KCNK16 encodes TALK-1, a two-pore-domain potassium channel that plays a critical role in pancreatic β-cell function and glucose homeostasis. TALK-1 conducts voltage-dependent outward rectifying K+ currents and is the most abundant β-cell-restricted K+ channel transcript 1. The channel regulates glucose-stimulated insulin secretion by modulating membrane potential depolarization and Ca2+ influx in β-cells 1. TALK-1 activity is enhanced by intracellular osteopontin interaction, which hyperpolarizes resting membrane potential and reduces glucose-stimulated Ca2+ influx, thereby inhibiting insulin secretion 2. Disease relevance is demonstrated by a gain-of-function mutation (Leu114Pro) in KCNK16 that causes maturity-onset diabetes of the young (MODY), representing the first non-KATP channel channelopathy associated with MODY 1. This mutation significantly impairs glucose-stimulated insulin secretion in both mouse and human islets 1. KCNK16 variants have been identified as susceptibility loci for type 2 diabetes in East Asian populations through genome-wide association studies 3. Additionally, genetic variants in KCNK16 influence fasting glycemia trajectories and β-cell function throughout childhood, contributing to early diabetes risk identification 4. The gene's miRNA target sites show enrichment for type 2 diabetes association signals, further supporting its role in diabetes pathogenesis 5.