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Whether GABA has any effect on \u03b2 cells of healthy and prediabetic\/glucose\u2010intolerant obese mice remains unknown. In the present study, we show that oral GABA administration (\n                    <jats:italic>ad libitum<\/jats:italic>\n                    ) to mice indeed increased pancreatic \u03b2\u2010cell mass, which led to a modest enhancement in insulin secretion and glucose tolerance. However, GABA treatment did not further increase insulin\u2010positive islet area in high fat diet\u2010fed mice and was unable to prevent or reverse glucose intolerance and insulin resistance. Mechanistically, whether\n                    <jats:italic>in vivo<\/jats:italic>\n                    or\n                    <jats:italic>in vitro<\/jats:italic>\n                    , GABA treatment increased \u03b2\u2010cell proliferation.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , the effect was shown to be mediated\n                    <jats:italic>via<\/jats:italic>\n                    the GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor. Single\u2010cell RNA sequencing analysis revealed that GABA preferentially up\u2010regulated pathways linked to \u03b2\u2010cell proliferation and simultaneously down\u2010regulated those networks required for other processes, including insulin biosynthesis and metabolism. Interestingly, single\u2010cell differential expression analysis revealed GABA treatment gave rise to a distinct subpopulation of \u03b2 cells with a unique transcriptional signature, including urocortin 3 (\n                    <jats:italic>ucn3<\/jats:italic>\n                    ),\n                    <jats:italic>wnt4<\/jats:italic>\n                    , and\n                    <jats:italic>hepacam<\/jats:italic>\n                    2. Taken together, this study provides new mechanistic insight into the proliferative nature of GABA but suggests that \u03b2\u2010cell compensation associated with prediabetes overlaps with, and negates, its proliferative effects.\u2014Untereiner, A., Abdo, S., Bhattacharjee, A., Gohil, H., Pourasgari, F., Ibeh, N., Lai, M., Batchuluun, B., Wong, A., Khuu, N., Liu, Y., Al Rijjal, D., Winegarden, N., Virtanen, C., Orser, B. A., Cabrera, O., Varga, G., Rocheleau, J., Dai, F. F., Wheeler, M. B. GABA promotes \u03b2\u2010cell proliferation, but does not overcome impaired glucose homeostasis associated with diet\u2010induced obesity. FASEB J. 33, 3968\u20133984 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201801397r","type":"journal-article","created":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T21:30:35Z","timestamp":1543872635000},"page":"3968-3984","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["GABA promotes \u03b2\u2010cell proliferation, but does not overcome impaired glucose homeostasis associated with diet\u2010induced obesity"],"prefix":"10.1096","volume":"33","author":[{"given":"Ashley","family":"Untereiner","sequence":"first","affiliation":[{"name":"Department of Physiology University of Toronto  Toronto Ontario 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