Researchers figure out how rapamycin causes diabetes

The drug known as rapamycin is widely used by cancer and transplant patients, and there are hints that it might even help us put off old age and live longer. But, it also comes with a downside: rapamycin leads to diabetes in as many as 15 percent of the people who take it.

Now, researchers reporting in the April Cell Metabolism, a Cell Press publication, have figured out why that is. The drug turns the insulin signal off in muscle, to prevent muscle cells from taking blood sugar in.

"This is a drug that is pretty well known for its benefits," said Pere Puigserver of Dana-Farber Cancer Institute. "Rapamycin is one of the few drugs, maybe the only one, that extends lifespan in organisms from yeast to mice to primates."

But the drug's diabetic side effects are troubling, and Puigserver's team now finds they arise in an interesting way. The key is a single transcription factor in muscle known as YY1. Mice lacking YY1 are protected from diabetes when they take rapamycin.

That's because rapamycin changes YY1 within muscle and that shift leads to chemical and structural modifications of the genes encoding insulin signals. Those changes effectively turn insulin off, keeping sugar from coming in.

That rapamycin leads to long life even as it causes insulin resistance remains something of a paradox, Puigserver says. His team does have hints that there may be other factors at play. For instance, he says diet might make the difference between those who develop diabetes while on rapamycin and those who do not.

The results also have fundamental interest as perhaps the first instance in which the nutrient signal mTOR -- the target of rapamycin -- has been tied to epigenetic changes in the genome. (Epigenetic changes are defined as chemical modifications to DNA that can take place without any change in the underlying sequence of As, Gs, Ts and Cs.) The finding may reveal a more general mechanism by which other nutrient changes could act via mTOR to control the epigenetic state of genes, with impacts in metabolism and diseases.

On the practical side, the findings support the notion that at least some people taking rapamycin should also take anti-diabetic drugs, Puigserver says. These side effects will also need to be factored into any cost-benefit analysis of further uses of the drug, the researchers say, including for any future use in lifespan extension.