The effect of GLP-1R agonists on the medical triad of obesity, diabetes, and cancer

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists have garnered significant attention for their therapeutic potential in addressing the interconnected health challenges of diabetes, obesity, and cancer. The role of GLP-1R in type 2 diabetes mellitus (T2DM) is highlighted, emphasizing its pivotal contribution to glucose homeostasis, promoting β-cell proliferation, and facilitating insulin release. GLP-1R agonists have effectively managed obesity by reducing hunger, moderating food intake, and regulating body weight. Beyond diabetes and obesity, GLP-1R agonists exhibit a multifaceted impact on cancer progression across various malignancies. The mechanisms underlying these effects involve the modulation of signaling pathways associated with cell growth, survival, and metabolism. However, the current literature reveals a lack of in vivo studies on specific GLP-1R agonists such as semaglutide, necessitating further research to elucidate its precise mechanisms and effects, particularly in cancer. While other GLP-1R agonists have shown promising outcomes in mitigating cancer progression, the association between some GLP-1R agonists and an increased risk of cancer remains a topic requiring more profound investigation. This calls for more extensive research to unravel the intricate relationships between the GLP-1R agonist and different cancers, providing valuable insights for clinicians and researchers alike.

Keywords: Cancer; Diabetes; GLP1RA; Obesity; Ozempic; Semaglutide.

Fig. 1

The link between cancer, obesity, diabetes, and GLP-1R’s effect on them. Generated using BioRender

Fig. 2

Effects of GLP-1RAs on organs. GLP-1R and agonists decrease hypertension, atherosclerosis, inflammation, plasma glucose levels, prostate cancer progression, insulin levels, albuminuria, renal failure progression, steatosis, gastric and acid secretion, and gastric motility levels amongst various organs in the body. GLP-1R and agonists increase heart rate regulation, vasodilation, oxidative stress regulation, pulmonary surfactants, β cell proliferation, insulin secretion and sensitivity, medullary thyroid cancer, diuresis, natriuresis, fat metabolism, neuronal excitability, energy expenditure, stress response, satiety, and visceral illness. For breasts, GLP-1R and agonists lead to an increase or decrease in breast cancer progression. Generated using BioRender

Fig. 3

Liraglutide and Exendin-4 decrease NF-κB, cell proliferation, and phosphorylated ERK in cancer. Liraglutide decreases Pl3K, Akt/PKB, and cell division while increasing GLP-1Rs, NOX4, ROS, caspase, MAPK, cAMP, Bcl-2, PKA, and cell apoptosis levels. Exendin-4 decreases Cylin D1 while increasing GLP-1Rs, MAPK, p21, p53, cAMP, Bcl-2, and cell apoptosis. Generated using BioRender

Fig. 4

GLP-1R agonists were studied in thyroid cancers. Both Liraglutide and Exendin-4 increase the levels of GLP-1R, RET/PTC, mTOR, and calcitonin expression amongst patients with thyroid cancer. Generated using BioRender