Review of Semaglutide (GLP-1) Peptide

Semaglutide, an agonist of the glucagon-like peptide-1 (GLP-1) receptor, has been suggested by researchers to be a revolutionary compound in experimental studies, marking the apparently significant activity of the modest 30 amino acid incretin hormone, GLP-1.

The digestive system secretes incretins, which are hormones that encourage the pancreas to secrete more hormones, especially insulin, and thus reduce the plasma glucose concentration. The incretin effect is the difference between the impact of glucose introduction directly into circulation and those that occur after glucose absorption, namely how the former stimulates insulin release more effectively.

As a result, Exenatide, Liraglutide, Albiglutide, and other degradation-resistant GLP-1 receptor agonists have been developed and are now researched in the context of type 2 diabetes mellitus. This apparent activity was the initial focus of research into GLP-1 following its identification in the 1980s. The body of research surrounding GLP-1 physiology has grown substantially since then, thanks to data collected from rigerous studies of these agonists, which has prompted the creation of new GLP-1 receptor agonists.

This themed article attempts to offer a comprehensive review of the many avenues of research conducted on Semaglutide, all associated with activating GLP-1 receptors, and the most recent findings examining how their naturally occurring and synthetic ligands may impact the central nervous system and other organs. Numerous new lines of inquiry have recently emerged in this area, and this article compiles several insightful assessments of these trends. It will summarize what is considered to be the significance of GLP-1 receptors in many organs and systems, including the central and peripheral neurological systems, the stomach (a major source of GLP-1), and others.

Research into biased agonism, the creation of positive allosteric modulators, and the creation of small molecules and peptides are all important areas of focus. This study sought to enhance the profile of GLP-1 receptor ligands by making them more impactful and easier to introduce via pharmacokinetic adjustments. In this area, a review by Jones (2021) examines biased agonism's restorative potential. Malik and Li (2021) zero in on the possibilities of small-molecule agonists and positive allosteric modulators of GLP-1 receptors in the context of type II diabetes.

Furthermore, studies suggest a considerably broader potential for GLP-1 peptide. Several new prospects exist to expand the potential of GLP-1 receptor agonists, which have already been speculated to be an effective class in the context of type 2 diabetes. Tanday et al. (2021) evaluated the possible research relevency of the peptide, which has been hypothesized to go beyond the traditional incretin action of GLP-1.

Semaglutide Peptide and Weight

As Wilding et al. (2021) suggested, these peptides may serve as potential weight regulators. It is still debatable and ongoing what specific brain regions these compounds may act on to trigger downstream impacts. The most compelling reason is that new data challenges some long-held beliefs on the functional relationship between GLP-1 activity in the brain and GLP-1 release in the intestines.

It has long been speculated that enteroendocrine cells may secrete GLP-1 into the circulation after caloric intake to serve as a CNS main satiation signal. But that theory had a hard time fitting with the first finding that GLP-1R knockout mice don't become fat, which had been explained, at least in part, by the idea of redundant signaling pathways and developmental compensatory mechanisms. Recent work by Trapp and Brierley and Brierley and de Lartigue reevaluate the vagus nerve's function in this process and add to the ongoing debate challenging this paradigm.

The processes that underlie the decrease in food intake after the presentation of GLP-1, either within the CNS or systemically, have started to be dissected by more comprehensive research on GLP-1 activity within the CNS. Researchers evaluated this study in this issue; they shed light on several GLP-1-modulated brain circuitry. Additionally, these circuits are believed to be involved in determining the reward value of food, inducing nausea or conditioned taste aversion in animal models, and fullness and satiation.

Findings imply that the stress reaction, rapid heart rate, and elevated systemic blood pressure have all been linked to GLP-1's potential on the brain and the activation of neurons that produce GLP-1. Several types of stress hormones have been speculated to activate GLP-1, generating neurons in the lower brainstem, and several rodent studies have linked GLP-1 with hypophagia, which is generated by restraint stress. In their literature evaluation, licensed professionals suggest that GLP-1 neurons in the brain might be a promising target for stress-related diseases. Helmstädter et al. hint that GLP-1R ligands could increase the sympathetic tone and provide cardiovascular protection via peripheral activities, such as anti-inflammatory effects.

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References

[i] Augestad, I. L., Dekens, D., Karampatsi, D., Elabi, O., Zabala, A., Pintana, H., Larsson, M., Nyström, T., Paul, G., Darsalia, V., & Patrone, C. (2021). Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice. British Journal of Pharmacology, 179 (4), 677–694. https://doi.org/10.1111/bph.15524

[ii] Borner, T., Tinsley, I. C., Doyle, R. P., Hayes, M. R., & De Jonghe, B. C. (2021). Glucagon-like peptide-1 in diabetes care: Can glycaemic control be achieved without nausea and vomiting? British Journal of Pharmacology, 179 (4), 542–556.

[iii] Brierley, D. I., & de Lartigue, G. (2021). Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating. British Journal of Pharmacology, 179 (4), 584–599.

[iv] Brierley, D. I., Holt, M. K., Singh, A., de Araujo, A., McDougle, M., Vergara, M., Afaghani, M. H., Lee, S. J., Scott, K., Maske, C., Langhans, W., Krause, E., de Kloet, A., Gribble, F. M., Reimann, F., Rinaman, L., de Lartigue, G., & Trapp, S. (2021). Central and peripheral GLP-1 systems independently suppress eating. Nature Metabolism, 3(2), 258–273.

[v] Cui, Q. N., Stein, L. N., Fortin, S. M., & Hayes, M. R. (2021). The role of glia in the physiology and pharmacology of GLP-1: Implications for obesity, diabetes, and neurodegenerative processes including glaucoma. British Journal of Pharmacology, 179 (4), 715–726.