Innovative Glucagon-like Peptide 1 Receptor Agonists: Exploring the Therapeutic Potential of Specific Modified Monomer, Dimer, and Tetramer in Type 2 Diabetes Treatment

Modified glucagon-like peptide 1 (GLP-1) plays a crucial role in type 2 diabetes (T2D) treatment. The comparative hypoglycemic effect among fatty-acid-modified GLP-1 monomer G20, dimer 2G21, and tetramer 4G18 was evaluated in T2D mice. The polymers exhibited an opposite solubility with their monomers. After single administration, the oral glucose tolerance test results showed that the monomers, dimer, or tetramer, respectively, had 3-9, 21, or 35 days of hypoglycemic effect or plasma stability. G20 had a moderate hypoglycemic effect, and its peak effect occurred in week 1 as semaglutide. 2G21 showed a strongly hypoglycemic effect in week 1-10, and its peak effect occurred in week 4. 4G18 had a weak effect initially but rapidly strengthened in weeks 6-10 and reached its peak effect in week 10. After the 10 week interference, compared to the model control group, G20 (-19.7 or -4.3%), 2G21-L/M/H (-15.9/-34.3/-26.7% or -6.0/-34.4/-36.2%), and 4G18-L/M/H groups (-44.3/-49.8/-53.8% or -40.9/-50.6/-50.8%) significantly exhibited hypoglycemic effects in postprandial glucose or fasting plasma glucose changes. Insulin altered +4.1% (G20), -9.6/+10.0/+36.5% (2G21-L/M/H), and +38.5/+28.7/+84.8% (4G18-L/M/H). HbA_1c or body weight reduced -11.9 or -0.18% (G20), -5.2/-15.2/-19.1% or +0.5/-4.7/-1.2% (2G21-L/M/H), and -5.8/-4.8/-5.4% or -2.9/-2.1/-3.1% (4G18-L/M/H), showing a dose-dependent reduction in 2G21, whereas the 4G18 had lower variations. 2G21 induced a hypoglycemic effect and diet stress, whereas 4G18 only did a hypoglycemic effect and showed a stronger protection to the model organs and more improvement in the nerve muscle than G20 or 2G21. The endogenous insulin release depends not only on the GLP-1 peptide dose but also on the peptide chain in the polymer skeleton.