The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK.
The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK.
Biochem Pharmacol. 2018 Sep;155:264-274. doi: 10.1016/j.bcp.2018.07.021. Epub 2018 Jul 18.
Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4. The hybrid peptide, N-ac(d-Ala)GIP/GLP-1-exe, was enzymatically stable for up to 12 h when incubated with DPP-4. N-ac(d-Ala)GIP/GLP-1-exe significantly (P < 0.001) stimulated insulin secretion from BRIN-BD11 cells and isolated mouse islets, and evoked dose-dependent increases (P < 0.001) in cAMP production in both GIP-R and GLP-1-R transfected cells. In mice, injection of the hybrid in combination with glucose significantly (P < 0.001) reduced glucose and increased insulin concentrations, with metabolic actions evident (P < 0.05) 8 h post-injection. Twice-daily injection of N-ac(d-Ala)GIP/GLP-1-exe to high fat fed (HFF) mice for 28 days significantly (P < 0.05-P < 0.001) reduced body weight, HbA, circulating glucose and insulin concentrations. Furthermore, both oral and i.p. glucose tolerance were improved (P < 0.001) and insulin sensitivity enhanced. The hybrid peptide also increased (P < 0.05-P < 0.001) beta cell number, islet area, pancreatic insulin content and islet insulin secretory responsiveness in HFF mice. Finally, N-ac(d-Ala)GIP/GLP-1-exe treated mice exhibited improved (P < 0.01) recognition memory which was accompanied by enhanced (P < 0.05-P < 0.001) hippocampal neurogenesis, synapse formation and reduced neuronal oxidative stress. These data demonstrate for the first time the beneficial actions of the novel GIP/GLP-1 hybrid, N-ac(d-Ala)GIP/GLP-1-exe, on glucose homeostasis and memory function in diabetes.
葡萄糖依赖性胰岛素促分泌激素（GIP）和胰高血糖素样肽-1（GLP-1）是肠促胰岛素激素，它们对代谢和认知功能有一系列有益作用。基于 GLP-1 的疗法在肥胖和糖尿病管理方面非常成功，然而迄今为止，GIP 疗法尚未发现临床应用。在本研究中，我们首次描述了基于 GIP、GLP-1 和临床批准的 GLP-1 类似物 exendin-4 的氨基酸序列的新型 GIP/GLP-1 杂合肽的治疗效果。杂合肽 N-ac(d-Ala)GIP/GLP-1-exe 在与 DPP-4 孵育时长达 12 小时保持酶稳定。N-ac(d-Ala)GIP/GLP-1-exe 显著（P < 0.001）刺激 BRIN-BD11 细胞和分离的小鼠胰岛中的胰岛素分泌，并在 GIP-R 和 GLP-1-R 转染细胞中引起剂量依赖性 cAMP 产生增加（P < 0.001）。在小鼠中，与葡萄糖联合注射该杂合肽可显著（P < 0.001）降低葡萄糖并增加胰岛素浓度，注射后 8 小时即可观察到代谢作用（P < 0.05）。28 天每天两次向高脂肪喂养（HFF）小鼠注射 N-ac(d-Ala)GIP/GLP-1-exe 可显著（P < 0.05-P < 0.001）降低体重、HbA、循环葡萄糖和胰岛素浓度。此外，口服和腹腔内葡萄糖耐量均得到改善（P < 0.001），胰岛素敏感性增强。该杂合肽还增加了 HFF 小鼠的β细胞数量、胰岛面积、胰腺胰岛素含量和胰岛胰岛素分泌反应性。最后，N-ac(d-Ala)GIP/GLP-1-exe 治疗的小鼠表现出改善的（P < 0.01）识别记忆，同时伴随着（P < 0.05-P < 0.001）增强的海马神经发生、突触形成和减少神经元氧化应激。这些数据首次证明了新型 GIP/GLP-1 杂合肽 N-ac(d-Ala)GIP/GLP-1-exe 在糖尿病中对葡萄糖稳态和记忆功能的有益作用。
