Growth Regulator mTORC2 Linked to Diabetes

Photo: mTORC2 in the liver

Model for the role of mTORC2 in
the regulation of the glucose
metabolism in the liver;
© University of Basel

The signalling protein mTOR is a key regulator that controls cell growth. Dysfunction of mTOR increases not only the likelihood of developing cancer but also diabetes.

The protein mTOR regulates both cell growth and metabolism and thus plays a key role in the development of many disorders. In the cell, this regulatory protein is found in two structurally and functionally distinct multiprotein complexes called mTORC1 and mTORC2. mTORC2 is less well studied than mTORC1. After the research group of Mike Hall from the Biozentrum of the University of Basel recently demonstrated how mTORC2 is activated in tumour cells, a new investigation by the same team has shed light on the role of mTORC2 in carbohydrate metabolism and in the development of diabetes.

In the healthy organism, insulin regulates blood glucose levels and activates the mTORC2 signalling pathway. Upon genetic inactivation of mTORC2 in the liver, blood glucose and insulin levels were elevated as soon as a few weeks after birth. In addition, the loss of mTORC2 led to insulin resistance. Consequently, liver cells could no longer respond to nutrients supplied via the diet and continued to produce new carbohydrates despite rising blood glucose levels.

The scientists also demonstrated how insulin resistance, originally affecting only the liver, spread to the whole body with the increasing age of the animals. The mice developed the typical symptoms of type 2 diabetes. The cell biologist Doctor Marion Cornu commented, "We were excited to see that the inhibition of mTORC2 in the liver caused an imbalance in carbohydrate metabolism not only in the liver but also in the the whole organism. This told us that mTORC2 in the liver controls metabolism of the whole body."

mTOR inhibitors currently being developed for use against tumour growth usually inhibit both mTOR complexes. Through the use of newer, more specific mTORC2 inhibitors doctors hope to be able to prevent uncontrolled growth of tumour cells without affecting healthy cells. The new findings of Hall and his team provide evidence that such cancer treatments must take into account the development of diabetes as a possible side effect.; Source: University of Basel