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  • Title: The glucagon receptor antagonist desHis1Pro4Glu9-glucagon(Lys12PAL) alters alpha-cell turnover and lineage in mice, but does not cause alpha-cell hyperplasia.
    Author: Lafferty R, Tanday N, Dubey V, Coulter-Parkhill A, Vishal K, Moffett C, O'Harte F, Flatt PR, Irwin N.
    Journal: Mol Cell Endocrinol; 2023 Jun 15; 570():111932. PubMed ID: 37080378.
    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, desHis1Pro4Glu9-glucagon (Lys12PAL), alters alpha-cell turnover or identity in mice. METHODS: Multiple low-dose streptozotocin (STZ) treated (50 mg/kg bw, 5 days) transgenic GluCreERT2;ROSA26-eYFP mice were employed. STZ mice received twice daily administration of saline vehicle or desHis1Pro4Glu9-glucagon (Lys12PAL), 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 desHis1Pro4Glu9-glucagon (Lys12PAL) 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 desHis1Pro4Glu9-glucagon (Lys12PAL) 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 desHis1Pro4Glu9-glucagon (Lys12PAL) 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.
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