Impairment of Glucose Uptake Induced by Elevated Intracellular Ca in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice.

Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca concentration ([Ca]) in their muscle cells. We have reported that the muscle dysregulation of [Ca] impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca] and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca] was recorded using a Ca-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca] and impaired insulin-dependent glucose uptake compared with the WT neurons. Additionally, exposure to isoflurane exacerbated these deficiencies in the MH-R163C neurons, while the WT neurons remained unaffected. Lowering [Ca] using a Ca-free solution, SAR7334, or dantrolene increased the glucose uptake in the MH-R163C neurons without significantly affecting the WT neurons. However, further reduction of the [Ca] below the physiological level using BAPTA decreased the insulin-dependent glucose uptake in both genotypes. Furthermore, the homogenates of the MH-R163C hippocampal neurons showed an altered protein expression of the PI3K/Akt signaling pathway and GLUT4 compared with the WT mice. Our study demonstrated that the chronic elevation of [Ca] was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca] within a specific range (100-130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D).