title: Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes.
abstract: 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.
authors.affiliation: Robarts Research Institute, Rome: 7240, University of Western Ontario, 1151 Richmond Street North, London, ON, N6A 5B7, Canada.
authors.forename: Allen L
authors.initials: AL
authors.lastname: Feng
authors.affiliation: Robarts Research Institute, Rome: 7240, University of Western Ontario, 1151 Richmond Street North, London, ON, N6A 5B7, Canada.
authors.forename: Yun-Yan
authors.initials: YY
authors.lastname: Xiang
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Le
authors.initials: L
authors.lastname: Gui
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Gesthika
authors.initials: G
authors.lastname: Kaltsidis
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Robarts Research Institute, Rome: 7240, University of Western Ontario, 1151 Richmond Street North, London, ON, N6A 5B7, Canada. wlu53@uwo.ca.|Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada. wlu53@uwo.ca.
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009118:Muscimol / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D058785:GABA-A Receptor Agonists; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D005934:Glucagon
keywords: Alpha cell; Beta cell; Diabetes; GAD; Glucagon; Insulin; Proliferation; Streptozotocin; Transdifferentiation; γ-Aminobutyric acid