A study published in Cell Metabolism reports that scientists at the Dana-Farber Cancer Institute have discovered why some patients who receive rapamycin, an immuno-suppressant that also has anti-cancer activity, and may even slow ageing, have developed symptoms similar to diabetes.

Rapamycin, which is commonly administered to prevent organ rejection, is currently undergoing clinical trials as a cancer treatment. However, about 15% of patients have developed insulin resistance and glucose intolerance after taking the drug. Until now, scientists have been unable to identify the reason.

According to the researchers, normal mice that were given rapamycin had a higher risk of experiencing difficulties in regulating their blood sugar. This was due to a drop in insulin signaling that was triggered by activity of a protein called Yin Yang 1 (YY1). The researchers observed that the muscles in mice with a ‘knocked out’ YY1 protein failed to respond to rapamycin, which signals that they appeared to be protected against developing symptoms similar to diabetes. The authors therefore concluded that the YY1 protein was responsible for the loss of normal insulin function in patients who took rapamycin.

Senior researcher, Pere Puigserver, PhD, says that findings showed that physicians should consider giving anti-diabetes drugs along with rapamycin. He adds that researchers and non-scientists who are excited about rapamycin’s life-extending potential should be very cautious, based on recent animal studies, including studies in mammals.

In terms of further research into rapamycin’s anti-ageing properties and related compounds, Puigserver says, that:

“The possibility of increased diabetes risk needs to be taken
into account.”

Rapamycin is a drug that has been developed from a bacterium that has been discovered on Easter Island. The FDA approved rapamycin in 1999 as an immunosuppressant in transplant patients.

One of rapamycin’s functions is to inhibit mTOR (mammalian target of rapamycin) signaling pathway in cells. The mTOR pathway plays a vital role in controlling cell-growth, proliferation, survival and motility. Many cancers are characterized by high mTOR activity. Rapamycin and a related drug are currently being assessed in clinical trials for the treatment of kidney cancer, brain tumors, and mantle cell lymphoma, as well as others.

Interestingly, some experiments demonstrated that rapamycin extended healthy lifespan in yeast, flies and mammals, and that it delays age-related diseases, for instance atherosclerosis and cancer. However, the elevated risk of deleterious pre-diabetes symptoms has raised concerns and remained unexplicable.

Puigserver and his team published an article in Nature in 2007, which said that mitochondria, the cell’s power plants, in skeletal muscles increase due to mTOR and inhibiting mTOR activity with Rapamycin, resulted in a diabetic state. Additionally, the study identified Yin Yang 1 (YY1), one of the proteins ‘below’ mTOR in the signaling pathway. YY1 is a protein that controls the expression of genes and acts as a transcription factor.

Puigserver says:

“We thought that maybe YY1 was responsible for
the diabetic effects.”

They observed that a rapamycin-caused elevated YY1 activity was able to inhibit insulin production and that of related hormones, which are needed so that muscles receive glucose (sugar) for energy and keep blood sugar levels stable.

They carried out an experiment in which they bred mice without the YYI gene and protein in their skeletal muscles and administered them with rapamycin. The outcome was that the mice showed no impact on their muscles’ glucose uptake or insulin signaling, they were simply immune to rapamycin’s diabetic effects.

Puigserver and his team are continuing their research and hope to discover the reason as to why a minority of human patients develops symptoms similar to diabetes when taking rapamycin. Puigserver speculates that one possibility could be that certain dietary factors could elevate the risk.

Written by Petra Rattue