Homodimerized GLP-1R agonists produce better efficacy in hypoglycemic effect or/and pancreatic protection in T2D models

Abstract

Background GLP-1R agonists play important role in T2D treatment. Methods Based on the GLP-1, Exendin-4, GIP-Exendin-4 chimeric peptide sequences, homodimerized GLP-1R agonists were synthesized and evaluated in normal and/or fat-diet-induced T2D mice. Results Dimers show opposite or similar water-solubility with their monomers. The H-like dimers 2G2-9 and 2G11-15 (internal single Cys→Ser substitution) respectively produced 5-20-11-3-14-14-2-7 and 2-8-4-9-16 days of hypoglycemic activities compared to their corresponding monomers G2-9 (2-9-3-1-4-4-1-2 day) and G11-15 (1-4-2-3-8 day) after 1.126-nmol of single administration, whereas the U-like dimer 2G1 or 2G10 (C-terminal Cys extension) did not impact glucose level, but it significantly promoted T2D pancreatic protection by inducing a dose-dependent decrease in TUNEL or amylase, and more Ki67 expression or HDL formation. The ultralente effect of dimer involves in delaying absorbance, the formations of 12Cys-12Cys in GLP-1 or 11Cys-11Cys in Exendin-4 and GIP-Exendin-4 analogues, symmetric fat-acid-chain-modulated 20Lys, αAib→2Ala substitution, and C-terminal amidation in one homodimer. 2G3 as a representative for the H-like dimers caused significant dose-dependent hypoglycemic effect in HbA1c changes (-1.6 ± 0.7, -4.6 ± 2.44, -6.4 ± 2.81 mmol/mol) from the Placebo (20.0 ± 5.03 mmol/mol) or FPG changes (-3.726 ± 3.09, -6.644 ± 4.31, -6.695 ± 3.96 mM) from the Placebo (14.149 ± 5.95 mM) as Liraglutide in HbA1c or FPG changes (-5.8 ± 2.83 mmol/mol or -7.107 ± 4.32 mM) from the Placebo. 2G3 induced the dose-dependent protections to T2D liver, heart, vascular wall integrity, or more ki67, HDL, islet number, or 1.92 times` insulin release without hypoglycemia than the same dose of Liraglutide by binding GLP-1R. Conclusions The better homodimerized GLP-1R agonists elucidates that the dimerization of hormone peptide produces better efficacy and may relieve serious concerns in course of therapy.