Cobalt exposure increases fasting plasma glucose by inhibiting hepatic glycogen synthesis and enhancing gluconeogenesis.

Cobalt (Co) is an important transition metal and widely distributed in the natural environment. Co exposure is associated with an increased risk of diabetes. Epidemiological studies have identified the associations between Co exposure and fasting plasma glucose (FPG) levels. However, the mechanism of cobalt associated with FPG increase is still unclear. In this study, we investigated the relationship between urinary Co and FPG through population surveys and explored the mechanism of Co-induced glucose metabolic disorders in mice and MIHA human normal liver cell line. We found a positive correlation between urinary Co concentrations and FPG levels in investigated population, and the PI3K/Akt signaling pathway was screened out by metabolomics and network toxicology analyses, which might be associated with Co-induced the elevation of FPG. Mechanistically, Co inhibited hepatic glucose uptake and glycogen synthesis and enhanced gluconeogenesis by suppressing PI3K/Akt signaling pathway activation that acted on glucose metabolism by FOXO1, GSK-3β and glucose transporter protein GLUT2. Furthermore, Co upregulated the expression of PTEN, an inhibitory protein of PI3K/Akt signaling, via reduced the miR-148b-3p, leading to the suppression of PI3K/Akt signaling, ultimately induced glucose metabolic disorders in liver. However, Co has no effects on the glucose metabolism of skeletal muscle in mice. Our research results provide a new discovery for Co disrupting glucose metabolic and increasing FPG levels through inhibiting glycogen synthesis and increasing gluconeogenesis, not affecting the glycolytic capacity in liver.