Glycine, a non-essential amino acid derived from serine, plays an increasingly recognized role in metabolic regulation. Epidemiological studies consistently show that reduced circulating glycine levels are associated with insulin resistance, type 2 diabetes (T2D), and obesity across diverse populations. However, the molecular mechanism linking glycine to insulin production has remained incompletely understood, limiting therapeutic applications.

A recent study published in Life Metabolism sheds light on this question by revealing a novel signaling pathway through which glycine protects pancreatic β cells and sustains their function via ER calcium homeostasis. Led by Prof. Linzhang Huang from the Institute of Metabolism and Integrative Biology at Fudan University, the research demonstrates that glycine activates the GLRA1 receptor on β-cells, enhancing endoplasmic reticulum (ER) calcium storage, which in turn alleviates ER stress and promotes insulin biosynthesis (Figure 1), providing a mechanistic explanation for the long-observed inverse correlation between glycine levels and hyperglycemia in humans.

The investigation began with an analysis of human cohorts, including the National Survey of Physical Traits (NSPT; n = 1,020) and the Chiglitazar-perturbed Human multi-Omics ProfilE (ChiHOPE; n = 835). Results confirmed that glycine levels were inversely correlated with both fasting and postprandial glucose. Notably, treatment with the glucose-lowering drug chiglitazar increased glycine concentrations, suggesting a potential therapeutic synergy.

To validate these findings in vivo, the team employed genetic mouse models. β-cell-specific deletion of GLRA1 impaired glucose tolerance and insulin secretion, without affecting peripheral insulin sensitivity. Conversely, enhancing glycine biosynthesis via overexpression of serine hydroxymethyltransferase 2 (SHMT2) improved β-cell function and islet morphology. These complementary approaches underscore the specificity of glycine−GLRA1 signaling in β-cells.

ER-targeted calcium sensors revealed that glycine−GLRA1 signaling sustains ER calcium levels via interaction with calmodulin. Pharmacological inhibition of either GLRA1 or calmodulin abolished these effects, confirming the specificity of this pathway and its essential role in calcium homeostasis.

Human genetic analyses further strengthened the clinical relevance of these findings. GLRA1 variants showed strong associations with glycemic traits (HuGE score = 45), and single-cell RNA sequencing confirmed GLRA1 downregulation in diabetic β-cells. These results highlight the importance of the pathway in human diabetes pathophysiology. Based on these findings, the study proposes two potential therapeutic strategies: GLRA1-targeted agonists or dietary glycine supplementation. Importantly, glycine interventions required functional β-cells, as they were ineffective in severe insulin-deficient models, suggesting a targeted application in T2D patients with preserved β-cell function.

In summary, this work establishes glycine as a signaling metabolite that activates a GLRA1−calmodulin−ER calcium axis to maintain β-cell function. The findings not only offer novel strategies for diabetes therapy but also exemplify how nutrient-sensing pathways directly regulate organelle homeostasis, opening new avenues for treating metabolic diseases.
DOI:10.1093/lifemeta/loaf044