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Type 2 diabetes and monogenic forms of diabetes arise from diverse genetic and molecular mechanisms that ultimately impair pancreatic β-cell function. Human genetic studies have identified KCNK16, encoding the two-pore domain potassium channel TALK1, as an Asian-specific diabetes risk gene; however, the mechanisms linking TALK1 dysfunction to β-cell failure remain elusive. Disease-associated gain-of-function mutations in TALK1 were examined for their effects on channel gating and β-cell excitability. Biophysical analyses indicate that the MODY-associated TALK1-L114P mutation destabilizes the selectivity filter, resulting in increased channel activity and reduced membrane excitability. To evaluate the physiological consequences of this channelopathy in vivo, a TALK1-L114P knock-in mouse model was generated. These mice exhibit impaired glucose tolerance and β-cell dysfunction, accompanied by altered islet electrophysiological properties and insulin secretion dynamics. In neonatal mice, TALK1-L114P channels show transient trafficking to the plasma membrane and are associated with a severe hyperglycemic phenotype. Adult TALK1-L114P mice that survive the neonatal period display moderate glucose intolerance, whereas background TALK1-mediated potassium conductance is comparable to controls. Collectively, these findings establish TALK1 as a key regulator of β-cell excitability and identify selectivity filter destabilization as a disease mechanism underlying TALK1-associated diabetes. This work links Asian-specific genetic risk to potassium channel biophysics and whole-organism physiology, providing mechanistic insight into how TALK1 dysregulation contributes to β-cell failure in diabetes.