I was diagnosed with type 1 diabetes nearly 16 months ago. At the time of my diagnosis I was horrified, but also a little bit cocky. My husband has had type 1 diabetes since 2002 and after over six years of living with a diabetic, I was sure I knew all I needed to know about managing diabetes. I thought I’d breeze my way into life as a diabetic – and then I had my first hypoglycemic attack, a sort of rite of passage.
What I quickly learned was that no matter how much information you have and no matter how close you’ve been to a diabetic, you don’t really know diabetes until it’s in your blood. And so while I still maintain to know an inordinate amount of information about my pancreas, I don’t claim to know it all. Not even close. In fact, new research on the defunct organ poking from beneath my stomach like a hitchhiker’s thumb indicates pancreatic cells are capable of something I’d never imagined – regeneration. A study, conducted at the University of Geneva and co-funded by the Juvenile Diabetes Research Foundation, has found that alpha cells in the pancreas, the cells which secrete the hormone glucagon, can regenerate themselves into insulin-producing beta cells after normal beta cells have been destroyed. The study is the first to show that this change of alpha cell into beta cell can happen naturally and spontaneously.
The researchers, led by Dr. Pedro L. Herrera, discovered that when they destroyed beta cells in mice to induce an artificial form of type 1 diabetes, the alpha cells in the pancreas then changed into insulin-producers. They found that when nearly all of the beta cells had been destroyed, if mice were given insulin therapy to keep them alive, the alpha cells spontaneously changed into functioning beta cells. After enough alpha cells converted into beta cells, insulin therapy was no longer needed. The Geneva researchers pointed out that the critical factor in sparking the alpha-to- beta-cell reprogramming was removing (or ablating) nearly all the original insulin-producing cells in the mice. In mice where the loss of beta cells was more modest, the researchers either found no evidence of beta cell regeneration (when only half the cells were destroyed) or less alpha cell reprogramming (when less than 95% of cells were destroyed).
Is this the first time alpha cells are being considered as a potential source of cells for beta cell treatment in diabetics?
It has been previously shown that alpha cells can be converted into beta cells, but this work relied on genetic manipulations – forcing expression of a key beta cell transcription factor, Pax4, in alpha cells. What is new in Dr. Herrera’s work is the demonstration that the ability of alpha cells to convert to beta cells appears to be intrinsic and can occur without genetic manipulation of the cells. We know a bit about some of the transcriptional changes that accompany the conversion of alpha cells to beta cells, but we still do not know the signals that trigger those changes. One of the current challenges is to identify the signals and pathways that are triggering the reprogramming of alpha cells to beta cells and ways to manipulate those pathways.
Are efforts being made to convert alpha cells to beta cells in vitro to see if we can increase the supply of beta cells for transplantation?
The first likely application for any beta cell reprogramming effort would be in vitro reprogramming for transplantation. However, when considering alpha cells as a starting cell it is important to remember that beta cells outnumber alpha cells in human islets. Therefore even a perfect conversion of all alpha cells would only give a modest increase in the number of beta cells available for transplant.
Many different studies have shown that we can make insulin producing cells. Do you believe that this is different and if so, how?
Being a beta cell is more than just producing insulin. Beta cells must be able to continuously sense the level of glucose and secrete insulin appropriately in response to the body’s needs. What is exciting about these results is the demonstration that the body can spontaneously make new beta cells from pre-existing alpha cells and that these new beta cells are functional and able to control glucose levels. The demonstration that the conversion of alpha cells to beta cells is a spontaneous and normal process raises hope that we can identify therapeutic interventions that will mimic this process to safely and efficiently reprogram alpha cells to beta cells for the treatment of diabetes.
There is research that shows the cells that line the ducts of the pancreas can convert to beta cells. Do you think these findings contradict or support the idea that beta cells might come from ducts?
These findings don’t rule out a ductal or duct-associated beta cell progenitor. One of the emerging themes coming from this work and other work is that the pancreas is more plastic than we previously appreciated – there appear to be multiple mechanisms and sources for beta cell regeneration.
Do you think these findings will significantly change the focus of research on the search for the beta cell stem cell?
JDRF maintains an active interest in identifying and characterizing an adult beta cell stem cell and will continue to support research in this regard. These and other recent results have increased our interest and support of research aimed at reprogramming of non-beta cells to beta cells. Reprogramming is emerging as a new priority area and growing part of our portfolio.
Do you dream about a clinical application for this?
At JDRF we are hopeful that reprogramming will one day become a clinical reality. However, it is important to remember that we are at very early stages – we still need to gain better insights into the pathways and triggers that tell alpha cells to convert to beta cells and develop strategies and approaches to manipulate those pathways.
For more details see Karmel Allison’s post.