Study Probes Role of Sestrin 3 in Glucose Metabolism and Diabetes Development

The gene for this protein in humans is located on chromosome 11q21. The sestrin family of proteins, of which Sesn3 is a member, comprises cysteine sulfinyl reductases, and they modulate peroxide signaling and antioxidant defense. These proteins selectively reduce or repair hyperoxidized forms of typical 2-cysteine peroxiredoxins (enzymes that metabolize peroxides) in eukaryotes.

Sestrin expression was found to be regulated by the tumor suppressor protein p53. Sesn3 was identified as a forkhead box O (FoxO) protein with antioxidant activity. Recently it was reported that Sesn3 may play an important role in Akt induced increase in reactive oxygen species (ROS), and it might be a promising target in selectively killing cancer cells containing high levels of Akt activity.

Akt, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Akt is hyperactivated in cancer. This hyperactivity leads to an increase in intracellular ROS mainly by inhibiting the expression of ROS scavengers downstream of FoxO, such as Sesn3.

In the current study, the investigators generated Sesn3 liver-specific transgenic and knockout mice. These animals were fed a diet with 18% of its calories from fat or a high-fat diet with 60% of calories from fat.

Results published in the November 5, 2014, online edition of the journal Diabetes revealed that mice lacking Sesn3 had elevated fasting blood glucose levels, indicative of impaired liver insulin sensitivity or poorly regulated glucose metabolism. Insulin and glucose tolerance tests were significantly improved in Sesn3-positive control mice.

Biochemical analysis revealed that Sesn3 interacted with and activated mTORC2 (mechanistic target of rapamycin complex 2) and subsequently stimulated Akt phosphorylation at serine 473. These findings suggested that Sesn3 could activate Akt via mTORC2 to regulate liver insulin sensitivity and glucose metabolism.

Senior author Dr. X. Charlie Dong, associate professor of biochemistry and molecular biology at the Indiana University School of Medicine, said, "We wanted to show that Sestrin 3 had critical liver-specific functions. This is a very fascinating protein. It is not very big, but it functions in a very dynamic manner controlling glucose production and insulin sensitivity. It is an important regulator for glucose homeostasis."

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Indiana University School of Medicine