Liraglutide (GLP-1) (3mg)

Liraglutide (GLP-1) Peptide

Liraglutide is a chemical peptide, which belongs to the class of glucagon-like peptide-1 receptor agonists (GLP-1RAs). It mimics the GLP-1 peptide hormone that occurs naturally, containing 31 amino acids in its active form. Specifically, Liraglutide appears to exert a 97% similarity to the active form of GLP-1. It appears to function primarily in lowering blood glucose levels through activation on beta cells of the Islet of Langerhans to produce insulin. Its apparent functions may not be limited to blood glucose reduction, it may also act on the gastrointestinal tract (GIT), cardiovascular system, and brain. It has also been researched for potential function within fat tissues, muscle tissues, bone, liver, lungs, and kidneys.

Specifications

Molecular Formula: C₁₇₂H₂₆₅N₄₃O₅₁

Molecular Weight: 3751.20 g/mol

Synonyms: GLP-1, proglucagon (72-108), Glucagon – peptide – 1, victoza, Liraglutida, Liraglutidum, NN2211

Liraglutide Research

Liraglutide Peptide and Incretin Action
According to research on GLP-1, the primary potential of the hormone that Liraglutide mimics, is its proposed “Incretin Action”.^[1] The researcher Dr. Holst explains that “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.” Incretins are hormones such as the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide (GLP-1).

In murine models, Liraglutide seems to activate the adenylate cyclase (AC) pathway upon binding to the glucagon-like peptide-1 receptor (GLP-1R), resulting in a rise in intracellular cyclic AMP (cAMP) levels.^[2] This increase in cAMP might potentially trigger protein kinase A (PKA), which is thought to upregulate insulin secretion by promoting the exocytosis of insulin-containing vesicles from pancreatic β-cells. Furthermore, Liraglutide might suppress glucagon secretion from pancreatic α-cells, which may lead to a reduction in hepatic glucose production.

Beyond this primary mechanism, there is some indication that Liraglutide may engage additional pathways, notably those involving PI3K/mTOR signaling. This pathway might contribute to pancreatic β-cell proliferation while reducing apoptosis, thereby indirectly sustaining insulin secretion over time. The engagement of exchange proteins directly activated by cAMP (EPAC), alongside PKA, may also play a role in closing ATP-sensitive potassium channels. This closure might result in membrane depolarization and an influx of calcium ions, which further potentiates glucose-induced insulin secretion. Together, these mechanisms suggest that Liraglutide has the potential to robustly modulate insulin and glucagon dynamics, although the precise outcomes in different physiological contexts may vary.

Liraglutide Peptide and Hunger Signaling
Studies on mouse models exposed to Liraglutide have been used to develop experimental theses on the impact of the peptide within the brain.^[3] The peptide appeared to reduce the drive to eat via interactions with the signaling within the brain structures, particularly those involved in hunger regulation. Liraglutide is hypothesized to potentially influence the arcuate nucleus (ARC) within the hypothalamus, a brain region associated with regulating energy balance and appetite.^[4] The ARC comprises two distinct neuronal populations: one group produces proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which are thought to decrease appetite, while another group synthesizes neuropeptide Y (NPY) and agouti-related peptide (AgRP), which are believed to stimulate appetite.

Research data suggests that Liraglutide may interact with neurons in the ARC and other hypothalamic areas by binding to glucagon-like peptide-1 receptors (GLP-1Rs). This binding appears selective for models expressing functional GLP-1Rs, as it is not observed in GLP-1R-deficient (Glp1r–/–) models, indicating that the ARC might play a crucial role in mediating Liraglutide’s actions through direct interaction with GLP-1Rs. POMC/CART neurons are proposed to be integral to satiety and energy expenditure, potentially due to their secretion of α-melanocyte-stimulating hormone (α-MSH), which engages melanocortin-4 receptors (MC4R) to suppress food intake. Conversely, NPY and AgRP neurons are believed to promote hunger, with NPY acting as a potent appetite stimulant and AgRP serving as an antagonist or inverse agonist at MC4R, thus encouraging food intake.

The interaction between these neuronal groups is considered vital for maintaining energy homeostasis. It is postulated that Liraglutide might be preferentially taken up by POMC/CART neurons, which are associated with appetite suppression. Electrophysiological findings propose that GLP-1 might directly activate POMC/CART neurons and indirectly inhibit NPY/AgRP neurons via gamma-aminobutyric acid (GABA)-dependent signaling. GABA, the brain’s principal inhibitory neurotransmitter, is suspected to play a pivotal role in this mechanism. By potentially upregulating GABAergic signaling, Liraglutide might reduce the activity of orexigenic NPY/AgRP neurons, thereby shifting the balance toward a state of increased satiety. Murine models exposed to the peptide appeared to experience gradual and linear weight loss, as a result of the reduced appetite.

