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

• DOI: 10.1016/j.celrep.2021.109785
• Publication Date: 2021-10-06T00:36:12Z
• Authors: Ben Zhou; Yuyao Zhang; Sainan Li; Lianfeng Wu; Geza Fejes-Toth; Aniko Naray-Fejes...; Alexander A. Soukas
• Keywords: AMP-Activated Protein Kinase; ASK1

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