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.