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 (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.