Spexin–Galanin Receptor Signaling in Insulin Resistance and Type 2 Diabetes Mellitus — a Narrative Review

Objective. To evaluate the role of spexin in insulin resistance, focusing on its molecular mechanisms, receptor signaling, and organ-specific metabolic effects in type 2 diabetes (T2D). Methods. A narrative review was conducted based on a comprehensive literature search that identified 8,881 articles. After duplicate removal and application of predefined inclusion and exclusion criteria, eligible studies were synthesized into four domains: molecular structure and biosynthesis of spexin, receptor signaling mechanisms, associations with insulin resistance in humans, and organ-specific metabolic effects. Results. Spexin, encoded by the C12ORF39 gene, primarily acts through galanin receptor subtypes 2 and 3 (GALR2 and GALR3), activating signaling pathways such as phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Current evidence demonstrates an inverse association between circulating spexin levels and insulin resistance. Mechanistically, spexin enhances glucose uptake in skeletal muscle, reduces inflammation and lipid accumulation in adipose tissue, and suppresses hepatic gluconeogenesis, thereby improving insulin sensitivity. Conclusions. Spexin plays an important role in insulin resistance through receptor-mediated and multiorgan metabolic mechanisms. These findings highlight its potential as a biomarker and therapeutic target in T2D. However, further mechanistic and clinical studies are required to confirm its translational applicability.