The glucagon receptor antagonist desHis1Pro4Glu9-glucagon(Lys12PAL) alters alpha-cell turnover and lineage in mice, but does not cause alpha-cell hyperplasia

Ryan Lafferty, Neil Tanday, Vaibhav Dubey, Aimee Coulter-Parkhill, Karthick Vishal, R. Charlotte Moffett, Finbarr O'Harte, Peter R. Flatt, Nigel Irwin

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2 Citations (Scopus)
54 Downloads (Pure)

Abstract

Objective: Glucagon receptor (GCGR) antagonism elicits antihyperglycemic effects in rodents and humans. The present study investigates whether the well characterised peptide-based GCGR antagonist, desHis 1Pro 4Glu 9-glucagon (Lys 12PAL), alters alpha-cell turnover or identity in mice. Methods: Multiple low-dose streptozotocin (STZ) treated (50 mg/kg bw, 5 days) transgenic Glu CreERT2;ROSA26-eYFP mice were employed. STZ mice received twice daily administration of saline vehicle or desHis 1Pro 4Glu 9-glucagon (Lys 12PAL), at low- or high-dose (25 and 100 nmol/kg, respectively) for 11 days. Results: No GCGR antagonist induced changes in food or fluid intake, body weight or glucose homeostasis were observed. As expected, STZ dramatically reduced (P < 0.001) islet numbers and increased (P < 0.01) alpha-to beta-cell ratio, which was linked to elevated (P < 0.05) levels of beta-cell apoptosis. Whilst treatment with desHis 1Pro 4Glu 9-glucagon (Lys 12PAL) decreased (P < 0.05-P < 0.001) alpha- and beta-cell areas, it also helped restore the classic rodent islet alpha-cell mantle in STZ mice. Interestingly, low-dose desHis 1Pro 4Glu 9-glucagon (Lys 12PAL) increased (P < 0.05) alpha-cell apoptosis rates whilst high dose decreased (p < 0.05) this parameter. This difference reflects substantially increased (P < 0.001) alpha-to beta-cell transdifferentiation following high dose desHis 1Pro 4Glu 9-glucagon (Lys 12PAL) treatment, which was not fully manifest with low-dose therapy. Conclusions: Taken together, the present study indicates that peptidic GCGR antagonists can positively influence alpha-cell turnover and lineage in identity in multiple low-dose STZ mice, but that such effects are dose-related.

Original languageEnglish
Article number111932
Pages (from-to)1-8
Number of pages9
JournalMolecular and Cellular Endocrinology
Volume570
DOIs
Publication statusPublished (in print/issue) - 18 Apr 2023

Bibliographical note

Funding Information:
This work was supported by an Invest Northern Ireland Proof-of-Concept grant ( PoC106 ), an Ulster University Vice-Chancellor funded PhD studentship and Ulster University Selective Research Funding. RCM is recipient of RD Lawrence Fellowship from Diabetes UK.

Publisher Copyright:
© 2023 The Authors

Keywords

  • Antagonist
  • Glucagon receptor
  • Peptide
  • Transdifferentiation

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