Primary Cilia as Integrative Hubs of Metabolic Signaling in Type 2 Diabetes: Inter‐Organ Evidence From Central, Peripheral, and Pancreatic Islet Tissues

Primary cilia are highly specialized, solitary microtubule-based organelles widely present on the surface of mammalian cells. Acting as integrative platforms for membrane-associated signaling and intracellular pathways, primary cilia regulate Hedgehog (Hh), Wnt, G protein-coupled receptor (GPCR), and mTOR signaling and are closely implicated in metabolic dysregulation associated with type 2 diabetes (T2D). This review systematically summarizes current methodological approaches for studying primary cilia and delineates their pathogenic roles in T2D from multiple dimensions. In the central nervous system, hypothalamic primary cilia regulate appetite and energy expenditure through ADCY3/MC4R and BBSome modules. In peripheral metabolic organs, primary cilia in adipose tissue, liver, and bone influence cellular differentiation, lipid metabolism, and insulin sensitivity. In pancreatic islets, primary cilia on α, β, and δ cells coordinate hormone secretion and vascular remodeling via GPCR-cAMP, Somatostatin-SSTR3-GLI2, and Eph/Ephrin signaling pathways. Ciliopathy-associated genetic disorders and defects in centrosomal proteins further substantiate the pathological association between primary ciliary dysfunction and T2D. In addition, the identification of primary cilia-related biomarkers, together with therapeutic explorations involving MC4R agonists, GLP-1 receptor agonists, and mutation-targeted repair strategies, provides a rationale for the clinical translation of cilium-targeted interventions. Collectively, primary cilia may function as central hubs for integrating metabolic signals, regulating intercellular communication, and maintaining energy homeostasis. Future studies should further elucidate cell type-specific differences in primary ciliary receptor localization, signal integration, and secretory regulation; clarify the temporal dynamics of primary ciliary function during development, metabolic stress, and disease progression; and evaluate the structural and functional plasticity of primary cilia, as well as potential therapeutic windows, to facilitate the translation of cilia biology from mechanistic insights to clinical applications in T2D.