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

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Abstract
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.

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