Activation of the Pancreatic “Metabolic Synapse” Aggravates Type 2 Diabetes Mellitus by Inducing PANoptosis in β-Cells

We identify a fibroblast-β-cell "metabolic synapse" in type 2 diabetes that couples stromal glutamate overflow to-β-cell N-methyl-d-aspartic acid receptor (NMDAR) activation. Single-cell maps and coculture assays show diabetogenic stress drives fibroblasts to hypersecrete glutamate, whereas β-cells upregulate NMDARs, triggering PANoptosis. In rodents, pharmacologic NMDAR blockade attenuates β-cell PANoptosis, preserves islet function, and improves glycemic control. Human pancreatic samples cohorts reveal fibrosis regression and stage-wise NMDAR upregulation, highlighting the glutamate-NMDAR axis as a therapeutic target.