The State of Type 1 Diabetes Research TodayFriday, December 21, 2012
JDRF’s Chief Scientific Officer Richard Insel, MD, provides an overview of the types of research the organization is funding; the scientific theories that are being advanced; and the future direction of the organization with regards to prevention.
By: John Parkinson, Clinical Content Coordinator, DiabetesCare.net
In 1970, Lee Ducat was a concerned parent of a young child with type 1 diabetes who got together with a group of other like-minded Philadelphia-area parents of type 1s. And what began as Ducat’s search for answers about her son’s disease developed into JDRF, formerly known as the Juvenile Diabetes Research Foundation.
Through the years, JDRF has grown into an international organization that has funded numerous grants for type 1 diabetes research, which has helped medical science better understand and treat the chronic disease and its complications. Overall, JDRF has awarded more than $1.7 billion in research.
In addition to providing grants for research, JDRF has been extremely active in fundraising with its own initiatives and has been hugely instrumental in petitioning the federal government for funding the Special Diabetes Program (SDP).
As the organization has matured, JDRF has created various research arms that are categorized into one of the following: cure, treat, or prevent.
Overseeing the research strategy for JDRF is Richard Insel, MD, Chief Scientific Officer, Research. His past professional experience includes work associated with the University of Rochester Medical Center. He held numerous positions including Acting Chair of Pediatrics; Professor of Pediatrics, Microbiology & Immunology, and the Cancer Center; Associate Chair for Pediatric Research; Director of the Strong Children`s Research Center; and Chief of the Division of Pediatric Immunology, Allergy and Rheumatology.
Dr. Insel (pictured, lower left) was also the founding director of the Center for Human Genetics and Molecular Pediatric Disease and a member of the departments of pediatrics and microbiology & immunology.
Along with his work at the University of Rochester, Dr. Insel was also a scientific co-founder of the bio-tech company, Praxis Biologics. This company developed the Hib vaccine, which was developed for the most common form of meningitis. This vaccine given to babies and young children has been instrumental in nearly eliminating the risk of developing this disease in the United States, according to the CDC.
Dr. Insel says medical science knows the development of type 1 diabetes involves an autoimmune process; yet, what remains a mystery is the combination of potential internal factors, such as peoples’ genetics and external factors, like the environment, that together trigger the disease into action.
With the past success of the Hib vaccine, Dr. Insel sees the possibility of universal immunization for small children as potentially the most cost-effective and efficient way to prevent type 1 diabetes in future generations.
In addition to looking at possibly preventing future cases of the disease, JDRF is taking two active approaches for cure therapies: beta cell replacement and regeneration of beta cells.
With JDRF at the center of exciting and new type 1 research, DiabetesCare.net sat down with Dr. Insel to discuss JDRF’s continuous future funding plans; where medical science is in terms of knowledge and further insights into type 1 diabetes; and what we can expect in terms of trials and news for the coming year.
DiabetesCare.net: JDRF is involved in various areas of type 1 research. What are JDRF’s criteria in determining which research projects get funded?
Insel: JDRF is involved in funding a limited amount of research areas. The first criterion is alignment with our priorities. Every year, JDRF seeks requests for application (RFAs) in particular priority areas. We list those areas on our website. We are also open to anyone coming to JDRF with new ideas.
We are funding in our priority areas based on the concept that there are very specific gaps and challenges we need to address in order to deliver drugs and devices to improve the lives of individuals with type 1 diabetes in the short term, and in the long term, to prevent, and ultimately to cure the disease.
DiabetesCare.net: In terms of cure therapies can you provide some insights into what areas you are focusing on?
Insel: JDRF is taking two different approaches to cure type 1diabetes: replacement and regeneration of beta cells. With replacement, this approach is trying to restore beta cell function by implanting a new source of replenish-able pancreatic beta cells that are encapsulated, whether it is pig islets or embryonic stem cell-derived islet cells.
