A Leu substitution with Pro at position 114 (L114P) of TALK1 K+ channels has recently been identified in a MODY (maturity-onset-diabetes-of-the-young) family. Previous in vitro studies have shown this gain-of-function TALK1-L114P mutant may attenuate Ca2+ homeostasis and inhibit insulin secretion; nevertheless, how this mutant induces diabetes in vivo remains elusive. In this study, we have generated a transgenic mouse line that carries a TALK1-L114P mutation. About three-quarters of TALK1L/P and TALK1P/- mice died within ten days after birth due to hyperglycemia. Interestingly, those survival mice till adulthood exhibited diverse levels of glucose intolerance with islet morphology that is commonly observed in patients with type 2 diabetes. Electrophysiological recording further indicated that only a portion of the beta cells is glucose responsive, and high glucose challenge often yielded in low-frequency action potential bursting. According to our results, we hypothesized that despite the augment of membrane K+ conductance by the TALK1-L114P channel, high glucose might still be enough to depolarize beta cells and generate action potential bursting. This dampened beta cell excitation may result in a weakened Ca2+ influx and insufficient insulin secretion to cause glucose intolerance. In conclusion, this study has revealed a vital role of the TALK1 channel in regulating glucose homeostasis and a plausible diabetogenic mechanism of TALK1-L114P mutation.


W.Tsai: None. S.Yang: None.


National Science and Technology Council, Taiwan (111-2320-B-001-008-MY3)

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