GABA promotes β‐cell proliferation, but does not overcome impaired glucose homeostasis associated with diet‐induced obesity

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 GABAA 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 hepacam2. 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). http://www.fasebj.org

Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell

“…Recent evidence suggests that GABA also has strong protective and regenerative effects on the beta cells themselves 5 . GABA increases beta cell mass in rodent and grafted human islets [6][7][8][9][10][11] and ameliorates diabetes in non-obese diabetic (NOD) mice 12 . Additionally, long-term GABA treatment in diabetic mice prevents alpha-cell hyperplasia 13 and promotes alpha cell trans-differentiation into beta cells 14,15 , although this latter effect is now disputed 16,17 .…”

Peer Review #1 of "Propofol inhibits stromatoxin-1-sensitive voltage-dependent K+ channels in pancreatic β-cells and enhances insulin secretion (v0.2)"

“…It exerts this effect through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABA A receptor (GABA A R) (Korol et al 2018;Sebel & Lowdon 1989). β-cell-specific highaffinity GABA A R subtypes and physiologically relevant GABA concentrations together modulate insulin secretion in human pancreatic islets (Dong et al 2006;Untereiner et al 2019;Wang et al 2019). Several studies indicate the involvement of GABA in human islet-cell hormone homeostasis, as well as the maintenance of the β-cell mass.…”

Gimmicks of gamma‐aminobutyric acid (GABA) in pancreatic β‐cell regeneration through transdifferentiation of pancreatic α‐ to β‐cells

“…The point to ponder is that whether during normal physiological or pathological conditions, significant amounts of GABA, which can trigger its receptors, are released in circulation or not. The answer lies in the fact that normal levels of GABA in circulation are within the range of 450–500 nM (Korol et al, 2018; Untereiner et al, 2019), which is enough to activate the GABA receptors on β cells because of their high affinity and their ability to optimally respond to the 100–1,000 nM of GABA (Korol et al, 2018).…”

“…Similarly, GABA and GABA‐R agonists promoted β‐cell replication in hyperglycemic mice and human islets (Bansal et al, 2011; Wang et al, 2014). Notably, the administration of GABA at a dose rate of 6 mg/mL elevated circulating GABA levels by fivefold, which increased the replication of islet cells and the β‐cell mass (Untereiner et al, 2019). This function involves GABA as autocrine signaling molecule binding to GABA A Rs and exerting depolarizing effects and opening of VDCCs, which leads to activation of PI3K/Akt cell growth and survival signaling pathway.…”