福克斯O1
内分泌学
内科学
胰岛素
葡萄糖稳态
下调和上调
钙调神经磷酸酶
平衡
生物
糖尿病
胰岛
化学
细胞生物学
小岛
磷酸化
胰岛素抵抗
生物化学
医学
蛋白激酶B
移植
基因
作者
Jia Yu,Yue Shi,Kaixuan Zhao,Guang Yang,Lina Yu,Yuxin Li,Eva-Marie Andersson,Carina Ämmälä,Shao‐Nian Yang,Per Olof Berggren
标识
DOI:10.1073/pnas.1908691117
摘要
Significance We reveal that increased expression of Ca V 3.1 channels in rat islets selectively impairs first-phase glucose-stimulated insulin secretion. This deterioration is recapitulated in human islets. Its causal role in diabetes development is clearly manifested in an in vivo diabetic model. Mechanistically, this is due to reduction of phosphorylated FoxO1 in the cytoplasm, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III in a Ca V 3.1 channel- and calcineurin-dependent manner. Our findings suggest that elevated expression of Ca V 3.1 channels in pancreatic islets drives FoxO1-mediated down-regulation of exocytotic proteins resulting in the diabetic phenotypes of impaired insulin secretion and aberrant glucose homeostasis. This causal connection pinpoints β cell Ca V 3.1 channels as a potential druggable target for antidiabetes therapy.
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