Youn Y S, Jeon J E, Chae S Y, Lee S, Lee K C
College of Pharmacy, Pusan National University, Busan, South Korea.
Diabetes Obes Metab. 2008 Apr;10(4):343-6. doi: 10.1111/j.1463-1326.2007.00823.x. Epub 2007 Nov 22.
PEGylation - covalent modification of therapeutic peptides with polyethylene glycol (PEG) - is viewed as an effective way of prolonging the short lifetime of glucagon-like peptide-1 (GLP-1). In this study, we investigated the hypoglycaemic efficacies of PEGylated GLP-1s administered intranasally in type 2 diabetic db/db mice.
Three types of site-specific (Lys(34)) PEGylated GLP-1 analogues (PEG molecular weight: 1, 2 or 5 kDa) were synthesized. Their metabolic stabilities were evaluated in nasal mucosa enzyme pools. Oral glucose tolerance test was conducted 30, 60 and 120 min after intranasally administering these analogues in type 2 diabetic db/db mice.
PEGylated GLP-1 analogues were found to have significantly longer half-lives than native GLP-1 in nasal mucosa enzymes (2.4-fold to 11.0-fold, p < 0.005). Non-PEGylated GLP-1 at 100 nmol/kg was not found to have marked efficacy irrespective of nasal administration time [total hypoglycaemic degree (HD(total)) values 2.8-17.3%]. On the contrary, PEGylated GLP-1s (100 nmol/kg) showed obvious efficacies with maximum HD(total) values of >51.8 +/- 5.8% (p < 0.005 vs. GLP-1).
This study highlights the pharmacological potential of intranasally administered PEGylated GLP-1s in terms of stabilizing postprandial hyperglycaemia in type 2 diabetic patients.
聚乙二醇化（用聚乙二醇（PEG）对治疗性肽进行共价修饰）被视为延长胰高血糖素样肽-1（GLP-1）短半衰期的有效方法。在本研究中，我们调查了经鼻给予聚乙二醇化GLP-1对2型糖尿病db/db小鼠的降血糖疗效。
合成了三种位点特异性（赖氨酸（34））聚乙二醇化GLP-1类似物（PEG分子量：1、2或5 kDa）。在鼻黏膜酶池中评估它们的代谢稳定性。在2型糖尿病db/db小鼠经鼻给予这些类似物后30、60和120分钟进行口服葡萄糖耐量试验。
发现聚乙二醇化GLP-1类似物在鼻黏膜酶中的半衰期明显长于天然GLP-1（2.4倍至11.0倍，p<0.005）。无论经鼻给药时间如何，100 nmol/kg的非聚乙二醇化GLP-1均未发现有显著疗效[总降血糖程度（HD（总））值为2.8 - 17.3%]。相反，聚乙二醇化GLP-1（100 nmol/kg）显示出明显疗效，最大HD（总）值>51.8±5.8%（与GLP-1相比，p<0.005）。
本研究突出了经鼻给予聚乙二醇化GLP-1在稳定2型糖尿病患者餐后高血糖方面的药理潜力。
