线粒体Ca2([Ca2]m)稳态对于β细胞功能至关重要,并且在糖尿病的发病机理中会受到破坏。[Ca2+]m的摄取依赖于细胞质Ca2+([Ca2+]c)的升高和内质网Ca2+([Ca2+]ER)的释放,两者均由双孔结构域K+通道TALK-1调节。这里,利用新型β细胞TALK-1敲除(β-TALK-1-KO)小鼠模型,我们发现TALK-1限制了β细胞[Ca2]m的积累和ATP的产生。然而,暴露于高脂肪饮食(HFD)后,ATP相关呼吸,葡萄糖刺激的耗氧率,和葡萄糖刺激的胰岛素分泌(GSIS)在对照组而不是TALK1-KO小鼠中增加。尽管β-TALK-1-KO动物在HFD治疗前后表现出相似的GSIS,这些小鼠受到HFD诱导的葡萄糖耐受不良的保护.总的来说,这些数据表明TALK-1通道对β细胞功能的控制降低了[Ca2+]m,并提示糖尿病患者的代谢重塑导致血糖异常.
Mitochondrial Ca2+ ([Ca2+]m) homeostasis is critical for β-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 β-cell TALK-1-knockout (β-TALK-1-KO) mouse model, we found that TALK-1 limited β-cell [Ca2+]m 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 [Ca2+]m and suggest that metabolic remodeling in diabetes drives dysglycemia.