Imagine millions of tiny insulin pumps that work really well, measuring your blood sugar hundreds of times each second and secreting just the right amount of insulin. That’s basically how the beta cells of a healthy individual’s pancreas work. Ben Stanger, M.D., Ph.D., and his research team at the University of Pennsylvania believe that people with Type 1 diabetes could harbor similar cells in their gut, and that these cells could work much better than any current form of insulin or drug therapy.
The introduction of beta-like cells into a patient to treat diabetes is a form of cell therapy. Dr. Stanger’s lab uses an approach called cellular reprogramming, which he delights in calling “cellular alchemy,” to transform cells on a genetic level. He has shown that gut cells in mice can be manipulated to detect and stabilize blood glucose levels, just like healthy beta cells. Dr. Stanger has conducted experiments on mice and samples of human intestinal cells grown in a lab, and he hopes to begin clinical studies on human subjects in the next five to 10 years.
Insulin therapy, whether by injections or a pump, is designed to mimic a functional pancreas. But doctors and patients alike recognize, even the most sophisticated pump and diligent patient can’t regulate blood glucose levels on par with an army of healthy beta cells.
“If we really want to have an effective therapy for diabetes, we need something that works as well as a beta cell,” Dr. Stanger explains, adding that cell therapy, rather than insulin or drug therapy, “actually gives cells back to people to replace the ones that are no longer working or have been destroyed.”
Efforts to treat diabetes using cell therapy have been underway for decades. From 2000-2010, most research focused on the development of embryonic stem cells that behave like beta cells. But embryonic stem cell research has been hindered by ethical and political controversy, as well as scientific limitations. Among other challenges, the body will naturally reject embryonic stem cells from a donor, considering them potentially dangerous intruders. Immunosuppressants can help the transplanted cells survive, but the patient is then at risk for various side effects, including increased susceptibility to infections. Finally, the supply of egg donors for stem cell research is limited.
By using gut cells from the patient instead of an embryonic stem cell from an external donor, Dr. Stanger aims to circumvent all of these issues.
The Edmonton Protocol: Thinking Beyond the Pancreas
How is it that a cell can do the job of a beta cell while sitting in the intestine? If the pancreas is blood sugar headquarters, is it possible for a group of volunteer beta-like cells to work remotely?
It turns out that it’s very possible indeed, which opens up all sorts of cell therapy possibilities, in the intestines and beyond. This became apparent following research out of the University of Alberta in Edmonton, published in the New England Journal of Medicine in 2000. In this study, now known as the Edmonton protocol, patients with Type 1 diabetes received pancreatic islet transplants into the portal vein, and subsequently maintained healthy blood sugar levels without insulin therapy. Those successes, however, did not last; after several years, all patients once again returned to their previous dependence on insulin.
While the Edmonton protocol did not bring about lasting blood glucose control, it showed that beta-like cells could function (albeit with varying success) outside of the pancreas, so long as they are in direct contact with blood. This direct contact enables cells to detect blood glucose levels and secrete the appropriate amount of insulin, whether they reside in the pancreas, liver, gut, or elsewhere. Just like millions of high-performing tiny insulin pumps.
Which brings us back to the gut. As Dr. Stanger’s research progresses, he hopes to develop beta-like gut cells that are even more like beta cells than those in his petri dishes and mice today – even more responsive and capable of regulating blood glucose levels from the intestine.
Can This Work for People With Type 1 Diabetes?
Dr. Stanger’s research focuses on developing cells that would support people with Type 1 diabetes, a population with an autoimmune response that destroys beta cells. So the question is, will these faux beta cells be destroyed in the same fell swoop?
While that crucial question has not been conclusively answered, Dr. Stanger is optimistic. The prevailing opinion is that in the Edmonton protocol, the expiration of the transplanted pancreatic islets was not due to an autoimmune response. (Islets fail for a variety of reasons, but that immune attack does not seem to be the principal one.) So it is plausible that the beta-like gut cells in Dr. Stanger’s lab will be “different enough” that they won’t trigger an autoimmune response.
It’s important to note, however, that despite Dr. Stanger’s promising research, and that of others, including Timothy Kieffer at the University of British Columbia, who are working on similar approaches, we are still a long way from making real, human-usable beta cells from gut cells.
If you are hopeful that this research will translate into an applicable treatment for Type 1 diabetes, you can help by urging your representatives in Congress to support National Institute of Health funding, as well as by getting involved with organizations that support diabetes research such as the JDRF and American Diabetes Association.
*Image published in Cell Reports – Courtesy Yi-Ju Chen and Ben Stanger