Mitochondria plays an important role in maintaining intracellular Ca2+homeostasis, and its defects may be responsible for disorders in glucose metabolism and type 2 diabetes (T2D). Mitochondrial Ca2+overload causes superoxide production and functional impairment, culminating in apoptosis. In previous studies, we first demonstrated that Kcnh6 knockout mice exhibited impaired glucose tolerance or diabetes. However, the precise role of Kcnh6 on glucose metabolism remains unknown. Here, we show that Kcnh6 can improve glucose metabolism in the liver. Kcnh6 increases glucose uptake and decreases glycogen synthesis in the liver accompanied by increased expression of glucose transporters, insulin receptor substrates and decreased expression of enzymes for glycogen synthesis. Kcnh6knockout mice display elevated levels of oxidative stress accompanied by increased mitochondrial and intracellular ROS and calcium. As a result of anti-oxidative stress, Kcnh6 improves hepatic glucose metabolism disorder through the JNK and p38MAPKsignaling pathways.
In summary, Kcnh6 can improve hepatic glucose metabolism by regulating mitochondrial Ca2+and Inhibiting oxidative stress. As in glucose metabolism in the liver is considered to be the primary cause of the development of T2D, Kcnh6 may serve as a new diabetes target.
J. Lu: None. L. Zhang: None. T. Shi: None.
National Key Research and Development Program of China (2017YFC0909600); National Natural Science Foundation of China (81800688); Beijing Municipal Administration of Hospitals Incubating Program (PX2019006)