GLP-1 R

GLP-1 R (Triple Agonist Peptide): Mechanistic Overview and Metabolic Implications

Molecular Overview

GLP-1 R (Glucagon-Like Peptide-1 Receptor Agonist, Triple Hormone Analog) is a next-generation investigational peptide engineered to simultaneously activate three critical metabolic receptors — GLP-1, GIP, and glucagon (GCGR). This poly-agonist mechanism integrates incretin and glucagon pathways to optimize glycemic regulation, energy expenditure, and body-weight homeostasis.

Unlike conventional single-pathway GLP-1 agonists, GLP-1 R achieves superior metabolic synergy by coordinating insulinotropic, lipolytic, and thermogenic signaling cascades, offering a systems-level intervention for obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD/NASH).

Mechanism of Action

• GLP-1 Receptor Activation
  Binding to the GLP-1R on pancreatic β-cells triggers Gs-protein–coupled cAMP signaling, enhancing glucose-dependent insulin secretion, reducing glucagon output, and slowing gastric emptying. In the central nervous system, GLP-1R activation suppresses hypothalamic orexigenic neurons, producing appetite reduction and decreased caloric intake.
   
• GIP Receptor Co-activation
  GIPR (Glucose-Dependent Insulinotropic Polypeptide Receptor) stimulation potentiates β-cell responsiveness to glucose and amplifies insulinotropic effects in synergy with GLP-1R signaling. This dual activation promotes sustained glycemic control and may contribute to improved adipocyte insulin sensitivity.
   
• Glucagon Receptor (GCGR) Engagemen
  Selective GCGR activation enhances hepatic fatty-acid oxidation and energy expenditure through upregulation of AMP-activated protein kinase (AMPK) and thermogenic pathways in adipose tissue. The balanced activation of this receptor contributes to fat mass reduction without excessive hyperglycemia.

Metabolic and Physiological Outcomes

• Substantial Weight Reduction: Dual incretin and glucagon signaling result in significant adipose tissue catabolism and central appetite suppression. Early clinical data demonstrate mean body-weight loss up to 24%, surpassing traditional GLP-1 monotherapy outcomes.

• Glycemic Optimization: Enhances insulin secretion in a glucose-dependent manner, increases peripheral glucose uptake, and reduces hepatic gluconeogenesis, improving HbA1c and fasting glucose indices in T2DM populations.

• Insulin Sensitivity Enhancement: Downregulation of inflammatory adipokines (e.g., TNF-α, IL-6) and modulation of adiponectin secretion improve insulin receptor signaling and glucose utilization.

• Anti-Inflammatory Modulation: GLP-1 R agonism suppresses NF-κB activity, lowering systemic inflammatory markers associated with atherogenesis and metabolic syndrome.

• Cardiovascular Protection: Improves lipid homeostasis (reduces LDL, increases HDL), enhances endothelial nitric oxide synthesis, and attenuates vascular oxidative stress, contributing to lower blood pressure and overall cardiovascular risk reduction.

• Hepatic Health: Preclinical and early clinical findings indicate decreased hepatic steatosis, reduced lipid accumulation, and improved NAFLD/NASH histological markers.

Clinical and Research Significance

GLP-1 R represents a novel multi-agonist therapeutic platform at the intersection of endocrine signaling, metabolic homeostasis, and energy regulation. By uniting GLP-1, GIP, and glucagon receptor activity, it demonstrates a uniquely comprehensive approach to metabolic disease intervention — promoting fat oxidation, glycemic stability, and systemic anti-inflammatory effects.

Although still under investigation and not yet FDA-approved, GLP-1 R is currently in advanced clinical trials and is considered a potential breakthrough in the peptide-based management of obesity, insulin resistance, and cardiometabolic disorders.

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This product is strictly for research purposes only and is intended solely for in vitro testing and laboratory experimentation. The information provided on this website is for educational use and does not permit the introduction of this product into humans or animals. Handling of this product is restricted to licensed and qualified professionals. It is not classified as a drug, food, or cosmetic, and should not be misrepresented or used as such.

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Molecular Formula

• Sequence: Tyr–{Aib}–Gln–Gly–Thr–Phe–Thr–Ser–Asp–Tyr–Ser–Ile–{α‑Me‑Leu}–Leu–Asp–Lys–{diacid‑C20‑γ‑Glu–(AEEA)–Lys}–Ala–Gln–{Aib}–Ala–Phe–Ile–Glu–Tyr–Leu–Leu–Glu–Gly–Gly–Pro–Ser–Ser–Gly–Ala–Pro–Pro–Pro–Ser–NH₂
• Formula: C₂₂₁H₃₄₂N₄₆O₆₈
• Molecular Weight: ~4,731.33 g/mol

View Certificate of Analysis

1. What is GLP-1 R, and why does it matter? 

GLP-1 R is a novel investigational peptide therapeutic designed to target three key metabolic pathways through its action as a triple hormone receptor agonist. It activates the GLP-1, GIP, and glucagon receptors, all of which are central to regulating appetite, blood sugar, and energy expenditure.What makes GLP1-R particularly noteworthy is its exceptional efficacy in early clinical studies. It has demonstrated unprecedented results in promoting weight loss and improving metabolic health, positioning it as a potentially groundbreaking option in the field of peptide-based treatments for obesity and type 2 diabetes.

2. What are the benefits of GLP-1 R?

Dramatic weight reduction: Clinical data shows average body weight loss of up to 24%, exceeding the effects of current GLP-1 therapies.Improved glycemic control: Supports healthier blood sugar levels in individuals with type 2 diabetes.Enhanced metabolic function: May improve insulin sensitivity, lipid profiles, and reduce blood pressure.Potential liver health benefits: Early data suggest it may reduce hepatic fat accumulation, making it a candidate for treating NAFLD/NASH.These multifaceted effects make GLP1-R one of the most promising peptide candidates in the metabolic health space.

3. What is GLP-1 R used for?

• Obesity
• Overweight with comorbidities such as hypertension or dyslipidemia
• ⁠Type 2 diabetes
• ⁠Non-alcoholic fatty liver disease (NAFLD/NASH)

Although not yet FDA-approved, GLP1-R is in advanced clinical trials and represents a next-generation peptide therapy with broad potential across several chronic metabolic conditions.

Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.
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Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.
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Retatrutide showing promise in obesity (and type 2 diabetes).
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A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity.
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Retatrutide-A Game Changer in Obesity Pharmacotherapy.
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Retatrutide.
Ramsbacher N.Clin Diabetes. 2024 Aug 1;42(4):579-580. doi: 10.2337/cd24-0062. eCollection 2024 Fall.PMID: 39429457 No abstract available.
 

The power of three: Retatrutide's role in modern obesity and diabetes therapy.
Abdul-Rahman T, Roy P, Ahmed FK, Mueller-Gomez JL, Sarkar S, Garg N, Femi-Lawal VO, Wireko AA, Thaalibi HI, Hashmi MU, Dzebu AS, Banimusa SB, Sood A.Eur J Pharmacol. 2024 Dec 15;985:177095. doi: 10.1016/j.ejphar.2024.177095. Epub 2024 Nov 6.PMID: 39515565 Review.
 

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Comparison of the effects of Liraglutide, Tirzepatide, and Retatrutide on diabetic kidney disease in db/db mice.
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