The problem we have had with transplanted beta cells is that they are rejected either because they are foreign to the transplanted person or because of the autoimmunity associated with type 1 diabetes. Once you have type 1 diabetes autoimmunity, it is a lifelong problem. So this sets up these new cells for rejection. These transplanted beta cells are placed in a capsule to thwart rejection by the immune system. We are working on various solutions for this approach.
The other cure therapy is regeneration where rather than working with exogenous beta cells sources, we are trying to regrow new beta cells within individuals who have established type 1 diabetes, and simultaneously trying to prevent the autoimmune response and rejection that happens with implanted cells.
We know that for people even with the disease long-term, there may be some residual beta cells.
The question is can we get them to divide and grow? We know in animal models we can do this, but we are trying to figure out some clever approaches to do this in humans. If residual beta cells do not exist, we are looking to stimulate a precursor to form new beta cells.
Another question is whether you can switch a non-beta cell into a beta cell such as a glucagon-producing alpha cell? Through genetic manipulations we can do this. Even without genetic manipulations, we know that in mice if you delete or remove all the beta cells, the alpha cells will spontaneously become beta cells without any kind of manipulation or drugs at all. We are trying to understand the rules by which this happens and figure out how we can make this into a novel therapy we could use. At the same time, if you do generate beta cells, you have the underlying autoimmune process that will destroy regenerated beta cells and that needs to be addressed.
DiabetesCare.net: In looking at islet cell transplantation (replacement) or beta cell regrowth (regeneration), would you say one of these approaches is further along than the other?
Insel: Today we know cadaver islet cell transplants can cure individuals with type 1 diabetes, and in fact, the success rate of cadaver islet transplantation—and success being defined as being insulin-independent for five years—has increased immensely in the last 10 years.
In some centers, over 50 percent of patients are realizing insulin-independence after transplantation. And the majority of patients who are still on insulin, post-transplantation have reduced insulin requirements.
Almost everyone has been cured of life threatening hypoglycemia unawareness—which is the main indication for the transplant. Even a little bit of beta cell function can go a long way of helping people have a better life.
This can be successful, but the problem is we can’t transplant all the people we need to; we can only transplant approximately 100-200 individuals every year because of the shortage of cadaver-donated islet cells.
If we can generate a new islet cell source and have an effective approach to encapsulation, you are there. In that sense, you are ahead of beta cell regeneration, which is still highly experimental and has not moved into clinical research.
Further, on the replacement side, we have two biotech companies that have announced they are trying to advance pre-clinical research using encapsulated embryonic stem cell-derived islet progenitors into clinical trials.
When these progenitors are put into animal models, these cells grow up and become mature islets with beta cell function that can cure diabetes in animal models.
So, we now have companies moving in that direction and we also have a company transplanting encapsulated pig islets. The early results show they are not achieving insulin-independence but they are improving beta cell function and HbA1c levels.
These programs are moving forward and on the regeneration side we are still working with animal models. We have not figured out how to regenerate beta cells in humans yet.
DiabetesCare.net: At a joint webinar that both you and NIH’s Dr. Judith Fradkin spoke at earlier this year you had said “type 1 diabetes is a disease of young children.” Why do you believe the prevalence in this age group is occurring more frequently?
Insel: Let me point out that we do estimate there are nearly an equal amount of children as well as adults being diagnosed with type 1 diabetes. And if you look at the population of the U.S., there are more adults with type 1 diabetes than children. Historically, JDRF has probably paid less attention to issues with adults and going forward we are very cognizant adults have different needs and we are attuned to that.
With respect to the rise of incidence in children and adults, we don’t have the best data here in the United States. The best data comes out of Europe; and we know the number of new cases have been increasing the last four decades, and the fastest rising population of newly diagnosed cases are young children between 1 to 5 years of age.
