Exploring Peganum harmala as a natural alternative to semaglutide: A novel approach to glucagon-like peptide-1 stimulation and insulin sensitization

Glucagon-like peptide-1 (GLP-1) is a crucial incretin hormone that regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, and delaying gastric emptying. While synthetic GLP-1 receptor agonists such as semaglutide have demonstrated efficacy in managing type 2 diabetes mellitus and obesity, their high cost, limited accessibility, and adverse effects have limited their applicability, necessitating the search for alternative therapeutic strategies. Peganum harmala (harmal), a traditional medicinal plant, has gained attention for its bioactive alkaloids, harmine, and harmaline, which have been shown to modulate key molecular pathways involved in GLP-1 secretion and insulin sensitization. These alkaloids enhance Akt phosphorylation (pS473-Akt), facilitating glucose transporter type 4 translocation and glucose uptake, while concurrently activating the nuclear factor erythroid 2-related factor 2 pathway, leading to increased antioxidant defenses and reduced oxidative stress in pancreatic β-cells and enteroendocrine L-cells. Furthermore, P. harmala alleviates insulin resistance by suppressing IRS-1 serine phosphorylation (pS307-IRS-1) and improving phosphoinositide 3-kinase/Akt signaling, thereby optimizing insulin receptor sensitivity and metabolic homeostasis. Despite these promising pharmacological properties, the poor solubility and rapid metabolism of harmine and harmaline pose challenges to their clinical application. Nanotechnology-based drug delivery systems, including liposomal encapsulation and polymeric nanoparticles, offer a potential solution to enhance bioavailability, prolong systemic circulation, and enable targeted delivery to GLP-1-secreting cells. This paper delves into the molecular mechanisms by which P. harmala stimulates GLP-1 secretion and improves insulin sensitivity, compares its effects with semaglutide, and highlights the potential role of nanotechnology in optimizing its therapeutic applications. By integrating traditional medicine with modern pharmaceutical advancements, P. harmala represents a promising, cost-effective, and sustainable approach to metabolic disorder management, warranting further investigation through pre-clinical and clinical studies.