Ion Channels and Transporters in Disorders of Glucose Homeostasis: From Molecular Mechanisms to Precision Medicine

Glucose homeostasis requires coordinated nutrient sensing, membrane excitability, hormone secretion, tissue glucose flux, and mitochondrial metabolism. Ion channels and transporters connect these processes, but mechanistic importance does not necessarily establish human disease causality or clinical actionability. This narrative review integrates human islet electrophysiology with glucose, metal-ion, and mitochondrial transport, distinguishing established causal human disease, replicated genetic susceptibility, limited genetic observations, human functional evidence, and predominantly experimental mechanisms. ATP-sensitive potassium (K_ATP) channel disorders provide the clearest bidirectional paradigm: activating KCNJ11 or ABCC8 variants can cause neonatal diabetes amenable to sulfonylureas, whereas inactivating variants cause congenital hyperinsulinism. Tissue-selective transporter syndromes, background potassium conductance, intercellular coupling, and organellar calcium handling illustrate additional mechanisms with different levels of human validation. Acquired remodeling in type 2 diabetes may be pathogenic, compensatory, or secondary to metabolic stress. We separate established management from investigational human replacement and preclinical targeting and critically assess functional assays, stem-cell models, transcriptomics, and genome engineering. Priorities are to resolve genotype–phenotype heterogeneity, establish causal direction and disease-stage dependence, and develop tissue-selective interventions with demonstrable patient benefit.