How Diabetes Is Controlled With The Use Of GLP-1, And Inflammation

Diabetes is a chronic condition often accompanied by chronic inflammation and high levels of inflammatory cytokines, which can lead to insulin resistance and various complications. Anti-inflammatory agents, including antidiabetic medications like semaglutide, a GLP-1 analogue, are being explored to address these issues. Semaglutide not only lowers glucose levels but also shows potential anti-inflammatory effects. Studies suggest it can modulate inflammatory responses, providing additional benefits for individuals with diabetes. However, the exact mechanisms behind its anti-inflammatory properties are not fully understood. This review aims to discuss recent findings on semaglutide’s anti-inflammatory effects and the potential pathways involved.

The global prevalence of diabetes mellitus (DM) is increasing rapidly, posing significant health challenges. Diabetes is characterized by elevated blood glucose levels and is associated with various metabolic complications and detrimental pathways affecting lipids and carbohydrates. In the diabetic state, pathways such as oxidative stress, inflammation, necrosis, and fibrosis are exacerbated, causing damage to cells and tissues, which can lead to disability or even death. Despite advances in antidiabetic treatments, effectively controlling inflammatory pathways remains a considerable challenge in diabetes management.

Semaglutide, an approved medication for type 2 diabetes mellitus (T2DM), is part of the incretin-based therapies. It has demonstrated significant antidiabetic effects by lowering blood glucose levels through multiple cellular pathways. Recent evidence suggests that semaglutide, like other GLP-1 receptor agonists, may offer additional benefits beyond glycemic control, including the suppression of harmful inflammatory pathways. However, the precise impact of semaglutide on inflammatory responses is not yet fully understood. This review aims to explore the potential benefits of semaglutide in mitigating inflammatory responses in diabetic patients.

Classifications of Diabetes Mellitus
Diabetes mellitus is classified into four main types:

• Type 1 Diabetes Mellitus (T1DM): Characterized by a deficiency of circulating insulin due to beta cell dysfunction or failure.
• Type 2 Diabetes Mellitus (T2DM): The most prevalent form, primarily associated with insulin resistance in peripheral tissues.
• Gestational Diabetes: Occurs in pregnant women, likely due to hormonal changes.
• Other Specific Types: Includes latent autoimmune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), and secondary diabetes resulting from conditions like pancreatitis or certain medications such as corticosteroids.

Inflammation and Its Role in Diabetic Complications

Chronic hyperglycemia, or high blood sugar levels, is strongly associated with increased incidence of inflammatory reactions, which play a significant role in the development of diabetes and its complications. Elevated glucose levels can activate immune cells and trigger the release of inflammatory cytokines, making chronic hyperglycemia a key driver of inflammation in diabetes. Inflammation disrupts insulin signal transduction and contributes to insulin resistance. Experimental and clinical evidence confirms that inflammation is implicated in the pathophysiology of diabetes-induced vascular disorders, including diabetic retinopathy, nephropathy, neuropathy, cardiovascular disorders, and fatty liver. Patients with diabetic complications typically exhibit elevated levels of inflammatory cytokines in their plasma.

GLP-1 Receptor Agonists and Semaglutide
Incretin-based medications, including GLP-1 receptor agonists, are a class of drugs commonly used in managing T2DM. These medications target the incretin system, which plays a crucial role in regulating blood sugar levels. Incretins are hormones released by the enteroendocrine L-cells of the gastrointestinal tract in response to food intake. They stimulate the release of insulin from the pancreas and reduce the production of glucagon, helping to normalize postprandial glucose levels. Incretin-based medications mimic the actions of natural incretins, such as GLP-1 and gastric inhibitory hormone (GIP). They increase insulin secretion from the pancreas, decrease glucose production by the liver, slow stomach emptying, and suppress appetite.

