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GABA promotes β‐cell proliferation, but does not overcome impaired glucose homeostasis associated with diet‐induced obesity
Author(s) -
Untereiner Ashley,
Abdo Shaaban,
Bhattacharjee Alpana,
Gohil Himaben,
Pourasgari Farzaneh,
Ibeh Neke,
Lai Mi,
Batchuluun Battsetseg,
Wong Anthony,
Khuu Nicholas,
Liu Ying,
Rijjal Dana Al,
Winegarden Neil,
Virtanen Carl,
Orser Beverley A.,
Cabrera Over,
Varga Gabor,
Rocheleau Jonathan,
Dai Feihan F.,
Wheeler Michael B.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201801397r
Subject(s) - endocrinology , medicine , cell growth , glucose homeostasis , cell , insulin resistance , insulin , in vivo , type 2 diabetes , gabaa receptor , receptor , biology , chemistry , diabetes mellitus , biochemistry , microbiology and biotechnology
ABSTRACT γ‐Aminobutyric acid (GABA) administration has been shown to increase β‐cell mass, leading to a reversal of type 1 diabetes in mice. Whether GABA has any effect on β cells of healthy and prediabetic/glucose‐intolerant obese mice remains unknown. In the present study, we show that oral GABA administration ( ad libitum ) to mice indeed increased pancreatic β‐cell mass, which led to a modest enhancement in insulin secretion and glucose tolerance. However, GABA treatment did not further increase insulin‐positive islet area in high fat diet‐fed mice and was unable to prevent or reverse glucose intolerance and insulin resistance. Mechanistically, whether in vivo or in vitro , GABA treatment increased β‐cell proliferation. In vitro , the effect was shown to be mediated via the GABA A receptor. Single‐cell RNA sequencing analysis revealed that GABA preferentially up‐regulated pathways linked to β‐cell proliferation and simultaneously down‐regulated those networks required for other processes, including insulin biosynthesis and metabolism. Interestingly, single‐cell differential expression analysis revealed GABA treatment gave rise to a distinct subpopulation of β cells with a unique transcriptional signature, including urocortin 3 ( ucn3 ), wnt4 , and hepacam 2. Taken together, this study provides new mechanistic insight into the proliferative nature of GABA but suggests that β‐cell compensation associated with prediabetes overlaps with, and negates, its proliferative effects.—Untereiner, 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 β‐cell proliferation, but does not overcome impaired glucose homeostasis associated with diet‐induced obesity. FASEB J. 33, 3968–3984 (2019). www.fasebj.org