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PEGylation improves the hypoglycaemic efficacy of intranasally administered glucagon‐like peptide‐1 in type 2 diabetic db / db mice
Author(s) -
Youn Y. S.,
Jeon J. E.,
Chae S. Y.,
Lee S.,
Lee K. C.
Publication year - 2008
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2007.00823.x
Subject(s) - pegylation , nasal administration , postprandial , medicine , glucagon like peptide 1 , polyethylene glycol , pharmacology , peg ratio , glucagon , type 2 diabetes , mucous membrane of nose , endocrinology , insulin , diabetes mellitus , chemistry , immunology , biochemistry , finance , economics
Aims: 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. Methods: 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. Results: 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). Conclusion: This study highlights the pharmacological potential of intranasally administered PEGylated GLP‐1s in terms of stabilizing postprandial hyperglycaemia in type 2 diabetic patients.