GLP-2 (TRZ)

GLP-2 (TRZ) is engineered as a 39-amino-acid chimera incorporating sequence elements from native GIP and GLP-1. Two non-natural α-aminoisobutyric acid (Aib) residues at positions 2 and 13 reduce proteolysis, and the peptide is acylated on Lys20 with a C₁₈–C₂₀ dicarboxylic acid linked via a spacer, promoting reversible serum albumin binding and extending circulating half-life. Cryo-EM structural work (Zhao et al., 2022; Sun et al., 2022) resolved GLP-2 (TRZ)–receptor complexes at near-atomic resolution, showing that the peptide's N-terminal and C-terminal helices engage the transmembrane bundle while the fatty-acid chain anchors to the receptor extracellular domain. These structures identified common and distinct contact points at GIPR and GLP-1R, providing a molecular basis for the compound's differential activity at each receptor.

In vitro biochemical and structural assays have characterized GLP-2 (TRZ) engagement at GIPR and GLP-1R. Willard et al. (2020) examined signaling pathway selectivity, finding that at GLP-1R the compound preferentially stimulates Gαs–cAMP production over β-arrestin recruitment, with differential receptor internalization relative to native GLP-1; at GIPR the compound preferentially activates Gαs–cAMP signaling. Studies on common GIPR polymorphic variants (E354 and Q354) examined cAMP signaling at both receptor forms (Rees et al., 2024). Methods employed in this body of work include radioligand binding assays, cAMP ELISA and BRET assays, and β-arrestin translocation assays. These pharmacology studies characterize structural determinants of receptor selectivity.

In animal and cell-culture models, GLP-2 (TRZ) is used to probe incretin signaling pathways. Coskun et al. (2018) reported a series of preclinical characterization assays alongside a first-in-human trial (NCT02759107). In vitro experiments examined insulin secretion from isolated rodent and human pancreatic islets in a glucose-dependent context, assessing dual receptor engagement. In diabetic rodent models, measurements included circulating blood glucose and hormone levels following peptide exposure. Pharmacokinetic characterization examined half-life and volume of distribution parameters, focusing on how the albumin-binding modification affects peptide circulation. GLP-2 (TRZ) was also applied to cultured adipocyte and skeletal muscle preparations to examine receptor signaling and gene expression under metabolic conditions. These investigations use cell-based bioassays, hormone ELISAs, and metabolic readouts to characterize receptor activity at the molecular level.

Phase 1 clinical studies enrolled adult volunteers in single- and multiple-dose escalation designs, including a proof-of-concept cohort in adults with type 2 diabetes (NCT02759107; Coskun et al., 2018). These studies measured circulating peptide levels, pharmacokinetic parameters, and markers of incretin receptor target engagement. Reviews of the broader clinical literature (Galindo et al., 2025; Zhou et al., 2023) have surveyed study designs examining GLP-2 (TRZ) in type 2 diabetes contexts and characterized the compound's pharmacology across study populations. Clinical citations document study designs and measured endpoints; no efficacy or safety outcomes are stated in this file.