Endogenous oxyntomodulin in metabolic homeostasis and clinical utility as a prognostic biomarker: a systematic review

While the role of glucagon-like peptide-1 (GLP-1) and its exogenous analogues in the obesity treatment is established, the physiology of endogenous oxyntomodulin (OXM), a dual GLP-1/glucagon receptor agonist, remains poorly defined. This systematic review aims to synthesize the current evidence on OXM secretion, its dysregulation in obesity and type 2 diabetes mellitus (T2DM), and its clinical utility. A systematic search of PubMed and Web of Science was conducted following PRISMA 2020 guidelines (PROSPERO: CRD420261308863). Studies on endogenous OXM in humans in various metabolic states (healthy volunteers, obesity, T2DM) and after interventions (diet, bariatric surgery, pharmacotherapy) were included in the analysis. Particular attention was devoted to the reliability of the analytical methods employed to ensure accurate interpretation of concentration dynamics. Available evidence indicates that OXM is a nutrient-stimulated hormone whose secretion depends on the caloric load and macronutrient composition of the stimulus, with higher sensitivity to lipid, which induces a stronger and longer secretory response than glucose. A reduction in OXM secretion was suggested in post-pancreatitis diabetes and, less consistently, in T2DM, where the highest-quality (mass-spectrometry-referenced) data were mixed; its independence from body mass index (BMI) could not be firmly established. Bariatric surgery induces a strong and sustained increase in postprandial OXM con-centrations, and early postoperative OXM dynamics were associated with long-term weight loss, improved lipid profile, and changes in dietary preferences, and, in small cohorts, predicted weight loss at least as well as GLP-1 (a hypothesis-generating observation). OXM may act as a nutrient-sensitive signal, whose secretion appears reduced in metabolic dysfunction and increased after bariatric surgery. OXM shows promise as a candidate predictive biomarker of obesity-treatment response; a potential role in cardiovascular risk stratification remains to be validated in outcome-linked studies and is proposed here only as a future direction. Nevertheless, its implementation in clinical practice requires standardization of pre-analytical and measurement procedures.