RT-GLP3

Description

Product Summary – GLP-3 –RT-GLP3(LY3437943)

Molecular Profile

Amino Acid Sequence of GLP-3 (RT-GLP3)

H-Tyr-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Leu(Me)-Lys(AEEA-γGlu-C20-diacid)-Ala-Gln-Ala-Ala-Phe-Ile-Glu-Tyr-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH₂

Structural Modifications

• Aib: 2-Aminoisobutyric acid (unnatural residue for DPP-4 resistance)
• Leu(Me): α-Methyl-L-leucine (stability enhancement)
• Lys(AEEA-γGlu-C20 diacid): Lysine conjugated to a C20 fatty diacid through a γ-glutamic acid and AEEA linker → extends half-life via albumin binding
• Ser-NH₂ (C-terminus): amidated serine for stability

Mechanism of Action of GLP-3 (RT-GLP3)

All three receptors (GIPR, GLP-1R, and GCGR) are class B G protein-coupled receptors to which GLP-3 binds and increases the intracellular cAMP, which further triggers the protein kinase A (PKA) and EPAC pathways.

In pancreatic beta-cells of the islets of Langerhans, RT-GLP3enhances the exocytosis of glucose-dependent insulin, while in alpha-cells, it acts on GLP-1R and reduces the release. RT-GLP3also increases the hepatic glucose output by the GCGR pathways. All these effects combine to improve the glycemic indices. Studies have shown that GLP-3 binds to receptors in such a way that it sustains Gs coupling and modulates the Arestin recruitment, resulting in prolonged receptor signaling. [1]

In hypothalamic and brainstem circuits, GLP-3 influences the GLP-1 pathway to reduce appetite by activating anorexigenic neurons and inhibiting orexigenic pathways. RT-GLP3 also targets the vagal afferent pathways to satiety. GCGR activation by RT-GLP3increases the overall energy expenditure through enhanced substrate oxidation and strong negative energy balance.

In the liver, RT-GLP3leads to fatty acid oxidation and mobilization of intra-hepatic triglyceride through GCGR pathways. RT-GLP3also reduces lipotoxicity by rapidly decreasing hepatic fat through the GLP-1R and GIP agonistic effects of RT-GLP3.

Chronic Weight Management & Obesity

Tritagonists effect of RT-GLP3at GIPR, GLP-1R, and GCGR, helps reduce the weight through its negative energy balance caused by anorectic CNS signaling, delayed gastric emptying, increased glucose-dependent insulin secretion, and appetite suppression. 

Type 2 Diabetes Mellitus

RT-GLP3improves the net glycemic control by enhancing the glucose-dependent insulin secretion and decreasing the inappropriate postprandial release, helping to control diabetes. 

MASLD / NASH

GLP-3’s effect on hepatic steatosis can be explained as the sum of two mechanistic axes. RT-GLP3indirectly causes decreased adipose lipolysis and reduced ectopic lipid deposition due to its negative energy balance. By direct activation of GCGR, RT-GLP3enhances the fatty acid oxidation and alters the VLDL trafficking. In MRI-PDFF studies, patients with Non-Alcoholic Steatohepatitis (NASH) have shown over 70% reduction in some cohorts. 

Cardiovascular Effects

Because of the reduced liposity, improvements in glycemic control and remodeling of atherogenic lipoproteins, RT-GLP3helps reduce the cardiovascular disease risks.

Renal Benefits

Kidney benefits are usually from the indirect effects of RT-GLP3, like amelioration of hyperglycemia, decreased systemic BP, glomerular hemodynamics improvements, and decreased inflammatory and lipotoxic mediators, which lead to albuminuria and progressive kidney injury. 

Neuroprotection

RT-GLP3, enhancing the GLP-1R and GIPR signaling, activates the cAMP/PKA and PI3K/AKT pathways, which in turn modulate the neuroinflammatory cascades, improvements in cerebral insulin signaling and mitochondrial resilience. [1]

Research Applications

RT-GLP3serves as a probe to investigate multi-receptor incretin biology.

• In vitro studies: Human islets to measure insulin and dynamics, cAMP signaling, and Ca²-dependent exocytosis.
• Neurobiology: Electrophysiology and calcium imaging in hypothalamic neurons to map GLP-1R/GIPR-mediated appetite control.
• Hepatic metabolism: Tracer flux studies and indirect calorimetry to quantify substrate oxidation driven by GCGR agonism.
• Clinical mechanistic trials: MRI-PDFF for liver fat, DEXA for body composition, euglycemic clamps for insulin sensitivity, and continuous glucose monitoring for glycemic variability.

Citations

• Li, W., Zhou, Q., Cong, Z., Yuan, Q., Li, W., Zhao, F., Xu, H. E., Zhao, L. H., Yang, D., & Wang, M. W. (2024). Structural insights into the triple agonism at GLP-1R, GIPR, and GCGR manifested by RT-GLP3. Cell discovery, 10(1), 77. https://doi.org/10.1038/s41421-024-00700-0
• Jastreboff, A. M., Kaplan, L. M., Frías, J. P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., Haupt, A., Milicevic, Z., Hartman, M. L., & RT-GLP3Phase 2 Obesity Trial Investigators (2023). Triple-Hormone-Receptor Agonist RT-GLP3for Obesity – A Phase 2 Trial. The New England journal of medicine, 389(6), 514–526. https://doi.org/10.1056/NEJMoa2301972
• Urva, S., Coskun, T., Loh, M. T., Du, Y., Thomas, M. K., Gurbuz, S., Haupt, A., Benson, C. T., Hernandez-Illas, M., D’Alessio, D. A., & Milicevic, Z. (2022). LY3437943, a novel triple GIP, GLP-1, and receptor agonist in people with type 2 diabetes: a phase 1b, multicenter, double-blind, placebo-controlled, randomized, multiple-ascending dose trial. Lancet (London, England), 400(10366), 1869–1881. https://doi.org/10.1016/S0140-6736(22)02033-5
• Sanyal, A. J., Kaplan, L. M., Frias, J. P., Brouwers, B., Wu, Q., Thomas, M. K., Harris, C., Schloot, N. C., Du, Y., Mather, K. J., Haupt, A., & Hartman, M. L. (2024). Triple hormone receptor agonist RT-GLP3for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature medicine, 30(7), 2037–2048. https://doi.org/10.1038/s41591-024-03018-2
• Sanyal, A. J., Kaplan, L. M., Frias, J. P., Brouwers, B., Wu, Q., Thomas, M. K., Harris, C., Schloot, N. C., Du, Y., Mather, K. J., Haupt, A., & Hartman, M. L. (2024). Triple hormone receptor agonist RT-GLP3for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine, 30(7), 2037–2048. https://doi.org/10.1038/s41591-024-03018-2
• Kopp, K. O., Li, Y., Glotfelty, E. J., Tweedie, D., & Greig, N. H. (2024). Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration. Biomolecules, 14(7), 872. https://doi.org/10.3390/biom14070872

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