👤 Anna Golonko

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumorigenesis remains debated. Preclinical findings in rodents have suggested that GLP-1R activation may influence thyroid C-cells and pancreatic ducts, while human studies have yielded inconsistent cancer risk signals. This review synthesizes current evidence on GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling in cancer biology, emphasizing the role of biased agonism and context-dependent effects. GLP-1R activation, predominantly via cAMP/PKA signaling, has shown antiproliferative effects in gastrointestinal adenocarcinomas and pancreatic ductal adenocarcinoma models, whereas GIPR activation frequently engages PI3K/Akt (PI3K, phosphoinositide 3-kinase; Akt, protein kinase B) and ERK/MAPK cascades (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase), enhancing proliferation in colorectal and neuroendocrine tumors. Conversely, GLP-1R stimulation can promote growth in GLP-1R-high neuroendocrine tumors, reflecting ligand- and tissue-specific signaling biases. Beyond direct tumor cell effects, GLP-1RAs modulate the tumor microenvironment by reducing NF-κB-driven inflammation, altering stromal activity, and potentially enhancing immune surveillance. Current clinical evidence does not support a generalized increase in cancer risk with GLP-1RA therapy; benefits in metabolic control may even reduce obesity-related cancer incidence. Nonetheless, caution is advised in patients with medullary thyroid carcinoma, MEN2, or GLP-1R-high neuroendocrine tumors. The emerging paradigm suggests precision approaches, integrating receptor profiling, biased agonist design, and risk stratification, will be key to safely leveraging incretin-based therapies in oncology. Show less

The interactions between lifestyle and genetic factors play an important role in obesity development. Mutations in melanocortin-4-receptor (MC4R) gene are one of the most common cause of monogenic obesity, however, the functional effects of polymorphic variants near MC4R gene in general populations remain uncertain. The aim of our study was to analyze whether the common single nucleotide polymorphisms (SNPs) of MC4R gene influence the food preferences, physical activity, body fat content and distribution, as well as fasting and postprandial energy expenditure and substrates utilization. We genotyped previously identified MC4R SNPs: rs17782313, rs633265, rs1350341, rs12970134 in 927 subjects, who underwent anthropometric, total body fat content, visceral (VAT) and subcutaneous adipose tissue (SAT) measurements, and daily physical activity and dietary intake analysis. In randomly selected 47 subjects the energy expenditure, carbohydrate and lipid utilizations were evaluated in fasting state and after high-carbohydrate and control meals intake. We found the significant associations between studied SNPs of MC4R gene and VAT and VAT/SAT ratio. Moreover, the GG genotype carriers of rs1350341, who had the lowest VAT accumulation (p = 0.012), presented higher relative increase in postprandial carbohydrate utilization (p = 0.013, p = 0.024). We have observed that common SNPs of the MC4R gene influence the body fat content and distribution, as well as relative increase in postprandial carbohydrate utilization. We believe that our study may help to understand better the impact of MC4R gene on obesity development, and to help to provide personalized prevention/treatment strategies to fight against obesity and its metabolic consequences. Show less