PEGylation improves the hypoglycaemic efficacy of intranasally administered glucagon-like peptide-1 in type 2 diabetic db/db mice

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 (Lys34) 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 51.8 ± 5.8% (p