Investigating the potential effect of l-citrulline on PI3K signaling pathway: in silico and in vitro evaluation
DOI:
https://doi.org/10.15587/2519-4852.2025.342290Keywords:
Insulin resistance, Type 2 diabetes mellitus, L-Citrulline, Metformin, PI3K signaling pathway, ADME, In vitro, In silico, Molecular docking, Skeletal muscle cellsAbstract
Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM), resulting from dysfunction in the insulin signaling pathway, which involves critical proteins such as IRS-PI3K-IRS-1-PKC-AKT2 and GLUT4. Metformin, a first-line T2DM treatment, exerts its effects via various mechanisms, but alternative therapies are needed. L-Citrulline, an amino acid with antiglycation and antioxidant properties, has shown potential as a therapeutic agent.
The aim. This study aims to evaluate the efficacy of L-Citrulline, alongside the well-established antidiabetic drug metformin, in a T2DM model using both in vitro and in silico approaches.
Materials and methods. Differentiated L6 skeletal muscle cells, induced with high glucose and insulin concentrations to model insulin resistance, were treated with either L-Citrulline or metformin. The expression of PI3K, a key protein in insulin signaling, was assessed using an ELISA Kit. In silico molecular docking studies were also conducted to examine the binding interactions of L-Citrulline and metformin with PI3K.
Results. L-Citrulline treatment significantly increased PI3K concentration levels in insulin-resistant skeletal muscle cells, indicating a potential restoration of insulin signaling. The enhancement in PI3K concentration was comparable to that observed with metformin, validating the effectiveness of L-Citrulline in modulating the PI3K pathway. Molecular docking studies revealed that L-Citrulline formed stable and favorable interactions with PI3K, suggesting strong binding affinity and potential enhancement of its catalytic activity.
Conclusion. L-Citrulline demonstrates potential in modulating the PI3K signaling pathway based on both in vitro and in silico findings, indicating a possible role in improving insulin responsiveness in type 2 diabetes mellitus (T2DM). Nevertheless, these results are preliminary, and further in vivo and clinical investigations are needed to confirm its therapeutic relevance
Supporting Agency
- DOST-ASTHRDP and the DOST- Research Enrichment Program for the purpose of conducting this research
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Copyright (c) 2025 Jessa Marielle U. Paulines, Patrick Nwabueze Okechukwu, Charlie A. Lavilla Jr
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