TALK-1-mediated alterations of (3-cell mitochondrial function and insulin secretion impair glucose homeostasis on a diabetogenic diet

Mitochondrial Ca2+ ([Ca2+]m) homeostasis is critical for (3 -cell function and becomes disrupted during the pathogenesis of diabetes. [Ca2+]m uptake is dependent on elevations in cytoplasmic Ca2+ ([Ca2+]c) and endoplasmic reticulum Ca2+ ([Ca2+]ER) release, both of which are regulated by the two -pore domain K+ channel TALK -1. Here, utilizing a novel (3 -cell TALK -1 -knockout ((3 -TALK -1 -KO) mouse model, we found that TALK -1 limited (3 -cell [Ca2+]m accumulation and ATP production. However, following exposure to a highfat 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 (3 -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 (3 -cell function reduces [Ca2+]m and suggest that metabolic remodeling in diabetes drives dysglycemia.