- This study investigated the role of serum- and glucocorticoid-induced kinase (SGK) in hepatic insulin resistance
- Mice in which liver-specific Sgk1 had been knocked out demonstrated improvement in insulin sensitivity, and those fed a high-fat diet were protected against insulin resistance, glucose intolerance, weight gain and fatty liver
- In vitro and in vivo experiments showed Sgk1 directly and substantially inhibited the activity of AMP-activated protein kinase, thus promoting insulin resistance
- Targeting hepatic SGK1 may have therapeutic benefit in type 2 diabetes
The insulin resistance characteristic of type 2 diabetes presents a troublesome paradox. Excess nutrition, including high-fat diets, causes the liver to resist the glucose-lowering properties of insulin, but preserves insulin-dependent hepatic lipogenesis.
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Researchers at Massachusetts General Hospital have discovered a way to break that paradox, potentially revolutionizing the treatment of type 2 diabetes. In Cell Reports, Alexander A. Soukas, MD, PhD, physician in the Diabetes Unit and researcher at the Center for Genomic Medicine at Massachusetts General Hospital, Ben Zhou, PhD, a former research fellow, and colleagues describe animal model studies in which targeting serum- and glucocorticoid-induced kinase 1 (SGK1) promoted the antihyperglycemic effects of insulin without promoting its lipogenic effects.
Sgk1 and Insulin Resistance
The researchers first confirmed that insulin resistance is associated with increased levels of Sgk1 (the mouse version of human SGK1). In mice that became insulin resistant by eating a high-fat diet, levels of Sgk1 in the liver were significantly higher after overnight fasting and refeeding than in mice that ate a normal chow diet.
The team then generated mice that lacked Sgk1 exclusively in the liver (Sgk1Lko mice). These animals were similar to controls in glucose tolerance but exhibited increased hepatic insulin sensitivity.
Sgk1Lko mice fed a high-fat diet were protected against insulin resistance, glucose intolerance, weight gain and fatty liver. Their livers showed decreases in mechanistic target of rapamycin complex 1 (mTORC1) signaling, which drives both hepatic lipogenesis and insulin resistance.
SGK1 and AMPK
A potential explanation for the decrease in mTORC1 could be an increase in the activity of AMP-activated protein kinase (AMPK), a central hub of metabolic regulation in the liver. Partly by opposing the activity of mTORC1, AMPK regulates hepatic insulin sensitivity, glucose metabolism and lipid metabolism.
The researchers observed in vitro and in vivo that Sgk1 directly and substantially inhibited the activity of AMPK, promoting insulin resistance.
Treating Insulin Resistance in Type 2 Diabetes
These results suggest that a major role of SGK1 in hepatic metabolism is to negatively regulate insulin signaling by decreasing AMPK activity. The next step will be in vivo studies of whether targeting hepatic SGK1 has therapeutic potential in type 2 diabetes.
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