What mechanisms, beyond canonical pathways, are indicated by GLP-1R?

GLP-1R employs various alternative signaling mechanisms, including PLC/PKC and GTP-binding protein pathways, alongside organelle interactions and concentration-dependent pathway switching.

Abstract

GLP‑1 receptor signaling involves several distinct, noncanonical mechanisms alongside its classic Gαs/cAMP/PKA pathway. Studies report that picomolar GLP‑1 concentrations trigger insulin release via a phospholipase C/protein kinase C (PLC/PKC) pathway rather than through PKA activation. In addition, the GLP‑1(9‑36) metabolite reduces glucagon secretion by engaging an inhibitory GTP‐binding protein independently of PKA. Other reports describe a cAMP/Epac/PI3K/Akt cascade mediating cardioprotective effects and a mode of Akt activation that bypasses traditional PI3K‐dependent phosphorylation in β‑cells.

Additional findings indicate that signaling bias plays a role in GLP‑1R function. Differential β‑arrestin recruitment is linked to receptor internalization and altered downstream responses, while concentration‐dependent shifts—such as a switch from PKC‐ to PKA‐dependent pathways—modulate physiologic outcomes. Furthermore, evidence from in vitro studies shows that GLP‑1R associates with endoplasmic reticulum and mitochondrial proteins (for example, VAP‑B and SPHKAP), suggesting a role in inter‑organelle communication and mitochondrial remodeling. These convergent observations demonstrate that GLP‑1R orchestrates a multifaceted network of PKA‑independent and context‑dependent signaling events.

Methods

We analyzed 40 sources from an initial pool of 497, using 7 screening criteria.

Key Findings from GLP-1R Signaling Mechanism Studies

Study Types

• In vitro cellular experiments: 35/40 studies
• Animal studies: 14/40 studies
• Clinical trials: 1 study
• Computational/modeling studies: 2 studies
• Design not clearly specified: 3 studies

Key Mechanisms

• General GLP-1R signaling: 4 studies
• β-arrestin-mediated signaling: 2 studies
• Biased agonism: 2 studies
• Non-canonical Akt activation: 2 studies
• PLC/PKC-dependent pathways: 2 studies

Non-Canonical Signaling Mechanisms

PKA-Independent Signaling Pathways

Several studies identified PKA-independent signaling pathways activated by GLP-1R:

• PLC/PKC-dependent pathway:
  • Shigeto et al. (2017a, 2017b) reported GLP-1 stimulates insulin secretion at physiological (picomolar) concentrations through this pathway
• Inhibitory GTP-binding protein mechanism:
  • Guida et al. (2019) found GLP-1(9-36) metabolite inhibits glucagon secretion through this PKA-independent mechanism

Concentration-Dependent Alternative Pathways

Several studies reported concentration-dependent activation of alternative signaling pathways by GLP-1R:

• PKC vs PKA-dependent pathways:
  • Shigeto and Kaku (2014) found:
    • Picomolar GLP-1: PKC-dependent pathway for insulin secretion
    • Nanomolar GLP-1: Canonical PKA-dependent pathway

Physiological Implications

Cell-Type Specific Effects

Studies reported diverse effects of GLP-1R signaling in different cell types:

• Pancreatic β-cells:
  • Enhanced insulin secretion through canonical and non-canonical pathways
• Cardiomyoblasts:
  • Novel GLP-1R/cAMP/Epac/PI3K/Akt signaling pathway mediates cardioprotective effects
• Neurons:
  • Neuroprotective effects in Parkinson’s disease models, involving improvements in mitochondrial and lysosomal function.

References

• Shigeto, M., Cha, C. Y., Rorsman, and Kaku. (2017). A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion. Journal of Molecular Medicine.
• Wong, C., Yusta, B., Koehler, J., Baggio, L., and McLean, B. A. et al. (2022). Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation. Cell Metabolism.