Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase.

Ben Zhou, Yuyao Zhang, Sainan Li, Lianfeng Wu, Geza Fejes-Toth, Aniko Naray-Fejes-Toth, Alexander A Soukas

Cell reports 2021 Oct 05

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A hallmark of type 2 diabetes (T2D) is hepatic resistance to insulin's glucose-lowering effects. The serum- and glucocorticoid-regulated family of protein kinases (SGK) is activated downstream of mechanistic target of rapamycin complex 2 (mTORC2) in response to insulin in parallel to AKT. Surprisingly, despite an identical substrate recognition motif to AKT, which drives insulin sensitivity, pathological accumulation of SGK1 drives insulin resistance. Liver-specific Sgk1-knockout (Sgk1Lko) mice display improved glucose tolerance and insulin sensitivity and are protected from hepatic steatosis when fed a high-fat diet. Sgk1 promotes insulin resistance by inactivating AMP-activated protein kinase (AMPK) via phosphorylation on inhibitory site AMPKαSer485/491. We demonstrate that SGK1 is dominant among SGK family kinases in regulation of insulin sensitivity, as Sgk1, Sgk2, and Sgk3 triple-knockout mice have similar increases in hepatic insulin sensitivity. In aggregate, these data suggest that targeting hepatic SGK1 may have therapeutic potential in T2D. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Ben Zhou, Yuyao Zhang, Sainan Li, Lianfeng Wu, Geza Fejes-Toth, Aniko Naray-Fejes-Toth, Alexander A Soukas. Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase. Cell reports. 2021 Oct 05;37(1):109785