Scientists at Columbia University Medical Center have demonstrated the conversion of human gastrointestinal cells into insulin-producing cells. Through the switching off of a single gene, in principle a drug could retrain cells inside a person’s GI tract to produce insulin.
This discovery opens the door to the possibility that cells lost in type 1 diabetes may be more easily replaced through the re-education of existing cells than through the transplantation of new cells created from embryonic or adult stem cells.
“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 senior author Domenico Accili, MD.
Surrogate Insulin-producing Cells
Researchers have been trying for almost two decades to produce surrogate insulin cells for type 1 diabetes patients. With type 1 diabetes, the body’s natural insulin-producing cells are destroyed by its own immune system.
While insulin-producing cells can now be made in the lab from stem cells, they do not yet have all the functions of naturally occurring pancreatic beta cells.
Because of this, some researchers have opted instead to attempt to transform existing cells in a patient into insulin-producers. Previous work by Dr. Accili and his team showed that mouse intestinal cells can be transformed into insulin-producing cells. This new study shows that this method also works in human cells.
Genetic Engineering a Deactivated Gene
The Columbia researchers succeeded in teaching human gut cells to make insulin in response to physiological conditions through the deactivation of the cells’ FOXO1 gene.
Accili, along with postdoctoral fellow Ryotaro Bouchi, begain by creating a tissue model of the human intestine with human pluripotent stem cells. Through genetic engineering, they then deactivated any working FOXO1 inside the intestinal cells. Some of the cells after seven days started releasing insulin and, equally key, only in response to glucose.
The team used a similar approach in its earlier 2012 mouse study. With the mice, insulin made by gut cells was released into the bloodstream. The insulin also worked like normal insulin, and was able to nearly normalize blood glucose levels in otherwise diabetic mice.
“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.
Dr. Accili is now searching for suitable compounds that can inhibit FOXO1 in the gastrointestinal cells of people, a key to this approach.
“FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures.”
Ryotaro Bouchi, Kylie S. Foo, Haiqing Hua, Kyoichiro Tsuchiya, Yoshiaki Ohmura, P. Rodrigo Sandoval, Lloyd E. Ratner, Dieter Egli, Rudolph L. Leibel & Domenico Accili
Nature Communications 5, Article number:4242 doi:10.1038/ncomms5242
Image Credit Columbia University Medical Center