Background

Neurotensin receptor activation augments the biosctivity of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). JMV-449, a C-terminal neurotensin-like fragment with a reduced peptide bond, represents a neurotensin receptor agonist.

Methods

The present study assessed the actions of JMV-449 on pancreatic beta-cells alone, and in combination with GIP and GLP-1. Further studies examined the impact of JMV-449 and incretin mimetics on glucose homeostasis and appetite control in mice.

Results

JMV-449 was resistant to plasma enzyme degradation and induced noticeable dose-dependent insulin-releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV-449 augmented (P < 0.05) the insulinotropic actions of both hormones, as well as enhancing (P < 0.001) insulin secretory activity of both incretin peptides. JMV-449 also increased beta-cell proliferation and induced significant benefits on beta-cell survival in response to cytokine-induced apoptosis. JMV-449 (25 nmol/kg) inhibited (P < 0.05–P < 0.001) food intake in overnight fasted lean mice, and enhanced (P < 0.01) the appetite supressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV-449 evoked glucose lowering actions, but more interestingly significantly augmented (P < 0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics. In terms of glucose-induced insulin secretion, only GIP receptor signalling was associated with increases in insulin concentrations, and this was not enhanced by JMV-449.

Conclusion

JMV-449 is a neurotensin receptor agonist that positively augments key aspects of the biological action profile of GIP and GLP-1.

General significance

These observations emphasise the, yet untapped, therapeutic potential of combined neurotensin and incretin receptor signalling for diabetes.

中文翻译：

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神经降压素受体激动剂 JMV-449 和肠促胰素模拟物对胰岛功能、葡萄糖稳态和食欲控制的独立和联合作用的比较

背景

神经降压素受体激活增强了胰高血糖素样肽-1 (GLP-1) 和葡萄糖依赖性促胰岛素多肽 (GIP) 的生物活性。JMV-449 是一种肽键减少的 C 端神经降压素样片段，代表神经降压素受体激动剂。

方法

本研究评估了 JMV-449 单独对胰腺 β 细胞的作用，以及与 GIP 和 GLP-1 的组合。进一步的研究检查了 JMV-449 和肠促胰岛素模拟物对小鼠葡萄糖稳态和食欲控制的影响。

结果

JMV-449 对血浆酶降解具有抗性，并在 BRIN-BD11 β 细胞中诱导明显的剂量依赖性胰岛素释放作用。JMV-449 与 GIP 或 GLP-1 结合，增强 ( P  < 0.05) 两种激素的促胰岛素作用，以及增强 ( P  < 0.001) 两种肠促胰岛素肽的胰岛素分泌活性。JMV-449 还增加了 β 细胞增殖，并在响应细胞因子诱导的细胞凋亡时对 β 细胞存活产生显着益处。JMV-449 (25 nmol/kg) 抑制（P  < 0.05– P  < 0.001）过夜禁食瘦小鼠的食物摄入，并增强（P < 0.01) 酶促稳定的 GLP-1 模拟物的食欲抑制作用。当与葡萄糖共同注射时，JMV-449 引起降糖作用，但更有趣的是显着增强（P  < 0.05）已建立的长效 GIP 和 GLP-1 受体模拟物的降糖作用。在葡萄糖诱导的胰岛素分泌方面，只有 GIP 受体信号与胰岛素浓度的增加有关，而 JMV-449 并未增强这一点。

结论

JMV-449 是一种神经降压素受体激动剂，可积极增强 GIP 和 GLP-1 生物作用谱的关键方面。

一般意义

这些观察结果强调了神经降压素和肠促胰岛素受体信号联合治疗糖尿病的尚未开发的治疗潜力。