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


CONCLUSIONS
This study highlights the pharmacological potential of intranasally administered PEGylated GLP-1s in terms of stabilizing postprandial hyperglycaemia in type 2 diabetic patients.
College of Pharmacy, Pusan National University, Busan, South Korea.
Y S
YS
Youn
J E
JE
Jeon
S Y
SY
Chae
S
S
Lee
K C
KC
Lee
D000280:Administration, Inhalation; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004337:Drug Carriers; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011092:Polyethylene Glycols
D001786:Blood Glucose; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; D011092:Polyethylene Glycols; D052216:Glucagon-Like Peptide 1