Semaglutide Research in Hormone Signaling

by | Nov 27, 2022 | Research

Semaglutide is a peptide agonist to the glucagon-like peptide-1 (GLP-1) receptors in the pancreas, the brain, and other organs. The hypothetical action of the compound is considered to be similar to GLP-1, a peptide hormone naturally produced in the intestine. It is an incretin, meaning it is considered to stimulate insulin secretion. Semaglutide is also a subject of extensive research, including pancreatic beta cell apoptosis and neuroprotective potential.

Semaglutide and Blood Sugar Control

Semaglutide has been hypothesized to act by activating the GLP-1 receptors in the pancreatic beta cells, stimulating insulin synthesis and release.[1][2] The stimulating effect on insulin synthesis is the primary mechanism via which Semaglutide may possibly lower both fasting and postprandial glucose levels. A meta-analysis of 26 RCTs suggests that Semaglutide may lower the fasting blood sugar levels and markers for long-term glucose control, such as HbA1c, in cases of type 2 diabetes.[3]

In addition to stimulating insulin secretion, Semaglutide may potentially reduce glucagon release and suppress hepatic gluconeogenesis.[4] These potential actions are supported by study findings in non-diabetic models, which lasted up to 12 weeks and reported over 38% reduction in blood sugar levels compared to a placebo after a carbohydrate-rich food delivery.[5] The researchers also suggested that Semaglutide may have slowed the speed of gastric emptying during the first hour after caloric intake compared to a placebo. The scientists suggested that this potential of Semaglutide may contribute to a gradual release of glucose and better glycemic control. Yet, the overall speed of gastric emptying over the entire 5-hour monitoring period after the meal appeared not affected.

Semaglutide has been hypothesized to reduce hyperglycemia without causing hypoglycemia. The risk of hypoglycemia is not considered to be higher when compared to a placebo as Semaglutide may possibly stimulate insulin secretion in a glucose-dependent manner.[6] In addition, the inhibition of glucagon release may not occur under hypoglycemic conditions.


Semaglutide and Weight

Semaglutide has been suggested to stimulate insulin secretion without leading to weight gain. Studies suggest that Semaglutide may reduce ad libitum energy intake, which may result in weight loss in the long term.[8] According to one study, Semaglutide reduced hunger hormone signaling to the brain, resulting in a reported 24% reduction in energy intake. Semaglutide may activate the GLP-1 receptors in the brain, which may play a major role in modulating appetite and reward-related behavior.[9] Furthermore, the potential of Semaglutide to slow down gastric emptying within the first hour of having a meal may also contribute to a reduced ad libitum energy intake.


Pancreatic Beta Cell Survival

Preliminary studies conducted in test animals suggest that Semaglutide may stimulate pancreatic beta cells’ survival and proliferation. These potential actions are considered to be of significant interest since cases of type 2 diabetes are often associated with pancreatic beta cell dysfunction and apoptosis in the long term.[10]

Animal research suggests that Semaglutide may help reverse the harmful changes of obesity and insulin resistance on pancreatic beta cells and stimulate their proliferation.[11] Researchers reveal that some studies also report that GLP-1 antagonists, such as Semaglutide, may protect pancreatic beta cells from apoptosis.[12] Several possible mechanisms are suggested in the protective potential of Semaglutide, and one of the most prominent is reducing the overload on the endoplasmic reticulum of the beta cells in diabetic conditions. GLP-1 receptor activation may also help stimulate autophagy, which prevents beta cell injury and death by protecting against inflammation and oxidative stress.


Semaglutide and Neuroprotection

Interestingly, Parkinson’s disease and type 2 diabetes are considered to share several genetic susceptibilities, such as single nucleotide polymorphisms in the growth factor signaling kinase gene Akt.[13] This has sparked interest in researching the potential of diabetes compounds for research studies on Parkinson’s disease. Currently, other GLP-1 receptor agonists, such as Exendin-4, have already been suggested to exhibit protective effects on Parkinson’s cases.[14] Another GLP-1 antagonist, Liraglutide, is under investigation for this hypothetical action.[16]

The research regarding the potential neuroprotective action of Semaglutide is still in its infancy, but many laboratory studies in animal models of PD suggest promising results.[15] The experiments report that Semaglutide may have neuroprotective characteristics and may increasethe survival of the dopaminergic neurons, the apoptosis of which is associated with the development of Parkinson’s.

In animals, Semaglutide appeared to have alleviated the chronic inflammatory responses in the brain, reduced lipid peroxidation, and increased the expression of growth factors that protect dopaminergic neurons in the substantia nigra and striatum.


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  16. Clinical trial identifier NCT02953665

Dr. Usman

Dr. Usman (BSc, MBBS, MaRCP) completed his studies in medicine at the Royal College of Physicians, London. He is an avid researcher with more than 30 publications in internationally recognized peer-reviewed journals. Dr. Usman has worked as a researcher and a medical consultant for reputable pharmaceutical companies such as Johnson & Johnson and Sanofi.