During Glucose-Stimulated Insulin Secretion (GSIS), β-cells exhibit oscillations in cytosolic Ca2+ ([Ca2+]c)and endoplasmic reticulum (ER) Ca2+ ([Ca2+]ER), which are regulated by the two-pore domain K+ channel, TALK-1. TALK-1 is the most abundant β-cell K+ channel and it controls Ca2+ homeostasis by modulating K+ permeability at both the plasma and ER membrane. However, how TALK-1 modulates ER stress and β-cell failure during the pathogenesis of diabetes has not been determined. To understand how TALK-1 controls β-cell function under diabetic conditions, we assessed how a mutation in TALK-1 (ND) which causes neonatal diabetes, impacts TALK-1 channel activity and [Ca2+]ER handling. While plasmallemal TALK-1 activity was inhibited with the ND mutation, [Ca2+]ER storage was significantly reduced by the ND mutation compared to control TALK-1. This suggests that TALK-1 ND enhances TALK-1 activity on the ER membrane leading to reduced [Ca2+]ER storage. Reducing [Ca2+]ER enhances ER stress, which would be expected to cause β-cell dysfunction. Indeed, TALK-1 ND significantly reduces β-cell insulin secretion compared to control. To further investigate the role of TALK-1 we developed a β-cell-specific TALK-1 KO mouse model (β-TALK1-KO). On a high fat diet, β-TALK1-KO mice show improved glucose tolerance compared to controls. Mitochondrial calcium ([Ca2+]mito) was also examined because it is modulated by [Ca2+]ER; we found that β-TALK1-KO mice have increased [Ca2+]mito. As reactive oxygen species (ROS) production is a byproduct of mitochondrial respiration, we investigated if TALK-1 affects ROS production. TALK1 KO islets were found to have reduced ROS production compared to wild type islets. Together, these data indicate that increased TALK-1 channel activity reduces [Ca2+]ER, [Ca2+]mito,and increases ROS; suggesting that TALK-1 plays an important role in modulating the β-cell responses to stress associated with diabetic conditions.

Disclosure

S.M. Graff: None. P. Dadi: None. C.E. Ibsen: None. M. Dickerson: None. K.L. Jordan: None. D. Jacobson: None.

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