Year: 2026
Type: article
Abstract: Insulin signaling is a critical determinant of metabolic health, and impairments in insulin action contribute to the development of type 2 diabetes. The kinase Akt is a central mediator of insulin signaling and is required for insulin's suppression of hepatic glucose output. Although the regulation of Akt by the insulin receptor-PI3K pathway is well understood, there are instances in which signaling downstream of Akt is dissociated from proximal insulin signaling, for example in insulin resistance. Nonetheless, little is known about PI3K-independent mechanisms of Akt regulation. Here, we discovered that hepatocyte manganese concentrations are a key determinant of PI3K-independent Akt function in vivo. We further demonstrated that manganese increases Akt's catalytic efficiency, and quantitative phosphoproteomics revealed that manganese and insulin act additively to enhance Akt activity. Moreover, we uncovered that hepatic manganese concentrations fluctuate during fasting and feeding via carbohydrate-dependent transcriptional regulation of the manganese efflux transporter Slc30a10. This dynamic metal-signaling axis provides a mechanistic link between nutrient status and Akt activation, and suggests a molecular explanation for the glucose-lowering effects of manganese observed in humans. Our findings establish manganese as a physiologically regulated cofactor for Akt and position metal bioavailability as a previously unrecognized layer of insulin signaling control.
DOI: 10.1172/jci200951
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: National Science Foundation, Fisher Center for Alzheimer's Research Foundation, Joslin Diabetes Center, National Institutes of Health, Diabetes Research Center, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences
Awards: G1647768613, G1713303463, G2587019979, The Role of ChREBP in Fructose Induced Metabolic Disease, Training in Cellular, Molecular and Biomedical Studies, Graduate Research Fellowship Program (GRFP), Mechanisms connecting dysregulated BCAA, glucose & lipid metabolism in the pathogenesis of metabolic disease, G8251284785, Clinical and Translational Science Award, Columbia Diabetes Research Center, Bile acid composition and insulin sensitivity, Insulin regulation of hepatic transport, Columbia University and Northern Plains Partnership for the Superfund Research Program, The Columbia University Digestive and Liver Disease Research Center, Center for Environmental Health in Northern Manhattan
OpenAlex ID: W7221756160