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Aquaporin 7 Is a ß-Cell Protein and Regulator of Intraislet Glycerol Content and Glycerol Kinase Activity, ß-Cell Mass, and Insulin Production and Secretion ^,

Kazuhiro Matsumura,^1,2, Benny Hung-Junn Chang,^1,* Mineko Fujimiya,³ Weiqin Chen,¹ Rohit N. Kulkarni,⁴ Yutaka Eguchi,⁵ Hiroshi Kimura,² Hideto Kojima,^1,2 and Lawrence Chan^1*

Division of Diabetes, Endocrinology & Metabolism, Departments of Medicine and Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030,¹ Department of Molecular Genetics in Medicine,² Department of Anatomy,³ Department of Critical and Intensive Care Medicine, Shiga University of Medical Science, Otsu, Japan,⁵ Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215⁴

Received 2 March 2007/ Returned for modification 24 April 2007/ Accepted 5 June 2007

To investigate if intracellular glycerol content plays a role in the regulation of insulin secretion in pancreatic ß cells, we studied the expression of the glycerol channels, or aquaglyceroporins, encoded by the aquaporin 3 (Aqp3), Aqp7, and Aqp9 genes in mouse islets. We found expression of Aqp7 only, not that of Aqp3 or Aqp9, in the endocrine pancreas at both the mRNA (by reverse transcription-PCR) and protein (by immunohistochemistry) levels. Immunohistochemistry revealed a complete overlap between insulin and Aqp7 immunostaining in the pancreatic islet. Inactivation of Aqp7 by gene targeting produced viable and healthy mice. Aqp7^–/– mice harbored an increased intraislet glycerol concentration with a concomitant increase of the glycerol kinase transcript level and enzyme activity. The islet triglyceride content in the Aqp7^–/– mice was also increased compared to that in the Aqp7^+/+ mice. Interestingly, Aqp7^–/– mice displayed reduced ß-cell mass and insulin content but increased insulin-1 and insulin-2 mRNAs. The reduction of ß-cell mass in Aqp7^–/– mice can be explained at least in part by a reduction in cell proliferation through protein kinase C and the c-myc cascade, with a reduction in the transcript levels of these two genes. Concomitantly, there was a decreased rate of apoptosis, as reflected by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and caspase 3 and Bax expression in Aqp7^–/– mice. Compared with Aqp7^+/+ islets, islets isolated from Aqp7^–/– mice secreted insulin at a higher rate under basal low-glucose conditions and on exposure to a high (450 mg/dl) glucose concentration. Aqp7^–/– mice exhibited normal fasting blood glucose levels but elevated blood insulin levels. Their plasma glucose response to an intraperitoneal (i.p.) glucose tolerance test was normal, but their plasma insulin concentrations were higher than those of wild-type mice during the 2-h test. An i.p. insulin tolerance test showed similar plasma glucose lowering in Aqp7^–/– and Aqp7^+/+ mice, with no evidence of insulin resistance. In conclusion, we found that pancreatic ß cells express AQP7, which appears to be a key regulator of intraislet glycerol content as well as insulin production and secretion.

Published ahead of print on 18 June 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

K.M. and B.H.-J.C. contributed equally to this work.