title: A new orally available glucagon-like peptide-1 receptor agonist, biotinylated exendin-4, displays improved hypoglycemic effects in db/db mice.
abstract: An orally active glucagon-like peptide-1 (GLP-1) formulation would have great advantages over conventional injectable therapies for the treatment of diabetic patients. Because GLP-1 absorption in the intestine is restricted by its natural physiological characteristics, biotinylated exendin-4 analogues might useful as orally active GLP-1 receptor agonists. Three different biotinylated exendin-4 analogues, Lys(27)-Biotin-Exendin-4 (MB1-Ex-4), Lys(12)-Biotin-Exendin-4 (MB2-Ex-4), and Lys(12, 27)-Biotin-Exendin-4 (DB-Ex-4) were prepared, and their biological activities and enzymatic stabilities were studied in vitro. The hypoglycemic effects and pharmacokinetics of these analogues after oral administration were evaluated in db/db mice and Sprague-Dawley rats, respectively. These biotinylated exendin-4 analogues preserved GLP-1 receptor binding affinity and stimulated insulin secretion in RIN-m5F murine insulinoma cells and in isolated rat islets, respectively, and were as potent as exendin-4. In particular, DB-Ex-4 showed 9.0-fold better stability against rat intestinal fluid than exendin-4. When 0.1, 1, and 10 microg/mouse of DB-Ex-4 were orally administered, mean total hypoglycemic degrees (HGD) were increased by 36.8+/-1.2, 46.9+/-1.8, and 54.3+/-4.5%, respectively, whereas 1 microg/mouse of native exendin-4 showed an increase of 8.8+/-7.3%. This study demonstrates that biotinylated exendin-4 analogues are absorbed in the intestine and that they have biological efficacies of exendin-4. Furthermore, it indicates that biotinylated exendin-4 analogues could be used as potential oral antidiabetic agent for the treatment of type 2 diabetes.
authors.affiliation: College of Pharmacy, SungKyunKwan University, Jangan-ku, Suwon City, South Korea.
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Jin
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.forename: Sohee
authors.initials: S
authors.lastname: Son
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Key An
authors.initials: KA
authors.lastname: Um
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001710:Biotin / Q000031:analogs & derivatives / Q000737:chemistry; D019921:Biotinylation / Q000379:methods; D001786:Blood Glucose / Q000378:metabolism*; D001826:Body Fluids / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics; D013388:Succinimides / Q000737:chemistry; D014357:Trypsin / Q000378:metabolism; D014688:Venoms / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D004337:Drug Carriers; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D054411:Receptors, Leptin; D013388:Succinimides; D014688:Venoms; C033788:biotinyl N-hydroxysuccinimide ester; D001710:Biotin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D014357:Trypsin; D005947:Glucose