well as upregulation of CaM-KIV activity within 2 min after stimulation. We investigated the influence on insulin promoter activity of the constitutively active form (CaM-KIVc) or dominant-negative mutant (CaM-KIVdn) of CaM-KIV in transfected INS-1 cells. CaM-KIVc alone was sufficient, and the upstream kinase, CaM-KK, was enhanced to upregulate the insulin promoter activity in INS-1 cells. Furthermore, cotransfection of CaM-KIVdn suppressed to a significant degree the glucose-upregulated activity of the insulin promoter. Taken together, these results indicated that the CaM-KK/CaM-KIV cascade might play an important role in glucose-upregulated transcriptional activation of the insulin gene.

Address correspondence and reprint requests to Koji Murao, MD, PhD, First Department of Internal Medicine, Kagawa Medical University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan. E-mail: mkoji{at}kms.ac.jp


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.