Significance: Metabolic syndrome (MetS) represents a cluster of cardiometabolic disorders, which accelerate the risk of developing diabetes, nonalcoholic fatty liver disease, and cardiovascular disorders such as atherosclerosis. Oxidative stress (OxS) and inflammation contribute to insulin resistance (IR) that greatly promotes the clinical manifestations of MetS components. Given the growing prevalence of this multifactorial condition, its alerting comorbidities, and the absence of specific drugs for treatment, there is an urgent need of prospecting for alternative nutraceutics as effective therapeutic agents for MetS. Recent Advances: There is a renewed interest in bioactive peptides derived from human and bovine milk proteins given their high potential in magnifying health benefits. Special attention has been paid to glycomacropeptide (GMP), a bioactive and soluble derivative from casein and milk whey, because of the wide range of its health-promoting functions perceived in the MetS and related complications. Critical Issues: In the present review, the challenging issue relative to clinical utility of GMP in improving MetS outcomes will be critically reported. Its importance in alleviating obesity, OxS, inflammation, IR, dyslipidemia, and hypertension will be underlined. The mechanisms of action will be analyzed, and the various gaps of knowledge in this area will be specified. Future Directions: Valuable data from cellular, preclinical, and clinical investigations have emphasized the preventive and therapeutic actions of GMP toward the MetS. However, additional efforts are needed to support its proofs of principle and causative relationship to translate its concept into the clinic. Antioxid. Redox Signal. 34, 201-222.
Keywords: cardiometabolic disorders; casein; glycomacropeptide; inflammation; microbiota; oxidative stress.