Liraglutide Peptide and the Brain
Studies have suggested that Liraglutide (GLP-1) peptides may improve cognitive function and protect brain neurons against neurodegeneration such as in Alzheimer’s disease models through mitigation of amyloid-beta accumulation.^[5] Its precise mechanism of action requires further research. Amyloid beta is considered to be the primary component found in Alzheimer’s disease that is associated with its severity.^[6]

Liraglutide Peptide and the Cardiovascular System
Researchers have hypothesized that Liraglutide may be distributed evenly across the heart, appearing to improve cardiac function by reducing the left ventricular end-diastolic pressure, and boosting the heart rate.^[7] The researchers note that

“The defective cardiovascular response to insulin was not attributable to a generalized defect in the stress response, because GLP-1R(-/-) mice responded appropriately to insulin with increased c-fos expression in the hypothalamus and increased circulating levels of glucagon and epinephrine.”

Increased LV end-diastolic pressure is one of the considered causes of LV hypertrophy, cardiac remodeling, and eventual heart failure. Thus, Liraglutide may function to mitigate these cases. Researchers further suggest that Liraglutide may improve the uptake of glucose by cardiac muscles, thus supporting cardiac muscles under the struggle of ischemia facilitate nutritional absorption to aid continuous function and avoid apoptosis. According to the research by Dr. Holst, the continuous exposure of GLP-1 receptor agonists like Liraglutude following a cardiac injury may “constantly increase myocardial performance in […] experimental models.”

Liraglutide Peptide and Beta-Cell Protection
In this research study, animal models were used to extrapolate possible impacts of Liraglutide on pancreatic beta cells.^[8] Here, Liraglutide was reported to apparently accelerate the growth and proliferation of pancreatic beta cells. Researchers also suggested that GLP-1 receptor agonists like Liraglutide may have increased the differentiation of new beta cells from beta-cell progenitors in the epithelium of the pancreatic duct. This reported impact elicited by the Liraglutide peptide has suggested a potential in diabetes-related research. In one of the studies, Liraglutide appeared to halt the death of beta cells caused by increased levels of inflammatory cytokines. In another experimental mouse model, where the mice had type 1 diabetes, Liraglutide appeared to protect the cells of the Islets of Langerhans from death.

Liraglutide Peptide and Adipose Cells
Adipose tissue, known for storing energy and producing various hormones, might be influenced by Liraglutide’s mechanisms, which might impact hormones such as leptin and peptide YY (PYY) that are believed to be involved in energy regulation and satiety.^[9] Leptin, primarily produced by fat cells (adipocytes), is thought to communicate with the central nervous system to influence food intake and energy expenditure. In most cases, rapid weight loss typically leads to a reduction in leptin levels, which may increase appetite and lower metabolic rate. Liraglutide might help sustain weight loss by potentially mitigating the drop in leptin levels that usually accompanies weight reduction.

Peptide YY (PYY) is a hormone that is believed to be secreted by the gut following food intake, and it may contribute to satiety and reduced appetite. Some studies suggest that Liraglutide might raise PYY levels, which may upregulate its potential appetite-suppressing actions. This interaction might explain the reduced energy intake and weight loss observed in some experimental settings involving Liraglutide. Additionally, Liraglutide may have the capacity to improve the function of adipocytes, which might lead to a more favorable metabolic profile. This improvement might involve changes in adipokine levels—hormones produced by adipose tissue—that might upregulate insulin sensitivity and potentially reduce inflammation associated with obesity models. However, these mechanisms remain to be fully understood and require further investigation.

Liraglutide Peptide and Gastrointestinal Tissues
Liraglutide appears to activate GLP-1 receptors (GLP-1Rs) located on enteroendocrine cells within the gut.^[10] These enteroendocrine cells are generally understood to play a role in responding to food intake by secreting GLP-1, a hormone involved in various gastrointestinal processes. Liraglutide may mimic these natural actions by engaging the GLP-1Rs. When Liraglutide activates these receptors, it is believed that signaling occurs through the enteric nervous system, which controls the motility of the gastrointestinal tract. This receptor engagement is hypothesized to influence neural pathways that regulate the rate of gastric contractions and the progression of contents through the digestive system, potentially leading to a decrease in gastric motility and a consequent delay in gastric emptying.

Additionally, Liraglutide’s activation of GLP-1 receptors might initiate signaling through the vagal nerve, which communicates with the central nervous system (CNS). This interaction might further modulate the autonomic nervous system’s regulation of gastric motility, possibly reinforcing the deceleration of gastric emptying. This suggests that Liraglutide may slow down gastric emptying via a complex mechanism, potentially involving the interplay between neural circuits that include GLP-1 receptors in both the CNS and peripheral nervous system.

Experimental observations in laboratory models indicate that Liraglutide may reduce gastric emptying by approximately 23% within the first hour after exposure, compared to a placebo. However, this initial delay does not appear to extend to the overall gastric emptying over a 5-hour period, as measured by the area under the curve (AUC0–300 min). This short-term reduction in gastric motility might, however, be sufficient to promote an early sense of satiety.^[11]

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References