A new orally available glucagon-like peptide-1 receptor agonist, biotinylated exendin-4, displays improved hypoglycemic effects in db/db mice

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, Lys27-Biotin-Exendin-4 (MB1-Ex-4), Lys12-Biotin-Exendin-4 (MB2-Ex-4), and Lys12, 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 μg/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 μg/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.