School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
Clin Sci (Lond). 2011 Aug;121(3):107-17. doi: 10.1042/CS20110006.
The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys(37)Myr) (N-acetylGIP with myristic acid conjugated at Lys(37)), a simple combination of both peptides and a Lira-AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys(37)Myr)] were incubated with DPP-IV (dipeptidyl peptidase-IV) to assess peptide stability, and BRIN-BD11 cells were used to evaluate cAMP production and insulin secretion. Acute glucose-lowering and insulinotropic actions were evaluated in Swiss TO mice. Subchronic studies on glucose homoeostasis, insulin secretion, food intake and bodyweight were evaluated in ob/ob mice. Liraglutide, N-AcGIP(Lys(37)Myr), a simple combination of both peptides and the Lira-AcGIP preparation demonstrated improved DPP-IV resistance (P<0.001), while stimulating cAMP production and insulin secretion (1.4-2-fold; P<0.001). The Lira-AcGIP preparation was more potent at lowering plasma glucose (20-51% reduction; P<0.05-P<0.001) and stimulating insulin secretion (1.5-1.8-fold; P<0.05-P<0.001) compared with Liraglutide and N-AcGIP(Lys(37)Myr) or a simple peptide combination. Daily administration of the Lira-AcGIP preparation to ob/ob mice lowered bodyweight (7-9%; P<0.05), food intake (23%; P<0.05) and plasma glucose (46% reduction; P<0.001), while increasing plasma insulin (1.5-1.6-fold; P<0.001). The Lira-AcGIP preparation enhanced glucose tolerance, insulin response to glucose and insulin content (P<0.05-P<0.001). These findings demonstrate that a combined preparation of the acylated GLP-1 and GIP peptides Liraglutide and N-AcGIP(Lys(37)Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.
本研究旨在探讨酰化 GLP-1（胰高血糖素样肽-1）和 GIP（葡萄糖依赖性胰岛素释放肽）肽在 2 型糖尿病和肥胖中的降血糖和促胰岛素分泌作用。GLP-1、GIP、利拉鲁肽、N-乙酰 GIP（Lys（37）Myr）（赖氨酸（37）上连接豆蔻酸的 N-乙酰 GIP）、两种肽的简单组合以及利拉鲁肽和 N-乙酰 GIP（Lys（37）Myr）的 overnight 制备物 [利拉鲁肽和 N-乙酰 GIP（Lys（37）Myr）的 overnight 制备物] 与 DPP-IV（二肽基肽酶-IV）孵育以评估肽的稳定性，并使用 BRIN-BD11 细胞评估 cAMP 产生和胰岛素分泌。在瑞士 TO 小鼠中评估急性降血糖和促胰岛素作用。在 ob/ob 小鼠中进行亚慢性研究以评估葡萄糖稳态、胰岛素分泌、食物摄入和体重。利拉鲁肽、N-乙酰 GIP（Lys（37）Myr）、两种肽的简单组合以及利拉鲁肽和 N-乙酰 GIP（Lys（37）Myr）的 overnight 制备物均显示出改善的 DPP-IV 抗性（P<0.001），同时刺激 cAMP 产生和胰岛素分泌（1.4-2 倍；P<0.001）。与利拉鲁肽和 N-乙酰 GIP（Lys（37）Myr）或简单的肽组合相比，利拉鲁肽和 N-乙酰 GIP（Lys（37）Myr）的 overnight 制备物更能降低血浆葡萄糖（降低 20-51%；P<0.05-P<0.001）并刺激胰岛素分泌（增加 1.5-1.8 倍；P<0.05-P<0.001）。利拉鲁肽和 N-乙酰 GIP（Lys（37）Myr）的 overnight 制备物每天给予 ob/ob 小鼠可降低体重（7-9%；P<0.05）、食物摄入量（23%；P<0.05）和血浆葡萄糖（降低 46%；P<0.001），同时增加血浆胰岛素（增加 1.5-1.6 倍；P<0.001）。利拉鲁肽和 N-乙酰 GIP（Lys（37）Myr）的 overnight 制备物增强了葡萄糖耐量、葡萄糖刺激的胰岛素反应和胰岛素含量（P<0.05-P<0.001）。这些发现表明，酰化 GLP-1 和 GIP 肽利拉鲁肽和 N-乙酰 GIP（Lys（37）Myr）的组合制剂与单独给予的两种肠降血糖素模拟物相比，显著改善了糖尿病肥胖患者的降血糖和促胰岛素作用。
