期刊
CELL REPORTS
卷 37, 期 1, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109785
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资金
- NIH [K08DK087941, R01DK101522, R56AG068999, R01AG058256]
- Howard M. Goodman Fellowship
- Glenn Foundation Award for Research on the Biological Mechanisms of Aging
- Weissman Family Massachusetts General Hospital (MGH) Research Scholar Award
- MGH Executive Committee on Research (ECOR) Postdoctoral Fellowship
SGK1 plays a crucial role in hepatic insulin resistance in type 2 diabetes, affecting AMP-activated protein kinase (AMPK). Liver-specific Sgk1 knockout mice show improved glucose tolerance and insulin sensitivity, suggesting therapeutic potential in targeting hepatic SGK1.
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 (Sgk1(Lko)) 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 AMPK alpha(Ser485/491). 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.
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