257-LB: A Novel MODY-Associated Gain-of-Function Mutation in TALK-1 Leads to Islet Dysfunction and Glucose Intolerance

The most islet-restricted and abundantly expressed K⁺ channel of the human ꞵ-cell, TALK-1, regulates electrical activity and glucose-stimulated insulin secretion (GSIS) . Recently we identified a gain-of-function (GOF) mutation near the pore domain of TALK-1 (Leu114Pro) that causes Maturity-Onset Diabetes of the Young (MODY) in an autosomal dominant manner, but only in a single family. To confirm TALK-1-Leu114Pro as the mutation that causes the MODY phenotype and investigate the impact of TALK-1 GOF on glucose homeostasis, a mouse model containing the TALK-1-Leu114Pro mutation was generated. Interestingly, mice with TALK-1-Leu114Pro mutation show neonatal lethality which may be due to alterations of islet hormone secretion during neonatal development (this was observed in heterozygous TALK-1-Leu114Pro C57BL/6J and homozygous TALK-1-Leu114Pro CD-1 (ICR) mice) . We first confirmed that TALK-1-Leu114Pro mutation resulted in a GOF in β-cell whole-cell K⁺ currents. On the ꞵ-cell plasma membrane the resulting TALK-1-Leu114Pro hyperpolarizing current blunted glucose-stimulated Ca²⁺ entry and subsequent Ca²⁺ oscillations, whereas on the endoplasmic reticulum membrane TALK-1-Leu114Pro enhanced IP₃-induced Ca²⁺ release. TALK-1-Leu114Pro^+/- islets also showed decreased GSIS and reduced plasma insulin levels in TALK-1-Leu114Pro^+/- mice when compared to controls. TALK-1-Leu114Pro^+/- mice exhibit a significant impairment in glucose homeostasis which is likely due to reduced islet Ca²⁺ influx and GSIS. However, TALK-1 activity in other islet cell types may also contribute to glucose dyshomeostasis in TALK-1-Leu114Pro^+/- mice. For example, pancreatic α-cell area and islet glucagon secretion are increased TALK-1-Leu114Pro^+/- mice. Taken together, these data prove that the MODY-associated TALK-1-Leu114Pro mutation disrupts glucose homeostasis and suggests that TALK-1 is an islet-restricted target for the treatment for diabetes.