06:31am Wednesday 23 August 2017

Joslin Shows Transplanted Beta Cells Learn to Deal with Stress

BOSTON, Mass. – For transplanted beta cells, life is tough. Not only are the insulin-producing cells in a stranger’s body, tucked into the liver rather than the pancreas, they are a bit short on oxygen and blood, and they are often exposed to raised levels of glucose. Joslin Diabetes Center scientists, however, have shown that the cells can protect themselves by actively adapting to their new homes—findings that may help to aid future transplants aimed at treating type 1 diabetes.

Researchers in the lab of Gordon Weir, M.D., looked at a cellular stress mechanism called the unfolded protein response or endoplasmic reticulum (ER) stress response in beta cells. This response is triggered when the ER, part of the cell’s protein assembly line, struggles to fold newly formed proteins into their exactly right shapes.

Earlier studies suggested this process contributes to the high mortality and low insulin production often displayed in beta cell transplants, which aim to replace cells that the body’s own immune system kills off in type 1 diabetes.

In work reported in the journal PLoS One in June, the scientists compared healthy human beta cells from surgical donors with beta cells that had been transplanted into mice with suppressed immune systems. They found that the transplanted cells strongly activate genes that help to guard against damage from ER stress, and suppress other genes that may trigger cellular attempts to self-destruct.

“Not only is this response likely to be helpful for proper insulin secretion but it also seems to hold back the death mechanisms that can be turned on when ER stress is really aggressive,” says Weir, who is co-head of Joslin’s Research Section on Islet Cell and Regenerative Biology.

“Nature is telling us about mechanisms that might rescue the cells from death,” notes Weir, who is also a Professor of Medicine at Harvard Medical School. “Knowing these mechanisms might suggest some treatments, such as genetic manipulations to the cells before they’re transplanted, or drugs after they’re transplanted, that help to guard the cells.”

Weir notes that blood glucose levels run higher in mice than in humans, so that in this way the transplanted cells were in an environment similar to that of an actual transplant. The glucose levels also were similar to those of people with the impaired glucose tolerance that leads toward type 2 diabetes. “This may be a general mechanism for beta cells under stress, so these results may also tell us something about glucose toxicity to beta cells in type 2 diabetes,” he adds.

Jeffrey Kennedy was first author on the paper. Other contributors include Hitoshi Katsuta, Min-Ho Jung, Lorella Marselli, Allison B. Goldfine, and Susan Bonner-Weir from Joslin; and Ulysses J. Balis and Dennis Sgroi from Massachusetts General Hospital. Lead funding was provided by the American Diabetes Association, the Juvenile Diabetes Research Foundation, the National Institutes of Health and the Diabetes Research and Wellness Foundation.

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