ABSTRACT Type 2 Diabetes (T2D), often preceded by reversible prediabetes, poses a major health challenge. Targeting early glucose dysregulation is a promising preventive strategy. Amino acids and their derivatives are emerging as key regulators of glucose homeostasis. Here, we investigate the role of O ‐acetyl‐serine (OAS), a serine‐derived metabolite produced by plants and microbes, including those of the gut microbiota, in glycaemia regulation. We developed a targeted method to quantify OAS in plasma and tissues, showing that it enters circulation and transiently accumulates in the pancreas. In vivo, OAS specifically and dose‐dependently improves postprandial glycaemia in lean mice. Mechanistically, OAS acts as a glucose‐dependent insulin secretagogue: a single oral dose increased pancreatic OAS levels by ~100‐fold and amplified glucose‐stimulated insulin secretion by 3.7‐fold, without affecting basal insulin levels. In vitro, OAS enhanced insulin secretion in both INS‐1 cells and rat islets, confirming a direct effect on pancreatic β‐cells. OAS also increased GLP‐1, but not GIP, levels at baseline and after glucose challenge. However, in vivo treatment with the GLP‐1 receptor antagonist exendin (9–39) revealed that GLP‐1 signaling only partially mediates OAS's effects, consistent with OAS direct action on insulin secretion. Finally, OAS restored glucose tolerance in a prediabetic mouse model induced by high‐fat diet, without altering insulin sensitivity. This improvement was associated with increased postprandial insulin and GLP‐1 levels. Together, these findings identify OAS as a glucose‐dependent insulin secretagogue with therapeutic potential to enhance insulin secretion and prevent progression from prediabetes to T2D.
Benatar et al. (Fri,) studied this question.