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Jun 30, 2014

Gutting Out a Cure for Diabetes? Human GI Cells Retrained to Make Insulin

Gutting Out a Cure for Diabetes? Human GI Cells Retrained to Make Insulin

Human gastrointestinal cells from patients were engineered to express insulin (fluorescent green) in the lab. [Columbia University Medical Center]

  • With newly created embryonic or adult stem cells continuing to fall short as surrogates for pancreatic, insulin-creating cells, some researchers chose to explore an alternative path—the retraining of existing patient cells. For example, two years ago, researchers at Columbia University Medical Center showed that mouse intestinal cells could be transformed into insulin-producing cells. Now these researchers have achieved similar results with human intestinal cells. This advance points to novel treatments for type I diabetes.

    A longstanding goal of type I diabetes research is to replace lost pancreatic β-cells with new cells that will release insulin into the bloodstream as needed. Though researchers can make insulin-producing cells in the laboratory from embryonic stem cells, such cells are not yet appropriate for transplant because they do not release insulin appropriately in response to glucose levels. If these cells were introduced into a patient, insulin would be secreted when not needed, potentially causing fatal hypoglycemia.

    But now, instead of differentiating embryonic or induced pluripotent stem (iPS) cells into β-like-cells through endodermal progenitors, it appears clinicians might reeducate existing cells. The new approach, which might actually be easier, involves deactivating gut cells’ FOXO1 gene. Evidence in support of this approach appeared June 30 in Nature Communications, in an article entitled “FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures.”

    “People have been talking about turning one cell into another for a long time, but until now we hadn’t gotten to the point of creating a fully functional insulin-producing cell by the manipulation of a single target," said the article's senior author, Domenico Accili, M.D.

    Dr. Accili and postdoctoral fellow Ryotaro Bouchi first created a tissue model of the human intestine with human pluripotent stem cells. Through genetic engineering, they then deactivated any functioning FOXO1 inside the intestinal cells. After seven days, some of the cells started releasing insulin and, equally important, only in response to glucose.

    “Using gut organoids derived from human iPS cells, we show that FOXO1 inhibition using a dominant-negative mutant or lentivirus-encoded small hairpin RNA promotes generation of insulin-positive cells that express all markers of mature pancreatic β-cells, release C-peptide in response to secretagogues and survive in vivo following transplantation into mice,” wrote the authors. “The findings raise the possibility of using gut-targeted FOXO1 inhibition or gut organoids as a source of insulin-producing cells to treat human diabetes.”

    The researchers had used a comparable approach in its earlier mouse study. In the mice, insulin made by gut cells was released into the bloodstream, worked like normal insulin, and was able to nearly normalize blood glucose levels in otherwise diabetic mice. That work, which was reported in 2012 in Nature Genetics, has since received independent confirmation from another group.

    “By showing that human cells can respond in the same way as mouse cells, we have cleared a main hurdle and can now move forward to try to make this treatment a reality,” Dr. Accili said. The key will be finding a drug that can inhibit FOXO1 in the gastrointestinal cells of people. Dr. Accili is now looking for suitable compounds.


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