Diabetologia

, 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
Article

Abstract

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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.

Keywords

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

Abbreviations

α1GABAARs

α1subunit of type A GABA receptor

α4GABAARs

α4 subunit of type A GABA receptor

ALDH1a3

Aldehyde dehydrogenase 1 family, member A3

GABA

γ-Aminobutyric acid

GABAAR

Type A GABA receptor

GLP-1

Glucagon-like peptide 1

mTOR

Mechanistic target of rapamycin

STZ

Streptozotocin

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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