Mitochondrial Ca ([Ca]) homeostasis is critical for β-cell function and becomes disrupted during the pathogenesis of diabetes. [Ca] uptake is dependent on elevations in cytoplasmic Ca ([Ca]) and endoplasmic reticulum Ca ([Ca]) release, both of which are regulated by the two-pore domain K channel TALK-1. Here, utilizing a novel β-cell TALK-1-knockout (β-TALK-1-KO) mouse model, we found that TALK-1 limited β-cell [Ca] accumulation and ATP production. However, following exposure to a high-fat diet (HFD), ATP-linked respiration, glucose-stimulated oxygen consumption rate, and glucose-stimulated insulin secretion (GSIS) were increased in control but not TALK1-KO mice. Although β-TALK-1-KO animals showed similar GSIS before and after HFD treatment, these mice were protected from HFD-induced glucose intolerance. Collectively, these data identify that TALK-1 channel control of β-cell function reduces [Ca] and suggest that metabolic remodeling in diabetes drives dysglycemia.
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| http://dx.doi.org/10.1016/j.celrep.2024.113673 | DOI Listing |
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