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

Pancreatic β-cells play a central role in type 2 diabetes mellitus (T2DM), yet the interactions between β-cells and stromal components within the islet microenvironment remain poorly defined. We investigated the contribution of pancreatic fibroblasts to β-cell dysfunction and T2DM progression. We used single-cell Sequencing technology and in vitro experiments to investigate the mechanisms by which bariatric surgery ameliorates T2DM. We introduce the novel concept of a "metabolic synapse" to describe the interaction between pancreatic fibroblasts and β-cells. Our findings reveal that pancreatic fibroblasts secrete excessive glutamate in the early stages of T2DM. Elevated glutamate concentrations within the islet microenvironment subsequently activate N-methyl-d-aspartic acid receptors (NMDARs), triggering PANoptosis in pancreatic β-cells and accelerating T2DM progression. Consistent with this, significant changes in NMDAR expression were observed in human pancreatic samples from patients with T2DM. These findings uncover a previously unrecognized fibroblast-β-cell communication pathway in the islet niche, provide mechanistic insights into T2DM pathogenesis, and highlight the glutamate-NMDAR axis as a potential therapeutic target for nonsurgical intervention.

Article highlights: 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.