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Whereas these autoantibodies are historically viewed as an epiphenomenon of the autoimmune response with no significant pathogenic function, we consider in this study the possibility that they impact the major islet function, namely glucose\u2010stimulated insulin secretion. Two human monoclonal GAD65Ab (GAD65 mAb) (b78 and b96.11) were investigated for uptake by live rat beta cells, subcellular localization and their effect on glucose\u2010stimulated insulin secretion. The GAD65 mAbs were internalized by live pancreatic beta cells, where they localized to subcellular structures in an epitope\u2010specific manner. Importantly, GAD65 mAb b78 inhibited, while GAD65 mAb b96.11 enhanced, glucose\u2010stimulated insulin secretion (GSIS). These opposite effects on GSIS rule out non\u2010specific effects of the antibodies and suggest that internalization of the antibody leads to epitope\u2010specific interaction with intracellular machinery regulating insulin granule release. The most likely explanation for the alteration of GSIS by GAD65 Abs is via changes in GABA release due to inhibition or change in GAD65 enzyme activity. This is the first report indicating an active role of GAD65Ab in the pathogenesis of T1D.<\/jats:p>","DOI":"10.1111\/iep.12437","type":"journal-article","created":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T03:45:32Z","timestamp":1646451932000},"page":"140-148","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Autoantibodies directed against glutamate decarboxylase interfere with glucose\u2010stimulated insulin secretion in dispersed rat islets"],"prefix":"10.1111","volume":"103","author":[{"given":"Varun","family":"Kamat","sequence":"first","affiliation":[{"name":"Department of Medicine University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared R.","family":"Radtke","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Washington  Seattle Washington 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