Increased expression of GAD65 and GABA in pancreatic beta -cells impairs first-phase insulin secretion

1 Departments of Medicine, Microbiology and Immunology, and Hormone Research Institute, 2 Department of Biochemistry and Biophysics and Metabolic Research Unit, 3 Department of Biochemistry and Biophysics and Hormone Research Institute, School of Medicine, University of California, San Francisco 94143; and 4 Department of Biology, University of California, Los Angeles, California 90095 The functional role of glutamate decarboxylase (GAD) and its product GABA in pancreatic islets has remained elusive. Mouse -cells express the larger isoform GAD67, whereas human islets express only the smaller isoform GAD65. We have generated two lines of transgenic mice expressing human GAD65 in pancreatic -cells (RIP7-hGAD65, Lines 1 and 2) to study the effect that GABA generated by this isoform has on islet cell function. The ascending order of hGAD65 expression and/or activity in -cells was Line 1 heterozygotes