The glucagon receptor antagonist desHis 1 Pro 4 Glu 9 -glucagon(Lys 12 PAL) alters alpha-cell turnover and lineage in mice, but does not cause alpha-cell hyperplasia.

Autor: Lafferty R; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK., Tanday N; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK., Dubey V; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK., Coulter-Parkhill A; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK., Vishal K; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK., Moffett C; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK., O'Harte F; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK., Flatt PR; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK., Irwin N; Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK. Electronic address: n.irwin@ulster.ac.uk.
Jazyk: angličtina
Zdroj: Molecular and cellular endocrinology [Mol Cell Endocrinol] 2023 Jun 15; Vol. 570, pp. 111932. Date of Electronic Publication: 2023 Apr 18.
DOI: 10.1016/j.mce.2023.111932
Abstrakt: 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 1 Pro 4 Glu 9 -glucagon (Lys 12 PAL), 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 1 Pro 4 Glu 9 -glucagon (Lys 12 PAL), 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 1 Pro 4 Glu 9 -glucagon (Lys 12 PAL) 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 1 Pro 4 Glu 9 -glucagon (Lys 12 PAL) 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 1 Pro 4 Glu 9 -glucagon (Lys 12 PAL) 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.
Competing Interests: Declaration of competing interest There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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