A new preclinical study led by researchers at Massachusetts General Hospital (MGH) demonstrates that an enzyme called serum- and glucocorticoid-regulated kinase (SGK) drives insulin resistance in the liver and may serve as a potential therapeutic target for type 2 diabetes (T2D).

Their findings are published in the journal Cell Reports in a paper titled, “Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase.”

“A hallmark of T2D is hepatic resistance to insulin’s glucose-lowering effects,” the researchers wrote. “The serum- and glucocorticoid-regulated family of protein kinases is activated downstream of the mechanistic target of rapamycin complex 2 (mTORC2) in response to insulin in parallel to AKT.”

The researchers sought to determine the role of SGK in insulin action and metabolism because it was very similar to another insulin-activated kinase called Akt, and that SGK would do the same thing as Akt.

“We had the idea, based upon some early experiments, that it might actually be working in opposition to Akt, and that it might represent a way to target insulin resistance in diabetes in a very different way, promoting metabolic health and insulin sensitivity,” explained senior author Alexander A. Soukas, MD, PhD, a principal investigator in MGH’s Center for Genomic Medicine and Diabetes Unit and an associate professor of medicine at Harvard Medical School.

The researchers observed that when mice ate an unhealthy diet, Sgk (the mouse version of SGK) hindered the action of insulin by inhibiting the beneficial metabolic effects of a liver molecule called AMP-activated protein kinase (AMPK). Blocking Sgk activity released the brakes on AMPK, causing the liver to be more sensitive to insulin and to burn fat in the process. “In this way, targeting Sgk may be a way to target metabolic changes in type 2 diabetes in a way not previously thought possible,” added Soukas.

The findings suggest that blocking SGK activity in the liver might prevent the insulin resistance that is typical of T2D.

“In essence, blocking SGK in the liver restores more normal insulin action, in the process helping to block the buildup of fat in the liver and the weight gain that so frequently accompanies eating a Western diet,” explained Soukas. “While we wouldn’t expect this to give people the power to eat fast food with impunity, when combined with exercise and attempts to eat more healthily, treatments like this could revolutionize the way we treat type 2 diabetes.”

Their findings pave a way for further studies that block serum- and glucocorticoid-regulated kinase to overcome insulin resistance and present a new therapeutic target for T2D.

“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,” wrote the researchers.

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