Novel Modified GLP-1 Derivatives with Prolonged Glucose-Lowering Ability In Vivo

The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has advanced new approaches to the generation of degradation-resistant GLP-1 analogs. Chemical coupling of GLP-1 analog to HSA is innovatively achieved by solid-phase peptide synthesis in this study and shows prolonged glucose-lowering ability in vivo. GLP-1(7–37)(Ala8Aib)-Cys-HSA was constructed by solid-phase peptide synthesis through two levels of modification: mutation of Ala8 to aminoisobutyric acid (Aib) to decrease DPP-IV degradation, and conjugation to large serum protein HSA by chemical modification to decrease renal filtration. Glucose tolerance test and insulin secretion assay were performed to examine the biological activity of GLP-1(7–37)(Ala8Aib)-Cys-HSA in vivo in the present research. Long-lasting glucose-lowering and insulin-releasing effects were evaluated up to 4 weeks in T2DM rats. GLP-1(7–37)(Ala8Aib)-Cys-HSA lowered blood glucose in normal mice and T2DM rats. Twice administration of GLP-1(7–37)(Ala8Aib)-Cys-HSA to T2DM rats daily significantly reduced glycemic excursion following IP glucose challenge (P < 0.01 to 0.05) and greatly increased insulin secretion during the 4-week study period. These findings demonstrate that the albumin-conjugated GLP-1 analog mimics the function of native GLP-1 with prolonged activity.