A widely prescribed antidiabetic drug, metformin, may help reproduce key metabolic effects of physical exercise in men undergoing treatment for Prostate Cancer, according to a recent study from the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. Published in EMBO Molecular Medicine, the research demonstrates that metformin can elevate levels of N-lactoyl-phenylalanine (Lac-Phe), a metabolite typically produced during intense physical activity and associated with appetite regulation, weight control, and energy balance. This finding is particularly relevant in oncology, where many patients, especially those receiving androgen deprivation therapy, experience fatigue, sarcopenia, insulin resistance, and metabolic dysfunction that limit their ability to engage in regular exercise.
Lac-Phe is formed through the conjugation of lactate generated during exertion with the amino acid phenylalanine, and emerging evidence suggests it plays a role in reducing food intake and improving metabolic efficiency. In the present study, prostate cancer patients treated with metformin exhibited significant increase in circulating Lac-Phe levels comparable to those observed after strenuous exercise, even in the absence of physical activity. These effects persisted after initiation of hormone therapy, indicating that metformin may activate exercise-associated metabolic pathways independent of muscle activity. Lac-Phe levels were not associated with tumour response, as measured by prostate-specific antigen (PSA), suggesting its role is confined to metabolic regulation rather than direct oncologic control.
Further mechanistic insights revealed that Lac-Phe operates independently of growth differentiation factor 15 (GDF-15), a cytokine previously linked to metformin-induced weight loss and appetite suppression, indicating that multiple parallel pathways may contribute to the drug’s metabolic effects. Similar increase in Lac-Phe was also observed in patients receiving other metabolic therapies, pointing to a broader physiological response rather than a metformin-specific phenomenon. These findings align with growing interest in exercise mimetics, which are pharmacological agents capable of activating molecular pathways typically induced by physical activity, such as AMP-activated protein kinase signaling, mitochondrial biogenesis, and improved glucose utilization.
While metformin cannot replace the systemic benefits of exercise, including cardiovascular conditioning, muscle strength, and functional capacity, it may offer a supportive strategy for maintaining metabolic health in patients unable to remain physically active. This is particularly relevant in cancer care, where metabolic derangements can adversely impact treatment tolerance, recovery, and long-term outcomes. The study highlights the importance of integrating metabolic health into oncologic management and suggests that targeting exercise-related biochemical pathways may enhance patient resilience and quality of life. Further large-scale and longitudinal studies are needed to determine whether modulation of metabolites such as Lac-Phe can translate into improved clinical outcomes, including reduced treatment-related morbidity and better survivorship in cancer populations.
Reference
- Bilusic M, Gannamedi DP, Challu B, Ferdous S, Mateo-Victoriano B, Pokharel S, et al. The anti-obesogenic metabolite, Lac-Phe, is elevated by metformin treatment in prostate cancer patients. EMBO Mol Med. 2026 Apr 6. doi:10.1038/s44321-026-00408-6