GABA and insulin but not nicotinamide augment alpha- to beta-cell transdifferentiation in insulin-deficient diabetic mice

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Abstract

Poorly controlled diabetes is characterised by a partial or complete loss of pancreatic islet β-cells, which deprives the remaining islet cells of important β-cell-derived soluble signals, such as insulin or GABA. We aimed to dissect the role of the two signals in the development of islet α-cells, focusing specifically on α-/β-cell transdifferentiation and using the stem cell differentiation factor nicotinamide as a comparator. Streptozotocin (STZ)-treated diabetic mice expressing a fluorescent reporter in pancreatic islet α-cells were injected with GABA (10 mg/kg once daily), nicotinamide (150 mg/kg once daily) or insulin (1U/kg three times daily) for 10 days. The impact of the treatment on metabolic status of the animals as well as the morphology, proliferative potential and transdifferentiation of pancreatic islet cells was assessed using biochemical methods and immunofluorescence. Metabolic status of STZ-diabetic mice was not dramatically altered by the treatment interventions, although GABA therapy did reduce circulating glucagon and augment pancreatic insulin stores. The effects of the exogenous agents on islet β-cells ranged from the attenuation of apoptosis (insulin, nicotinamide) to enhancement of proliferation (GABA). Furthermore, insulin and GABA but not nicotinamide enhanced the differentiation of α-cells into β-cells and increased relative number of 'bihormonal' cells, expressing both insulin and glucagon. Our data suggest a role for endogenous insulin and GABA signalling in α-cell plasticity, which is likely to bypass the common nicotinamide-sensitive stem cell differentiation pathway. [Abstract copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.]
Original languageEnglish
Article number115019
Pages (from-to)115019
JournalBiochemical Pharmacology
Volume199
Early online date28 Mar 2022
DOIs
Publication statusPublished - 31 May 2022

Bibliographical note

Funding Information:
These studies were supported in part by Young Investigator Award from Diabetes UK to RCM and Ulster University Vice-Chancellor Research Studentship award to DS. We thank Professor Frank Reimann (University of Cambridge) for the donation of breeding pairs of Glu CreERT2 ; ROSA26e-YFP mice.

Publisher Copyright:
© 2022 The Authors

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords

  • alpha/beta cell transdifferentiation
  • type 1 diabetes
  • apoptosis
  • insulin
  • GABA
  • nicotinamide
  • glucagon
  • Glucagon
  • Insulin
  • Type 1 diabetes
  • α/β-cell transdifferentiation
  • Nicotinamide
  • Apoptosis

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