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Oxyntomodulin (OXM) is a 37-amino acid peptide derived from proglucagon, primarily produced in the pancreas and gut. OXM acts as a dual agonist of the glucagon receptor (GCGR) and GLP-1 receptors (GLP1R), which are critical regulators of glucose metabolism and appetite. Due to its unique role in controlling energy balance, OXM has attracted attention as a potential biomarker for metabolic disorders, including obesity and type 2 diabetes.
Fig. 1 Effects of oxyntomodulin in humans.
(Pocai A. Mol Metab. 2013)
OXM is a product of the glucagon precursor, proglucagon, produced and released from the endocrine L-cells of the gut after enzymatic processing by the precursor PC1/3. It comprising in total 37 amino acids corresponding to the proglucagon sequence 33-69.
Fig. 2 Processing of Proglucagon to Oxyntomodulin.
(Holst JJ.; et al. Peptides. 2018)
Through its interaction with the GCGR, OXM promotes hepatic glucose production and release, while its binding to the GLP1R enhances insulin secretion in response to glucose. This dual receptor activity positions OXM as a potent regulator of glucose homeostasis. In addition to its effects on glucose metabolism, OXM plays a significant role in appetite regulation. It acts centrally by binding to GLP1R, reducing appetite and increasing satiety, also can influence energy balance and body weight. Furthermore, OXM has been shown to increase energy expenditure by stimulating thermogenesis in adipose tissue.
OXM regulates glucose metabolism by activating both GLP1R and GCGR, with synergistic effects in central and peripheral systems. In patients with type 2 diabetes, where insulin resistance and dysregulated glucose production are common, GCGR activation partially limits the acute antihyperglycemic effect of GLP1R activation but contributes to its insulinotropic properties. Chronic treatment with OXM results in superior weight-lowering and comparable antihyperglycemic effect to a GLP1R-selective agonist. Its combined effects on glucose regulation and appetite suppression make OXM a promising candidate for therapies aimed at both weight loss and improving metabolic control in diabetic patients.
OXM causes weight loss in obese patients via suppression of food intake and increases in energy expenditure. It stimulates areas of the brain associated with satiety, such as the hypothalamus. Elevated levels of OXM have been correlated with decreased appetite and a positive energy balance, suggesting that OXM could be used as a biomarker for obesity management. Its ability to promote satiety and weight loss positions OXM as a potential therapeutic agent in obesity treatment.
Based on the mass spectrometry platform, a study shows the secretion of oxyntomodulin in patients with type 2 diabetes is significantly impaired, and that its level is increased by more than 10-fold after gastric bypass surgery. This suggests OXM as a marker for type 2 diabetes and gastric bypass surgery. Another study reported that OXM may be a potential biomarker for distinguishing new-onset diabetes after acute pancreatitis (NODAP) from type 2 diabetes. The study found significantly lower OXM levels in NODAP compared to prediabetes/diabetes followed by acute pancreatitis and healthy controls. However, external validation studies are warranted before it can be recommended for routine use in clinical practice.
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