Manganese availability determines insulin sensitivity by enhancing Akt activity
Gamarra, J. R.; Higuchi, S.; Yuan, T. L.; Xie, Y.; Shanmugarajah, N.; Yang, H.; Kelly, M. O.; Hannou, S. A.; Schilling, K.; Navas-Acien, A.; Choi, E.; Glasgow, A.; Astapova, I. I.; Herman, M. A.; Haeu · physiology · 2026-09-07 · 原文
DOI：10.64898/2026.09.02.746017作者：15 位
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 activatio
讲义
讲义·推断 依据「原文」自动生成的结构化摘要（推断），非原文表述；以原文为准。
1. 人话版
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.
2. 领域脉络
本文类目：physiology，属于其所在研究脉络的最新进展。
3. 机制拆解
摘要未展开方法细节——精读时重点看方法/模型部分。
4. 证据与数字
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.
5. 反例与边界
摘要未声明局限与反例——这是需要警惕的信号，精读时先问边界。
6. 跨领域连接与意外收获
思考本文机制能否迁移到你正在跟进的问题。
7. 可复用方法
把本文机制与你手头项目对照，找一个两周内能验证的最小实验。
8. 术语表
精读时把不熟的术语记入此处，作为下次回忆的锚点。