by Trinity College Dublin

Elevated serum Lac-Phe in patients with T2D. a, Distribution of 33 non-diabetic (non-T2D), pre-diabetic (pre-T2D) and diabetic (T2D) participants in the Brigham and Women’s Hospital cohort study. b, Volcano plot comparing metabolomes of obese non-T2D (n = 11) and obese T2D (n = 8) individuals. Significantly upregulated (blue) and downregulated (red) metabolites are shown, and N-lactoyl amino acids are highlighted. c, Lac-Phe levels in non-T2D (n = 21), pre-T2D (n = 4) and T2D (n = 8) individuals (*P = 0.0198 and ****P < 0.0001; NS, non-significant). d, Spearmanʼs rank correlation between Lac-Phe and N-lactoyl-tyrosine (Lac-Tyr) in the total Brigham and Women’s Hospital cohort (n = 33). Graph shows mean linear regression with 95% confidence intervals. e, Lac-Phe in non-T2D (n = 5,876) and T2D (n = 162) individuals from the TwinsUK cohort (****P < 0.0001). Data are mean ± s.d. (c); violin plot with median (dashed line) plus maximum and minimum quartiles (dotted line) (e). Data were analyzed using two-tailed Student’s t-test (b,e) or one-way ANOVA with Dunnett’s post test (c). Brigham cohort, Brigham and Women’s Hospital cohort. Credit: Nature Metabolism (2024). DOI: 10.1038/s42255-024-01018-7

In a study, just published in Nature Metabolism, scientists from Trinity College Dublin and Princeton and Harvard Medical School share newly uncovered secrets to natural appetite control, which offers promise in the battle against obesity and type-2 diabetes.

The new research shows the diabetes drug Metformin and solid foods elevate a hunger-reducing factor (Lac-Phe) in the body, while sugary drinks have minimal effects.

Obesity is a key driver of type-2 diabetes, and the 2022 Eurostat report revealed that 1 in 5 Irish adults are obese. Indeed, global diabetes cases have more than tripled in the last 20 years, alongside the rise in obesity. The cost of managing diabetes represents approximately 9% of EU Member States' health care budgets—totaling €149 billion in 2019.

There is no cure for diabetes, and every year in Europe, 114,000 people lose their lives from diabetes-related complications.

The scientists today report new insights into how the widely used diabetes drug metformin benefits patients with type-2 diabetes. Metformin is described by some as a "wonder drug" even though we still do not know exactly how it works.

This study shows that metformin increases the amount of an appetite-suppressing factor called Lactoyl-Phenylalanine (Lac-Phe), identified in 2022 as a natural appetite suppressant and which is known to be raised by vigorous exercise.

The scientists probed data from other studies involving large numbers of patients to conclusively demonstrate that Lac-Phe levels rise after individuals take metformin. This work opens a new avenue for developing targeted anti-obesity treatments.

Barry Scott, the first author of the research, is a former stock market trader and now a Ph.D. Candidate in Trinity's School of Biochemistry and Immunology, based in the Trinity Biomedical Sciences Institute (TBSI).

He said, "I'm hopeful our research can have a big impact. Metformin is the most prescribed drug for type-2 diabetes, and it's very safe and well-tolerated. How metformin affects appetite was not known, but this work shows that its influence on Lac-Phe is a key part of its hunger-suppressing impact."

The team also discovered that Lac-Phe increases after eating and so contributes to the feeling of fullness after a meal.

David Finlay, Associate Professor in Immunometabolism, Trinity, who co-supervised the work with Professor Lydia Lynch, Princeton and Harvard Medical Schools, said, "Our study shows that the type of food you eat matters. For instance, eating sugar-rich date fruits caused an immediate and large surge in Lac-Phe, for example, whereas drinking a sugar-rich drink did not. This could help explain why liquid calories can drive obesity."

Professor Lydia Lynch said, "Identifying the factors that control appetite and satiety after a meal is important to help us to understand and ultimately treat the current obesity epidemic. Further understanding Lac-Phe's actions may lead to a new class of safe and effective anti-obesity drugs."

More information: Barry Scott et al, Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans, Nature Metabolism (2024). DOI: 10.1038/s42255-024-01018-7

Provided by Trinity College Dublin