Metrnl in diabetes and its complications: divergent evidence and translational prospects

BACKGROUND: Meteorin-like protein (Metrnl) is a novel secreted protein produced by multiple tissues, which is involved in metabolic regulation, immune homeostasis, and tissue repair. In recent years, research on the role of Metrnl in diabetes has advanced significantly. However, substantial controversies persist regarding its expression dynamics, protective roles, and underlying molecular mechanisms in diabetes and its complications. MAIN BODY: This review synthesizes current evidence to systematically analyze the complex roles of Metrnl in diabetes. Preclinical studies have demonstrated that Metrnl primarily improves insulin resistance, protects pancreatic β-cells, and mitigates diabetes related damage to kidney, heart, and skin through multiple pathways, including the KIT receptor, AMPK and Wnt/β-catenin signaling pathways.In contrast, clinical data exhibit significant heterogeneity. Reports on circulating Metrnl levels in patients with type 2 diabetes are highly inconsistent, with findings of decreased, increased, or no significant changes. Such discrepancies are largely attributed to methodological inconsistencies and clinical confounders. Similar inconsistencies are observed in studies on gestational diabetes. Importantly, Metrnl also displays markedly different or even opposing expression patterns across various diabetic complications, highlighting its tissue-specific regulatory characteristics. CONCLUSIONS: In summary, Metrnl is a pleiotropic molecule involved in the pathophysiological processes of diabetes and its complications, and it holds potential as a candidate biomarker or therapeutic target. However, its clinical translation faces key challenges, including insufficient standardization of detection methods, unclear characterization of receptor systems, and undefined pharmacological properties. Therefore, although Metrnl shows promise in preclinical models, its clinical utility requires rigorous validation, and its roles should be interpreted cautiously based on the current body of evidence.