With age and ailments like diabetes, naturally produced concentrations of GLP-1 begin to decline in the body. Synthetic peptides developed to mimic GLP-1, like Semaglutide, have become critical in research studies, as they may combat this deficiency and provide additional therapeutic benefits.
Scientific and Historical Background
Semaglutide peptide is an artificially synthesized analog of human glucagon-like peptide-1 (GLP-1). Similar to the GLP-1 peptide hormone, Semaglutide, as the GLP-1 receptor agonist, may be able to decrease insulin levels, reduce appetite, and help with weight loss and diabetes.(2) Semaglutide was first synthesized and developed in 2012, and in that time, researchers have extensively explored its potential.
Mechanism of Action
Continued research studies report that the peptide may produce effects via various pathways, including:
- Upon binding with the GLP-1 receptors and promoting insulin secretion, i.e., glucose-dependent insulin release(5)
- By suppressing the release of glucagon and inhibiting the hepatic synthesis of glucose
- By improving the pancreatic beta cell functioning and improving the proinsulin to insulin ratio in the body(6)
- Delaying gastric motility and reducing appetite, leading to a reduction in body weight(7)
Potential Functions of the Semaglutide Peptide
Some therapeutic effects of the peptide may include:
- Ability to protect beta cells in the pancreas
- Decrease blood glucose levels (anti-diabetic effect)
- Ability to reduce hunger and food intake (anti-obesity effect)
- Cardioprotective functions
- Neuroprotective functions
Semaglutide and the Incretin Effect
One supposed effect most Semaglutide peptide researchers reported is the “incretin effect.” Incretins are a group of hormones released by the gastrointestinal tract in response to food intake, which triggers a reduction in blood glucose levels.
In the case of Semaglutide, the peptide appears to bind to the GLP-1 receptors located on the surface of the beta cells found in the pancreas. As a result of this linkage, it appears to stimulate insulin secretion and thereby decrease the excess blood glucose levels in the body – which is the same effect induced by incretin. Hence, the term “incretin effect” was coined.(2)
As per the scientist J. J Holst, “The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions.” Being a GLP-1 receptor agonist, Semaglutide peptide may contribute to incretin hormone production and regulate blood sugar levels.
Semaglutide Peptide and Appetite Suppression
GLP-1 receptor agonists such as Semaglutide peptide may delay the motility of gastric acid in the stomach, which contributes to the stomach feeling “fuller” and reduces appetite.(2) Laboratory experiments in Semaglutide administration suggest that the peptide may help gradually reduce excess weight, promoting better heart health and increasing stamina.
A clinical trial(8) was conducted on a similar incretin mimetic compound, where 314 patients were enrolled for an 82-week study. All patients were subjected to this compound throughout the study duration. After completing this study, it was reported that all patients showed a significant reduction in their weight and demonstrated improvement in some cardiovascular activity. As per L Blonde et al., this compound appeared to exhibit “progressive reduction in weight, as well as improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycemia.”
Semaglutide Peptide and Pancreatic Beta Cells
A study(9) was conducted on non-obese and diabetic mice models. These were either subjected to a blend of Semaglutide and Lisofylline or Semaglutide and Exendin-4. Lisofylline is a compound that diminishes autoimmune ability (such as diabetes), and Exendin-4 is a compound that helps in the proliferation of beta cells. After completing this study, the results indicated that the peptide may have stimulated the growth of pancreatic beta cells, potentially preventing cellular apoptosis (i.e., cellular death).
Considering the results garnered from this study, and others like it, there are reasons to suppose that the peptide may help protect the pancreatic beta cells. Moreover, even after discontinuing peptide administration, the blood glucose levels were maintained at an optimum for a minimum of 145 days. These results indicate that the peptide has a strong potential to be an efficient anti-diabetic medication for human use.
Neurological Effects of Semaglutide Peptide
Research(9) has shown that the GLP-1 receptor, namely GLP-1R, is vital in improving cognitive (learning) abilities. Both GLP-1 and its receptor GLP-1R are expressed in the brain cells. When receptors GLP-1R are deficient in the brain, it produces seizures, poor learning abilities, and injury to the brain or nervous system. Being a synthetic analog of GLP-1, Semaglutide peptide may bind with the GLP-1R receptor to similarly enhance learning skills in patients.
Mathew J During et al. suggested, “Systemic administration of GLP-1 receptor agonists in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for cognitive-enhancing and neuroprotective agents.” These results suggest that the Semaglutide peptide may have potential benefits when used to treat neurological ailments such as Alzheimer’s.
