Targeted Disruption of the Protein Tyrosine Phosphatase-Like Molecule IA-2 Results in Alterations in Glucose Tolerance Tests and Insulin Secretion

Author:

Saeki Keiichi1,Zhu Min2,Kubosaki Atsutaka1,Xie Jingping1,Lan Michael S.2,Notkins Abner Louis1

Affiliation:

1. Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland

2. Research Institute for Children, Children’s Hospital, and Departments of Pediatrics and Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana

Abstract

IA-2 is a major autoantigen in type 1 diabetes. Autoantibodies to IA-2 appear years before the development of clinical disease and are being widely used as predictive markers to identify individuals at risk for developing type 1 diabetes. IA-2 is an enzymatically inactive member of the transmembrane protein tyrosine phosphatase family and is an integral component of secretory granules in neuroendocrine cells. To study its function, we generated IA-2−deficient mice. Northern and Western blot analysis showed that neither IA-2 mRNA nor protein was expressed. Physical examination of the IA-2− /− animals and histological examination of tissues failed to reveal any abnormalities. Nonfasting blood glucose levels, measured over 6 months, were slightly elevated in male IA-2−/− as compared to IA-2+ /+ littermates, but remained within the nondiabetic range. Glucose tolerance tests, however, revealed statistically significant elevation of glucose in both male and female IA-2−/− mice and depressed insulin release. In vitro glucose stimulation of isolated islets showed that male and female mice carrying the disrupted gene released 48% (P < 0.001) and 42% (P < 0.01) less insulin, respectively, than mice carrying the wild-type gene. We concluded that IA-2 is involved in glucose-stimulated insulin secretion.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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