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 5kDa) were synthesized. Their metabolic stabilities were evaluated in nasal mucosa enzyme pools. Oral glucose tolerance test was conducted 30, 60 and 120min 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 100nmol/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 (100nmol/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.