Glucagon-Like Peptide-1 Receptor Agonists: Multifaceted Roles in Immune and Inflammatory Regulation, Glycemic Control, and Synergistic Therapeutic Applications

Abstract

Glucagon-like peptide-1 (GLP-1) has gained considerable attention in recent years for its crucial role in glycemic and weight control, as well as its potential impact on inflammation and immune function. Secreted by enteroendocrine cells in response to nutrient intake, GLP-1 stimulates insulin secretion, reduces glucagon release, and slows gastric emptying [1]. Beyond these effects, GLP-1 has multifaceted roles, including a complex interplay between inflammatory processes and immune regulation. The use of GLP-1 receptor agonists (GLP-1RAs) has been linked to significantly lower risks of all-cause mortality, cardiovascular events, and both cardiovascular and liver-related mortality [2]. Recent studies have further explored the anti-inflammatory properties of oGLP-1 drugs and their effect on the immune system, unveiling additional mechanisms of action.

Originally developed as a diabetes treatment due to its ability to stimulate insulin secretion from beta cells, GLP-1's effects extend beyond glucose regulation to include significant roles in immune cell function. One of its notable impacts is on macrophage polarization. Research indicates that GLP-1 can modulate macrophage activity, highlighting its potential in controlling chronic inflammation. Activation of the GLP-1 receptor has been shown to shift macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. This transition is associated with a reduction in inflammatory mediators and an enhancement of tissue repair mechanisms [3]. For instance, in a murine model of diet-induced non-alcoholic fatty liver disease (NAFLD), liraglutide demonstrated protective effects by promoting cAMP-PKA-STAT3-dependent polarization of Kupffer cells towards an M2 phenotype [4].

Moreover, GLP-1 receptor expression in T cells, particularly apoptotic and anergic cells, functions as a negative costimulatory molecule for T cells. This action has been shown to prolong allograft survival, mitigate alloimmunity, and even trigger antitumor immunity in a mouse model of colorectal cancer [5].

A recent study uncovered a novel mechanism by which GLP-1 receptor agonists (GLP-1RAs) increase intestinal Escherichia coli levels. This increase has been associated with sympathetic nervous system activation, resulting in the release of norepinephrine into the intestinal lumen. Elevated E. coli levels may contribute to bacterial translocation by downregulating the expression of intestinal tight junction genes under stress. However, the implications of this rise in E. coli levels require further investigation [6].

Activation of the GLP-1 receptor has also been shown to have significant anti-inflammatory effects. In a study by Chaudhuri et al., 24 obese individuals with type 2 diabetes mellitus (T2DM) were treated with the GLP-1 analog exenatide for 12 weeks. This treatment significantly reduced the mRNA expression of pro-inflammatory cytokines, TNF-α and IL-1β, in peripheral blood mononuclear cells compared to placebo [7]. In another study by Savchenko et al., liraglutide was shown to exert potent anti-inflammatory effects by inhibiting NF-κB pathways and upregulating SIRT1 expression. This resulted in the downregulation of several pro-inflammatory factors, including cytokines such as TNF-α, toll-like receptors TLR2 and TLR4, and inflammation markers like ceruloplasmin [8].

Collectively, these studies underscore the significant anti-inflammatory properties of GLP-1RAs, highlighting their potential pathways and immune responses beyond glycemic control.

The global incidence and prevalence of T2DM among adolescents continue to rise.

Sjögren's syndrome, recognized as an autoimmune disease, has been identified as an independent risk factor for diabetic vascular complications. Furthermore, studies have shown that approximately 1% of patients with primary Sjögren's syndrome may subsequently develop systemic lupus erythematosus (SLE) [9-11]. Adolescents with T2DM are particularly prone to treatment failure, with respiratory diseases and dysglycemia being the most common causes of hospitalization [12].

GLP-1 RAs such as exenatide, liraglutide, and semaglutide not only lower blood glucose levels but also confer additional metabolic benefits, including weight loss. Semaglutide (2.4 mg) has been shown to provide superior reductions in body weight and promote reversion to normoglycemia compared with a placebo in participants with obesity and prediabetes [13, 14]. Furthermore, a recent study demonstrated that liraglutide treatment, compared to pioglitazone, improved myocardial perfusion, energetics, and the 6-min walk distance in patients with T2DM [15].

Combining GLP-1RAs with other medications may enhance the therapeutic outcomes []. Studies investigating the synergistic effects of GLP-1RAs and sodium-glucose co-transporter-2 (SGLT-2) inhibitors have shown promising results. For example, a systematic review and meta-analysis by Li et al. demonstrated that combination therapy with GLP-1RAs and SGLT-2 inhibitors led to superior reductions in HbA1c, body weight, fasting plasma glucose, 2-h postprandial glucose, systolic blood pressure, body mass index, and low-density lipoprotein cholesterol, all without major safety concerns, compared to monotherapy in patients with T2DM [16].

Moreover, a study by Simms-Williams found that the combination of GLP-1RAs and SGLT-2 inhibitors was associated with a lower risk of major adverse cardiovascular events and serious renal events than either drug class used alone [17].

These findings highlight the potential of GLP-1RAs not only as monotherapy but also in combination with other agents to provide comprehensive treatment strategies for various metabolic and inflammatory conditions. By offering holistic metabolic control and addressing inflammation, these combinations can significantly advance the management of complex metabolic and inflammatory diseases.

The anti-inflammatory and immunomodulatory properties of GLP-1RAs have expanded their therapeutic use beyond glycemic control. Recent studies have explored their application in various diseases, focusing particularly on their anticancer and immunomodulatory effects. For example, research has noted a 38% increase in the risk of T2DM among patients with psoriatic arthritis. In patients with both T2DM and psoriasis, exenatide treatment has been shown to rapidly reduce symptoms and diminish psoriatic plaques [18, 19].

This emerging field is garnering considerable attention as researchers investigate GLP-1 receptor signaling in different immune cells, seeking to uncover the detailed mechanisms and long-term effects on chronic inflammatory conditions. Future research is expected to explore the benefits and potential reduction in the side effects of combining GLP-1RAs with other medications to treat a range of diseases. These studies enhance patient outcomes across various clinical settings, paving the way for innovative and effective treatments.

Such ongoing research holds promise for significant advancements in the therapeutic use of GLP-1RAs, potentially revolutionizing treatment paradigms and offering new hope for patients with inflammatory and autoimmune diseases.

Chia-Chien Hsu, Chi-Jen Hsu, and Xiangpei Fang contributed equally to this work and shared first authorship. All three were involved in the conceptualization, literature review, and drafting of the manuscript. Fu-Shun Yen contributed to the critical revision of the content and provided expertise in immunology and endocrinology. Pui-Ying Leong supervised the overall project, provided guidance throughout the writing process, and finalized the manuscript for submission. All authors have read and approved the final manuscript.

The authors declare no conflicts of interest.