胰高血糖素受体拮抗剂 desHisProGlu-胰高血糖素（LysPAL）改变了小鼠胰岛α细胞的增殖和分化，但不会导致胰岛α细胞增生。
The glucagon receptor antagonist desHisProGlu-glucagon(LysPAL) alters alpha-cell turnover and lineage in mice, but does not cause alpha-cell hyperplasia.
机构信息
Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK.
Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK.
出版信息
Mol Cell Endocrinol. 2023 Jun 15;570:111932. doi: 10.1016/j.mce.2023.111932. Epub 2023 Apr 18.
OBJECTIVE
Glucagon receptor (GCGR) antagonism elicits antihyperglycemic effects in rodents and humans. The present study investigates whether the well characterised peptide-based GCGR antagonist, desHisProGlu-glucagon (LysPAL), alters alpha-cell turnover or identity in mice.
METHODS
Multiple low-dose streptozotocin (STZ) treated (50 mg/kg bw, 5 days) transgenic Glu;ROSA26-eYFP mice were employed. STZ mice received twice daily administration of saline vehicle or desHisProGlu-glucagon (LysPAL), 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 desHisProGlu-glucagon (LysPAL) 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 desHisProGlu-glucagon (LysPAL) 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 desHisProGlu-glucagon (LysPAL) 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.
目的
胰高血糖素受体（GCGR）拮抗剂在啮齿动物和人类中产生抗高血糖作用。本研究旨在探讨经充分表征的肽基 GCGR 拮抗剂，desHisProGlu-胰高血糖素（LysPAL）是否会改变小鼠的胰岛细胞更替或特性。
方法
采用多次低剂量链脲佐菌素（STZ）处理（50mg/kg bw，5 天）的转基因 Glu;ROSA26-eYFP 小鼠。STZ 小鼠接受低剂量或高剂量（分别为 25 和 100nmol/kg）的生理盐水载体或 desHisProGlu-胰高血糖素（LysPAL），每天两次，持续 11 天。
结果
未观察到 GCGR 拮抗剂引起食物或液体摄入、体重或葡萄糖稳态的变化。如预期的那样，STZ 显著降低（P<0.001）胰岛数量，并增加（P<0.01）α-细胞与β-细胞的比例，这与β-细胞凋亡水平升高（P<0.05）有关。虽然 desHisProGlu-胰高血糖素（LysPAL）治疗降低了（P<0.05-P<0.001）α-和β-细胞面积，但它也有助于恢复 STZ 小鼠经典的啮齿动物胰岛α-细胞套层。有趣的是，低剂量 desHisProGlu-胰高血糖素（LysPAL）增加了（P<0.05）α-细胞凋亡率，而高剂量降低了（P<0.05）该参数。这种差异反映了高剂量 desHisProGlu-胰高血糖素（LysPAL）治疗后，α-细胞与β-细胞的转分化显著增加（P<0.001），而低剂量治疗并未完全表现出这种情况。
结论
综上所述，本研究表明，肽基 GCGR 拮抗剂可在多次低剂量 STZ 小鼠中积极影响胰岛细胞更替和特性，但这种作用与剂量有关。
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