Glycine-GLRA1-calmodulin signaling regulates ER calcium to sustain insulin secretion and β-cell function

Abstract Glycine, a non-essential amino acid, has been linked to improved metabolic health and enhanced insulin secretion, yet its mechanistic role in β-cell function remains poorly defined. Here, we identify a glycine–GLRA1–calmodulin signaling axis that regulates endoplasmic reticulum (ER) calcium homeostasis to support insulin biosynthesis and β-cell survival. Dietary glycine deficiency impairs insulin secretion, reduces islet mass, and worsens glucose intolerance, while overexpression of serine hydroxymethyltransferase 2 (Shmt2), a key glycine biosynthetic enzyme, increases circulating glycine, enhances insulin output, and improves glucose control. Conversely, β-cell-specific deletion of Glra1 phenocopies glycine deficiency, disrupting ER calcium dynamics, amplifying ER stress, and impairing insulin gene expression and secretion. Mechanistically, GLRA1 interacts with calmodulin to sustain ER calcium levels and alleviate ER stress, preserving β-cell viability under metabolic stress. Human genetic and transcriptomic analyses reveal that GLRA1 expression and variants are associated with insulin secretion and glycemic traits, underscoring clinical relevance. These findings establish glycine as a signaling metabolite that activates a receptor–calcium axis to maintain β-cell function, offering a mechanistic rationale for targeting GLRA1 or dietary glycine in diabetes therapy.