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Targeted Disruption of the IA-2ß Gene Causes Glucose Intolerance and Impairs Insulin Secretion but Does Not Prevent the Development of Diabetes in NOD Mice

¹ Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
² Department of Cell Biology, Nijmegen Center for Molecular Life Sciences, University of Nijmegen, the Netherlands
³ Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland

Insulinoma-associated protein (IA)-2ß, also known as phogrin, is an enzymatically inactive member of the transmembrane protein tyrosine phosphatase family and is located in dense-core secretory vesicles. In patients with type 1 diabetes, autoantibodies to IA-2ß appear years before the development of clinical disease. The genomic structure and function of IA-2ß, however, is not known. In the present study, we determined the genomic structure of IA-2ß and found that both human and mouse IA-2ß consist of 23 exons and span 1,000 and 800 kb, respectively. With this information, we prepared a targeting construct and inactivated the mouse IA-2ß gene as demonstrated by lack of IA-2ß mRNA and protein expression. The IA-2ß^–/– mice, in contrast to wild-type controls, showed mild glucose intolerance and impaired glucose-stimulated insulin secretion. Knockout of the IA-2ß gene in NOD mice, the most widely studied animal model for human type 1 diabetes, failed to prevent the development of cyclophosphamide-induced diabetes. We conclude that IA-2ß is involved in insulin secretion, but despite its importance as a major autoantigen in human type 1 diabetes, it is not required for the development of diabetes in NOD mice.

Abbreviations: IA, insulinoma-associated protein; PTP, protein tyrosine phosphatase

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