In another study,(10) the GLP-1 peptide and its analogs were suggested to protect the brain’s hippocampal areas against cellular apoptosis. These results of the study indicated that the peptide might halt and possibly reverse any neurodegenerative disorder such as Alzheimer’s. Interestingly, similar studies report that the peptide may also reduce the concentration of beta amyloids in brain neurons. Beta amyloids are the precursor to Alzheimer’s, but there are reasons to believe that Semaglutide peptide may be able to prevent, or at least control, such amyloids.(11)
Semaglutide Peptide and the Cardiovascular System
In a similar manner to its neurological mechanisms, GLP-1 receptors (GLP-1R) also appear to be vital in maintaining cardiac health. Being widely spread in the cardiovascular system, these receptors must bind with the peptide to produce these biological effects.(12) GLP-1 and its peptide analogs, like Semaglutide peptide, may help maintain blood pressure levels and decrease left ventricular diastolic pressure. When these two are not adequately maintained, the risk of cardiac issues such as myocardial infarction or hypertrophy dramatically increases.
Moreover, Semaglutide is believed to support cardiac health post-heart attack, as the peptide appears to improve the glucose uptake of the heart muscles, which typically become weak and ischemic post-myocardial infarction. This weakening may be reversed (or prevented) if the subject is administered the peptide, potentially improving the cardiac condition.
Semaglutide peptide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). This peptide may help patients with diabetes as it appears to exhibit control over blood glucose levels. It may also stimulate the pancreas to produce more insulin after meals and reduce the sugar released from the liver. Semaglutide peptide also potentially reduces appetite, helping with weight loss. This is particularly noted in research involving subjects with type 2 diabetes.
The results from clinical trials indicate it may be as effective as other GLP-1 RA medications and suggest it may provide a longer duration of action, allowing for fewer instances of administration than similar medications. It also appears to be relatively well tolerated, with reported side effects being infrequent and mild. Further clinical trials are in progress to further explore the action of the peptide and understand its therapeutic potential.
- National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 16133830, Glucagon-like Peptide-1 (7-37). https://pubchem.ncbi.nlm.nih.gov/compound/Glucagon-like-Peptide-1-_7-37.
- Mahapatra MK, Karuppasamy M, Sahoo BM. Semaglutide is a glucagon like peptide-1 receptor agonist with cardiovascular benefits for the management of type 2 diabetes. Rev Endocr Metab Disord. 2022 Jun;23(3):521-539. doi: 10.1007/s11154-021-09699-1. Epub 2022 Jan 7. PMID: 34993760; PMCID: PMC8736331. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8736331/.
- National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 56843331, Semaglutide. https://pubchem.ncbi.nlm.nih.gov/compound/Semaglutide.
- FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. June 04, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
- Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019 Apr 12;10:155. doi: 10.3389/fendo.2019.00155. PMID: 31031702; PMCID: PMC6474072. https://pubmed.ncbi.nlm.nih.gov/31031702/
- Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, Aroda VR. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care. 2018 Feb;41(2):258-266. doi: 10.2337/dc17-0417. Epub 2017 Dec 15. PMID: 29246950. https://pubmed.ncbi.nlm.nih.gov/29246950/
- Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide as a promising anti-obesity drug. Obes Rev. 2019 Jun;20(6):805-815. doi: 10.1111/obr.12839. Epub 2019 Feb 15. PMID: 30768766. https://pubmed.ncbi.nlm.nih.gov/30768766/
- Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD, Kendall DM. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab. 2006 Jul;8(4):436-47. doi: 10.1111/j.1463-1326.2006.00602.x. PMID: 16776751. https://pubmed.ncbi.nlm.nih.gov/16776751/
- During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN. The glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9. doi: 10.1038/nm919. Epub 2003 Aug 17. PMID: 12925848. https://pubmed.ncbi.nlm.nih.gov/12925848/
- Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002 Sep;302(3):881-8. doi: 10.1124/jpet.102.037481. PMID: 12183643. https://pubmed.ncbi.nlm.nih.gov/12183643/
- Perry TA, Greig NH. A new Alzheimer’s disease interventive strategy: GLP-1. Curr Drug Targets. 2004 Aug;5(6):565-71. doi: 10.2174/1389450043345245. PMID: 15270203. https://pubmed.ncbi.nlm.nih.gov/15270203/
- Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN, Parker TG, Huang Q, Drucker DJ, Husain M. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003 Jun;144(6):2242-52. doi: 10.1210/en.2003-0007. PMID: 12746281. https://pubmed.ncbi.nlm.nih.gov/12746281/
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Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.