For people with type 1 diabetes, transplanting insulin-producing (beta) cells can offer hope of a life without daily injections. But even when the transplant is initially successful, the treatment can later fail from within. A new study is trying to prevent this hidden failure – with the help of a small peptide that protects the cells from breaking down.
For many years, researchers and clinicians have worked to give people with type 1 diabetes new beta cells so they can avoid daily injections with an insulin pen into the skin of their abdomen.
Clinical trials are already underway, and the first results are promising – but the effect does not always last over time.
Part of the explanation is that the transplanted cells become stressed and begin to form amyloid plaques – small clumps of protein made from the insulin-related hormone islet amyloid polypeptide (IAPP), which slowly suffocate the cells and cause the treatment to fail.
“When the cells are exposed to stress during and after transplantation, they can start to form amyloid plaques,” explains Joey Lau Börjesson, Associate Professor, Department of Medical Cell Biology, Uppsala University, Sweden.
Joey Lau Börjesson is one researcher behind a new study that tackles this challenge directly: how to prevent plaque formation – and thereby give the transplanted cells a better chance of surviving and functioning properly.
“The aim is to increase cell survival after transplantation so that the probability of success is as high as possible. Here, we show how the peptide BRICHOS can be used to prevent plaque formation and, in that way, stop some insulin-producing cells from dying,” says Joey Lau Börjesson.
The research has been published in Diabetologia.
The problem does not stop at transplantation
Joey Lau Börjesson works with preclinical models of type 1 diabetes and researches how stem cells can be used to replace some of the beta cells lost as the disease develops.
Research in this field has come a long way, but the problem of plaque formation in beta cells has yet to be solved.
Amyloid plaques are also known from Alzheimer’s disease, in which similar protein accumulations cause nerve cells in the brain to gradually lose their function. The same underlying problem is present in type 2 diabetes, in which amyloid can damage the insulin-producing beta cells.
Taken together, the picture is that we currently lack effective ways to intervene directly to avoid plaque formation – and thereby protect the cells.
“A solution to the problem of plaque formation will therefore have potential in several fields,” explains Joey Lau Börjesson.
This makes the discovery relevant far beyond type 1 diabetes, since amyloid plaques play a central role in several serious diseases in which cells gradually lose their function.
A natural peptide protects cells from plaque
This is where the story takes a turn: the BRICHOS peptide enters the picture. Previous studies indicate that BRICHOS plays an important role in regulating plaque formation.
“BRICHOS acts as a kind of molecular bodyguard,” says Joey Lau Börjesson. “When beta cells are put under stress, an insulin-related protein can fold the wrong way and start sticking together. BRICHOS helps keep those proteins apart, so they don’t form the toxic clumps that eventually kill the cells.”
That is precisely what makes the peptide useful in transplantation, when the cells are already under pressure.
Joey Lau Börjesson’s group previously showed that BRICHOS can counteract plaque formation in beta cells. The new study investigated whether it can also protect beta cells produced from stem cells.
Stem cell–derived beta cells are the type of cells used in clinical trials in which people with type 1 diabetes are given the opportunity to produce insulin on their own again.
When cells are stressed, BRICHOS shows its effect
The study worked with cell cultures in which human stem cells are developed in the laboratory into insulin-producing beta cells – a preclinical model used to test how robust the cells are before transplantation.
When these cells are exposed to high concentrations of glucose in their surroundings, they begin to form amyloid plaques.
This is the same process that takes place in the pancreas of people with type 2 diabetes and after transplantation among people with type 1 diabetes.
The results showed that the cells given additional BRICHOS formed far fewer of the harmful protein clumps.
The cells were made to produce more BRICHOS using a well-established laboratory technique in which a gene is introduced into the cells.
“BRICHOS is already expressed in cells at low concentrations to, among other things, keep plaque formation in check under normal conditions. Under other circumstances – such as during the development of type 2 diabetes or following transplantation in type 1 diabetes – BRICHOS at natural levels cannot keep up. But getting the cells to produce more of the peptide than normal continues to inhibit plaque formation,” explains Joey Lau Börjesson.
Next step: does it also work in living organisms?
Joey Lau Börjesson is optimistic, based on both the new study and previous results with BRICHOS.
“If we can protect the cells better, we increase the chance that the transplant will actually last in the long term,” she says.
In practice, this could mean that when stem cell–derived beta cells are transplanted, the level of BRICHOS is increased at the same time to reduce the risk of harmful plaque formation.
If the results are confirmed in the next round of studies, it could make the difference between a treatment that works only for a short time and a transplant that provides a lasting alternative to daily insulin injections. Before this can become a reality, however, the effect must be confirmed in living organisms.
“Investigating this in a cell model is relatively easy, since we have control over what happens in the Petri dish. The next step is to study the effect in an animal model and see whether the same protection applies in a living system – and whether there are any side-effects,” concludes Joey Lau Börjesson.
