Metformin boosts an exercise-linked metabolite and may help control weight in prostate cancer patients

by · News-Medical

A clinical study suggests metformin may reproduce part of exercise’s metabolic signature in prostate cancer patients, raising Lac-Phe levels while supporting better weight control during hormone treatment.

Study: The anti-obesogenic metabolite, Lac-Phe, is elevated by metformin treatment in prostate cancer patients. Image Credit: Julien Tromeur / Shutterstock

Cancer continues to be a major global cause of death, and excess weight is closely associated with poorer disease progression and reduced treatment effectiveness. Newer appetite-suppressing and weight-reducing therapies have drawn attention for their possible roles in cancer care. However, the biological mechanisms driving these effects remain incompletely understood.

Evidence from clinical studies suggests that weight control and exercise improve cancer outcomes, yet the mechanisms underlying these effects remain poorly understood. Metformin, a widely prescribed medication that improves insulin sensitivity, has been linked to increased Lac-Phe levels, which may influence appetite and weight regulation. These observations suggest that metformin may mimic some of the exercise-related metabolic benefits in cancer patients.

Prostate Cancer Metformin Study Design

In the present study, researchers examined whether the association between metformin and Lac-Phe extends to prostate cancer, where metabolic dysregulation is common.

The team analyzed serum samples obtained from non-diabetic, overweight or obese patients with biologically recurrent, hormone-sensitive prostate cancer. The sample population comprised participants in the BIMET-1 trial. None of the participants had received androgen deprivation therapy (ADT). All participants were considered at elevated risk of developing metastatic disease.

The trial included a bicalutamide treatment arm and a metformin-bicalutamide co-treatment arm. The co-treatment group received 1,000 mg of metformin twice daily. Researchers also evaluated a phase of metformin monotherapy. They classified patients as responders or non-responders based on changes in prostate-specific antigen (PSA).

To strengthen their findings, the investigators expanded the analysis to an additional set of 25 men with prostate cancer. The dataset spanned metastatic hormone-sensitive, biochemically recurrent, and metastatic castration-resistant prostate cancer. Some individuals in this dataset were receiving metformin for metabolic dysfunction. Samples from this broader cohort were profiled across disease settings, although collection conditions varied, and fasting information was not available for all patients.

The researchers performed targeted metabolic profiling using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) to quantify lactate and Lac-Phe levels. They confirmed metabolite identity using authentic standards based on retention time and spectral matching. Absolute concentrations determined using internal standards ensured accuracy.

Metabolic Profiling and Weight Trend Analysis

In addition, following metformin treatment, the researchers performed antibody-based cytokine profiling to measure growth differentiation factor 15 (GDF15) levels, a well-established mediator of metformin’s metabolic effects, particularly appetite suppression and weight loss. Lastly, they evaluated whether changes in Lac-Phe correlated with metformin exposure, therapeutic response, and weight changes across both BIMET-1 study groups and the broader patient cohort, including those with advanced castration-resistant disease.

Metformin Increased Lac-Phe Across Prostate Cancer Settings

All BIMET-1 trial participants in the metformin-treated arm demonstrated a marked rise in Lac-Phe from baseline, although these changes did not reliably distinguish treatment responders from non-responders based on PSA outcomes. Expanding the analysis to a broader cohort, the team observed that patients receiving metabolism-modifying interventions, particularly metformin, had significantly higher Lac-Phe levels compared to those not on such therapies. A few patients on other metabolism-modifying drugs also showed elevated Lac-Phe levels. Minimal variation in Lac-Phe among untreated patients suggested that dietary or post-prandial effects contributed little to its circulating levels.

Importantly, metformin-treated patients showed improved weight management during anti-androgen therapy. Most treated individuals maintained or lost weight over six months, unlike controls. Both Lac-Phe and GDF15 increased following metformin treatment. However, only Lac-Phe showed a stronger overall association with favorable weight trends, although this relationship was not conclusive and did not establish causation.

Lac-Phe Implications for Cancer Metabolic Care

The study findings highlight N-lactoyl-phenylalanine as a potential metabolite associated with the metabolic benefits of metformin in prostate cancer. By demonstrating that metformin robustly elevates this exercise-associated metabolite and is associated with improved weight management during hormone therapy, the study provides new insight into the role of metabolic interventions in supporting cancer care. These results are particularly relevant for patients receiving ADT, who face increased risks of weight gain and cardiometabolic complications.

Looking ahead, larger and more diverse studies are needed to confirm these findings and determine whether targeting the metformin-Lac-Phe axis can improve long-term cancer outcomes. The work also raises the possibility that metformin could mimic the metabolic benefits of exercise, offering a therapeutic strategy for individuals who may be unable to engage in regular physical activity.

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