Manganese availability determines insulin sensitivity by enhancing Akt activity
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…
Type 2 diabetes is linked to insulin signaling impairments, with the kinase Akt playing a critical role in suppressing hepatic glucose output. While the relationship between insulin receptor-PI3K and Akt signaling is clear, signaling downstream of Akt can become dissociated, particularly in insulin resistance cases. However, the mechanisms of Akt regulation that are independent of PI3K remain poorly understood.
Researchers have now discovered that manganese concentrations in hepatocytes significantly influence PI3K-independent Akt function. Their findings reveal that manganese boosts Akt's catalytic efficiency, and quantitative phosphoproteomics showed that manganese and insulin work together to increase Akt activity additively. Furthermore, they found that hepatic manganese levels fluctuate during fasting and feeding through carbohydrate-dependent transcriptional regulation of the manganese efflux transporter Slc30a10.
This metal-signaling axis provides a link between nutrient status and Akt activation, potentially explaining the glucose-lowering effects of manganese observed in humans. These results suggest that manganese acts as a physiologically regulated cofactor for Akt, adding metal bioavailability as a new layer of insulin signaling control.
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