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

Diabetologia. 2017 Jun;60(6):1033-1042. doi: 10.1007/s00125-017-4239-x. Epub 2017 Mar 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Cell Proliferation / drug effects
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / metabolism*
  • GABA-A Receptor Agonists / pharmacology
  • Glucagon / metabolism
  • Glucagon-Secreting Cells / cytology*
  • Glucagon-Secreting Cells / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscimol / pharmacology
  • gamma-Aminobutyric Acid / pharmacology*

Substances

  • Blood Glucose
  • GABA-A Receptor Agonists
  • Muscimol
  • gamma-Aminobutyric Acid
  • Glucagon