Beyond Glucose Control: The Impact of Metformin on the Appetite-Suppressing Metabolite Lac-Phe and Fatty Acid Metabolism in Humans

Abstract

Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels, suppress appetite, and exert anti-inflammatory effects. However, despite extensive research on its clinical benefits, the precise molecular mechanisms through which metformin exerts its therapeutic effects remain only partially understood. To address this, we conducted a comprehensive analysis using untargeted metabolomics data from 11 cohorts, employing Liquid Chromatography- Mass Spectrometry (LC-MS) to explore the metabolic alterations associated with metformin treatment. This investigation began with our own in-house cohort, recruited by the lab, and was expanded to include data from 10 additional external cohorts. Our analysis led us to focus on three primary areas: the impact of metformin on N- lactoyl phenylalanine (Lac-Phe), the relationship between Lac-Phe and feeding, and the effect of metformin on β-hydroxy fatty acids. To understand the relationship between metformin treatment and Lac-Phe levels, we analyzed untargeted metabolomics data from four cohorts—two observational and two interventional. We found a significant elevation of Lac-Phe in the blood of individuals treated with metformin, in both metabolically healthy individuals and those with T2D. This increase was consistent following either a single dose or sustained treatment. Additionally, we investigated Lac-Phe levels in response to feeding using data from six cohorts—one observational and five interventional. Lac-Phe levels were observed to rise post-prandially under a range of feeding interventions, regardless of the individuals’ metabolic health status. However, interventions involving only glucose, such as the liquid Oral Glucose Tolerance Test (OGTT) or glucose infusion via euglycemic hyperinsulinemic clamp, resulted in only a modest rise in Lac-Phe, implying that the production of Lac-Phe is not solely dependent on caloric content but also on the type and composition of nutrients. We examined the impact of metformin on β-hydroxy fatty acids across four cohorts— three observational and one interventional. We discovered that metformin treatment significantly increased the levels of these fatty acids, which are intermediates in the β-oxidation of fatty acids. Medium-chain β-hydroxy fatty acids are known to activate the G-protein-coupled receptors HCA3 and GPR84, both of which are involved in inflammatory pathways, with preliminary data suggesting these receptors may also influence appetite regulation. Our findings suggest that metformin may alter multiple metabolic pathways beyond glucose regulation by promoting the accumulation of both Lac-Phe and β-hydroxy fatty acids. This raises the possibility that these metabolites contribute to metformin’s broader therapeutic benefits, including appetite suppression and anti-inflammatory effects. The evidence gathered across 11 cohorts underscores the robustness of these findings. Together, they provide new insights into the complex metabolic changes induced by metformin and open new avenues for exploring its mechanisms of action beyond glucose control.