Mimicking beta cells to treat diabetes

December 8, 2016 § Leave a comment

 

Diagram of a HEK cell engineered to behave like a beta cell. Credit: ETH Zurich

A HEK cell engineered to behave like a beta cell.
Credit: ETH Zurich

Type I diabetes occurs when the body’s immune system destroys the beta cells which produce insulin in the pancreas. While insulin pumps and blood monitoring systems have come a long way since B.B. King was touting new devices that didn’t hurt his fingers, the disease, which affects more than 40 million people worldwide, is still almost entirely managed with injections of insulin. This can cause health problems and lower quality of life when patients take an improper dose of insulin.

In efforts to replace the destroyed beta cells, researchers report in a paper just published in the journal Science that they have transformed cultured human embryonic kidney-293 cells into functional mimics of the human pancreatic beta cells.

Human pancreatic islets are currently the gold standard in beta-cell replacement therapy, but are difficult to maintain in cell culture and often in short supply. The researchers wanted to explore alternatives to the replacement therapy.

The researchers noticed that beta cells measure blood glucose levels metabolically rather than rely on a dedicated receptor that counts the number of glucose molecules near the plasma membrane. The cells use transport proteins to draw glucose in before metabolizing the sugar, which causes the ATP level to increase. This increase in the ATP level depolarizes the membrane by closing potassium channels. The closing of the potassium channels causes calcium channels to open. The subsequent calcium influx sets off a voltage-gated calcium-dependent signaling cascade which then kicks out the granules containing the insulin.

“We found that all it takes to turn a HEK cell into a beta cell is expressing the voltage-gated calcium channel,” says Martin Fussennegger at the Swiss Federal Institute of Technology. Because the HEK-293 cells already have channels for glucose and potassium, Fussenegger and colleagues modified them to express the voltage-gated calcium channel as well as produce insulin in response to it.

To test the human-derived artificial beta cells, the researchers encapsulated them in alginate beads to protect them from the mouse immune system. “We put them in kind of a teabag,” says Fussenegger.

They then injected the artificial cells into the body cavities of mice with type I diabetes, where the cells joined up to the bloodstream. Over a three-week period, the researchers saw that the artificial cells restored glucose homeostasis more reliably than encapsulated beta-cell islets from organ donors and more efficiently than encapsulated cells from a human beta-cell line called 1.1E7. They also noted that these artificial beta cells showed higher insulin secretion capacity in cell culture than both the 1.1E7 beta cells and the human pancreatic islets.

While this particular replacement therapy would be several years off because it has to undergo clinical trials, Fussenegger is optimistic about how it would work for patients. “Every four months you would need to replace this cell-based self-containing teabags by new implants,” says Fussenegger. The procedure, which would consist of a small incision, could be done by a primary care physician. “As a diabetic, either type I or type II, you could have a pretty normal life during the four months, then you have a little replacement of your implant,” he says. “These kind of cells could take over from the pancreas and could control your insulin in response to the glucose levels in your blood.”

This post was written by John Arnst, ASBMB Today’s science writer. 

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