, Volume 60, Issue 6, pp 1033–1042 | Cite as

Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes

  • Allen L. Feng
  • Yun-Yan Xiang
  • Le Gui
  • Gesthika Kaltsidis
  • Qingping Feng
  • Wei-Yang Lu



This study aimed to elucidate the mechanism of increased proliferation of alpha cells in recent-onset type 1 diabetes. Pancreatic beta cells express GAD and produce γ-aminobutyric acid (GABA), which inhibits alpha cell secretion of glucagon. We explored the roles of GABA in alpha cell proliferation in conditions corresponding to type 1 diabetes in a mouse model and in vitro.


Type 1 diabetes was induced by injecting the mice with streptozotocin (STZ). Some of the STZ-injected mice were treated with GABA (10 mg/kg daily) for 12 days. Isolated pancreatic islets were treated with STZ or STZ together with GABA for 2 days. The effects of GABA treatment on STZ-induced alpha cell proliferation in vivo and in vitro were assessed. The effect of muscimol, a GABA receptor agonist, on αTC1-6 cell proliferation was also examined.


STZ injection substantially decreased levels of GAD, GABA and insulin in pancreatic beta cells 12 h after injection; this was followed by an upsurge of phosphorylated mechanistic target of rapamycin (p-mTOR) in the alpha cells at day 1, and a significant increase in alpha cell mass at day 3. Treating STZ-injected mice with GABA largely restored the immunodetectable levels of insulin and GAD in the beta cells and significantly decreased the number of aldehyde dehydrogenase 1 family, member A3 (ALDH1a3)-positive cells, alpha cell mass and hyperglucagonaemia. STZ treatment also increased alpha cell proliferation in isolated islets, which was reversed by co-treatment with GABA. Muscimol, together with insulin, significantly lowered the level of cytosolic Ca2+ and p-mTOR, and decreased the proliferation rate of αTC1-6 cells.


GABA signalling critically controls the alpha cell population in pancreatic islets. Low intraislet GABA may contribute to alpha cell hyperplasia in early type 1 diabetes.


Alpha cell Beta cell Diabetes GAD Glucagon Insulin Proliferation Streptozotocin Transdifferentiation γ-Aminobutyric acid 



α1subunit of type A GABA receptor


α4 subunit of type A GABA receptor


Aldehyde dehydrogenase 1 family, member A3


γ-Aminobutyric acid


Type A GABA receptor


Glucagon-like peptide 1


Mechanistic target of rapamycin




Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.


This research was supported by a Canadian Institutes of Health Research operating grant (MOP-133504) to WYL. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

ALF, YYX, LG and GK made substantial contributions to conception and design, acquisition of data and drafting the article critically. QF contributed to interpretation of the results and revisions of the manuscript. WYL contributed to study design, data analysis, interpretation of the results and drafting and revisions of the manuscript. All authors approved the final version of the manuscript. WYL is responsible for the integrity of the work as a whole.

Supplementary material

125_2017_4239_MOESM1_ESM.pdf (514 kb)
ESM Figs (PDF 513 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Allen L. Feng
    • 1
  • Yun-Yan Xiang
    • 1
  • Le Gui
    • 2
  • Gesthika Kaltsidis
    • 2
  • Qingping Feng
    • 2
  • Wei-Yang Lu
    • 1
    • 2
  1. 1.Robarts Research Institute, Rome: 7240University of Western OntarioLondonCanada
  2. 2.Department of Physiology and Pharmacology, Schulich School of Medicine and DentistryUniversity of Western OntarioLondonCanada

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