Why the Cancer Drug Rapamycin Causes Diabetes

 @rpalmerscience on April 03 2012 12:43 PM

Many organ transplant recipients and cancer patients depend on rapamycin, a drug that suppresses the immune system and targets proteins involved in cell division. But this highly effective drug has an unfortunate side effect: Many of the people who take it develop diabetes. Scientists now say they've figured out the root of the problem by studying the drug's effects on mice.

Normally, the body uses a hormone called insulin to help cells absorb and use blood sugar derived from food. People with diabetes either do not make enough insulin, or their cells cannot respond properly to it.

Rapamycin leads to diabetes because it disrupts the insulin-signaling pathway in muscles and the liver, thereby preventing muscle cells from absorbing blood sugar, a team led by researchers from the Dana-Farber Cancer Institute in Boston and Harvard Medical School reported in the journal Cell Metabolism on Tuesday.

The key, it turns out, is in a gene called Yin Yang 1: The scientists created mice that lacked this gene in their muscles and found they did not develop diabetic symptoms when treated with rapamycin.

While it's still not completely understood how rapamycin interacts with YY1 -- which is also present in humans -- the new research does suggest a possible target for therapies to counteract the drug's diabetic side effects.

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

The results suggest that people taking rapamycin might also want to take anti-diabetic drugs that increase insulin sensitivity, said Puigserver.

The current paper comes on the heels of another report published in the journal Science last week, in which University of Pennsylvania and Massachusetts Institute of Technology scientists theorized that they could separate rapamycin's anti-aging effects from the diabetes-inducing effect.

Rapamycin inhibits two protein complexes in the liver called mTORC1 and mTORC2, but the Penn-MIT team found that just inhibiting mTORC1 was enough to extend the lifespan of mice without causing any insulin resistance.

University of Pennsylvania professor Joseph A. Baur, the senior author of the Science paper, speculated on how this finding could be transformed into a treatment in a statement on March 29.

The hope is that in the future, we will be able to develop molecules that target mTORC1 specifically, separating out the beneficial effects of rapamycin on aging and disease, and leaving behind the insulin-resistance side effect, Baur said.

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