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Innovative Medicines & Omics Peganum harmala and GLP-1: A natural approach

targeted GLP-1 stimulation in L-cells and pancreatic appears to exert its effects by stimulating endogenous
β-cells. Semaglutide, a synthetic GLP-1RA, directly GLP-1 secretion and enhancing insulin signaling.
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mimics incretin activity, leading to robust glucose Harmine and harmaline have been shown to influence
homeostasis regulation. However, its high cost and GLP-1 synthesis by modulating cellular glucose-sensing
injectable administration limit widespread accessibility. mechanisms in enteroendocrine L-cells. Activation of the
On the other hand, P. harmala offers a plant-based, cost- Akt/GLUT4 pathway plays a pivotal role in this process.
effective alternative with broader metabolic benefits, By enhancing Akt phosphorylation at serine 473 (pS473-
including neuroprotection and antioxidative stress Akt), P. harmala facilitates the translocation of GLUT4
reduction. Nevertheless, its lower bioavailability and lack to the cell membrane, promoting glucose uptake and
of regulatory approval necessitate further refinement increasing intracellular ATP levels. This, in turn, triggers
before clinical adoption. calcium-dependent exocytosis of GLP-1 granules, thereby
Recent discoveries highlight the interplay between enhancing the secretion of this incretin hormone. In
GLP-1 and the gut microbiome, suggesting that modulating addition, P. harmala’s effects extend beyond direct glucose
microbial composition may enhance endogenous incretin sensing. The alkaloids modulate oxidative stress and
secretion. In addition, novel GLP-1R isoforms with tissue- inflammation, two factors that influence GLP-1 secretion.
specific functions are being investigated; presenting By activating Nrf2, harmine and harmaline upregulate
opportunities to refine targeted therapies. Exploring antioxidant enzymes such as glutathione peroxidase and
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P. harmala’s influence on these pathways could expand its superoxide dismutase, reducing oxidative damage to
therapeutic scope. The high manufacturing costs of GLP- L-cells and preserving their function. This antioxidant
1RAs pose accessibility challenges, particularly in low- effect contributes to sustained GLP-1 production, making
income regions. P. harmala’s widespread availability and P. harmala a promising candidate for enhancing incretin-
ease of cultivation position it as a scalable alternative. based therapies. One of the primary mechanisms by which
P. harmala improves insulin sensitivity is through its
Oral semaglutide formulations face significant interaction with the PI3K/Akt signaling pathway. Insulin
bioavailability hurdles due to gastrointestinal degradation. resistance, a hallmark of T2DM, is often characterized
Research on absorption enhancers such as sodium by impaired Akt activation and GLUT4 translocation.
N-(8-[2-hydroxybenzoyl]amino) caprylate with the aim to Harmine and harmaline counteract this dysfunction by
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improve uptake efficiency is currently underway. Applying enhancing PI3K-mediated phosphorylation of Akt, leading
similar advancements to oral P. harmala formulations may to improved downstream insulin signaling, reducing IRS-1
enhance its pharmacokinetic properties, ensuring clinical serine phosphorylation (pS307-IRS-1), a key marker of
viability. Beyond metabolic disorders, GLP-1 signaling insulin resistance, thereby enhancing insulin receptor
is implicated in neurodegenerative and cardiovascular sensitivity, and promoting GLUT4 vesicle mobilization,
conditions. Investigating P. harmala’s impact on AD, facilitating glucose uptake into peripheral tissues,
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atherosclerosis, and gut-brain axis regulation could particularly muscle and adipose cells. The combined
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unveil novel therapeutic applications. Furthermore, effects of these pathways position P. harmala as a potent
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combinatory approaches involving P. harmala and other insulin-sensitizing agent, capable of improving metabolic
natural compounds warrant exploration for synergistic flexibility and reducing hyperinsulinemia. Beyond its role
metabolic benefits. Notably, P. harmala has the potential in insulin signaling, Akt activation indirectly enhances the
to revolutionize various treatments by mimicking Nrf2 antioxidant response, creating a synergistic effect that
semaglutide’s mechanism of action. This is particularly strengthens cellular defense mechanisms. Harmine and
relevant given the emerging paradigm shift in utilizing harmaline have been shown to inhibit GSK-3β, an upstream
semaglutide not only for T2DM but also as a promising regulator that negatively modulates Nrf2 activity. By
therapy for type 1 diabetes, highlighting its broader inactivating GSK-3β, P. harmala prevents the degradation
metabolic and therapeutic implications. 39 of Nrf2, thereby amplifying its transcriptional activity and
increasing the expression of cytoprotective genes. This
7. Discussion interplay between Akt and Nrf2 pathways establishes P.

The growing body of evidence suggests that P. harmala, harmala as a dual-action therapeutic, simultaneously
through its bioactive alkaloids harmine and harmaline, improving insulin sensitivity and mitigating oxidative
holds significant potential in modulating key molecular stress, both of which are crucial in the pathophysiology
pathways associated with glucose homeostasis and of diabetes and neurodegenerative disorders. Despite its
insulin sensitivity. Unlike synthetic GLP-1RAs such as promising pharmacological effects, the bioavailability
semaglutide, which directly activate the GLP-1R, P. harmala of harmine and harmaline remains a critical challenge.

Volume 2 Issue 3 (2025) 64 doi: 10.36922/IMO025060009