Semaglutide is a specific type of incretin-based medication known as a GLP-1 analogue. It binds to its specific receptors on pancreatic beta cells, enhancing insulin secretion in response to postprandial hyperglycemia. It also inhibits glucagon release, which helps reduce excessive glucose production by the liver. Additionally, semaglutide can promote a feeling of fullness, reduce food cravings, and lead to a reduction in food intake and, consequently, weight loss in some individuals. There is also evidence suggesting that semaglutide induces the expression of Glut-4. Semaglutide is often administered as an injectable medication, but it is also available in an oral form, making it the only oral GLP-1 analogue currently available. Three forms of semaglutide, namely Ozempic, Rybelsus, and Wegovy, have been approved by the FDA. Like all synthetic drugs, semaglutide may induce some adverse effects, such as nausea and diarrhea.

Semaglutide and Inflammation
While semaglutide is primarily known for its metabolic benefits, such as regulating glucose levels, promoting weight loss, and normalizing lipid profiles, there is emerging evidence suggesting that it may also have additional anti-inflammatory effects. Strong evidence indicates that semaglutide can modulate or reduce inflammatory processes. Considering that inflammation is a key factor in many diabetic complications, these anti-inflammatory effects of semaglutide could provide additional benefits, particularly in the cardiovascular system.

Although there is still limited evidence exploring the specific mechanisms involved, current knowledge suggests two major pathways by which semaglutide exerts its anti-inflammatory effects: reducing inflammatory cytokine levels and modifying immune system activity. These pathways may overlap and be interconnected in many cases. In the following sections, we present the latest findings regarding the anti-inflammatory roles of semaglutide and discuss the possible mechanisms involved, drawing from both clinical trials and experimental studies.

Reducing Inflammatory Cytokines
Semaglutide, a GLP-1 receptor agonist, has been shown to have anti-inflammatory effects by suppressing the release of pro-inflammatory cytokines, such as IL-6 and TNF-α. In animal models, semaglutide demonstrated neuroprotective effects and improved cognitive function by inhibiting the release of inflammatory cytokines mediated by the NLRP3 inflammasome, a complex involved in regulating the innate immune system and inflammatory responses. These effects were observed in models of seizures, endotoxemia, polymicrobial sepsis, and acute lung injury. Clinical evidence also supports the anti-inflammatory effects of semaglutide. For example, in a study involving men with T2DM, semaglutide treatment significantly reduced circulating levels of inflammatory cytokines, potentially lowering the risk of cardiovascular disorders. A meta-analysis also found a significant reduction in high-sensitive C-reactive protein (hsCRP) levels in patients with T2DM treated with semaglutide.

Modulation of Immune System Response
Semaglutide can modulate immune system activity through various pathways. GLP-1 receptors are found on different immune cells, such as neutrophils and eosinophils, and their activation has modulatory effects on immune responses and inflammatory processes. Evidence suggests that semaglutide can activate these receptors and modulate immune system activity. For example, in mice, semaglutide activation of GLP-1 receptors on endothelial and hematopoietic cells led to a reduction in inflammatory cytokines in hepatocytes. In human studies, semaglutide decreased inflammatory processes in epicardial fat and reduced neutrophil activity, which is associated with cardiovascular risk.

Furthermore, semaglutide modulates immune system activity by decreasing the recruitment or activity of immune cells. Studies have shown that semaglutide reduces leukocyte recruitment, rolling, and atherogenic plaque formation in mice. Other pathways by which semaglutide modifies immune system activity include reducing the proliferation of inflammatory cells, lowering the uptake of activated macrophages in blood vessels, and reducing the development of atherosclerotic plaque lesions.

Indirect Pathways
Inflammatory processes can be activated in response to other pathways, such as oxidative stress. Additionally, they are associated with pathological conditions like obesity, characterized by underlying chronic inflammation. Evidence suggests that semaglutide indirectly exerts anti-inflammatory effects by suppressing these mediating mechanisms. It has been shown to reduce oxidative stress-dependent inflammation in cells treated with lipopolysaccharide (LPS) through an AMPK-dependent pathway, leading to decreased production of reactive oxygen species (ROS) and lower levels of NF-κB, TNF-α, and IL-1β. Semaglutide also ameliorates obesity-induced inflammation by down-regulating inflammatory markers in neutrophils of obese mice. Contact us to find out more about how to help!

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