In the United States, that doesn’t seem to be the case. T1D is increasing but the fastest growing age range is in the preadolescent years, not the youngest children. It doesn’t mean we won’t see that change in the future. We don’t know why the numbers are so high for very young children in Europe and why the incidence is increasing, but we postulate that there is something different about the environment. Our gene pool doesn’t change that quickly to suggest it is something genetic. We are not sure what it is in the environment.
One of the programs Dr. Fradkin and I talked about is The Environmental Determinants of Diabetes in the Young (TEDDY) Program. More than 400,000 newborns in the United States and in Europe were screened at birth for risk of developing T1D. And approximately 6,000 at-risk infants are now being followed for their first 15 years of life with sampling for environmental exposures including antibiotics, toxins, drinking water, and pet exposure. The families are keeping food diaries to see if there is anything in their diets that accounts for this risk.
We hypothesize that children born today don’t have the same regulation of their immune system. Type 1 is an immune disorder. Not only are cases of type 1 increasing in the young, but if you look at food allergies they are also more commonplace. What they have in common is that they are defects of immune regulation. The set point for self immune regulation is not being set in the same way as it has been set in the past, leaving more individuals susceptible to these diseases.
It appears that the microbiota that lives in our gastrointestinal tract is what educates our bodies for immune regulation, and we believe that the microbiota in infants is different today than several decades ago.
This is an area of research that JDRF is exploring. Now whether or not antibiotic usage, caesarian section (C-section) deliveries, or other changes in the environment are altering immune regulation is not known. In fact, about one-third of deliveries performed today are C-sections. That is approximately 5 or 6 times higher than the rate observed 40 years ago. And we know children born via C-section are at a higher risk of developing type 1 diabetes.
We know that C-sections do alter the microbiota; we don’t know if this is directly causal for T1D. JDRF is funding research exploring the microbiota of young children who don’t go on to have type 1 diabetes versus those who do develop the disease.
If this is contributing to the increasing prevalence of T1D then we may be able to develop safe approaches that manipulate microbiota-induced autoimmune regulation.
DiabetesCare.net: Genetic risk identification is one area of research that seems to be progressing with between 60 to 70 percent of the genetic code risk identified in humans. Do you someday want to be able to screen all children to see if they are at-risk for diabetes?
Insel: Approximately half the risk of type 1 is genetic and the other half is environmental. On the environmental side, we don’t know environmental etiologies, but on the genetic side, we do have a profound understanding of the genetic workings of this disease.
We have identified over 50 genes or genetic regions that confer susceptibility to type 1 diabetes so we believe we have identified most of the genes associated with the disease.We want to prevent type 1 diabetes, and there are two forms of prevention: primary prevention and secondary prevention.
One is to screen either newborns or relatives of individuals with T1D for risk and follow at–risk individuals to determine their progression to insulin dependence and intervene to preserve beta cell function to prevent such. This is secondary prevention.
In the U.S. today, we screen annually approximately 20,000 individuals who have an affected relative for risk of T1D as part of the Pathway to Prevention study conducted by TrialNet. These at-risk individuals are offered an opportunity to participate in secondary prevention clinical trials. There are several secondary prevention trials ongoing today or about to be launched.
The other form of prevention is primary prevention, where we try to prevent the onset of the autoimmunity associated with T1D in at-risk individuals. This could be performed by screening for risk or even without screening. Can we go into a population that is at high- risk and immunize every child of that population to prevent the onset of the autoimmune process associated with type 1 diabetes?
We know that in Finland the risk of a child born there today has about a one in 130 chance of developing type 1 diabetes by the age of 15. Almost one percent of Finland’s children will develop type 1 diabetes. Finland has the highest attack rate in the world. The risk is so high that if you had a safe vaccine that could prevent type 1 diabetes, you would immunize every infant.
Ultimately universal childhood immunization may be used to prevent type 1 diabetes. And directionally, that is where JDRF wants to go, though it will likely take a long time to get there.
We are betting on vaccines and JDRF is funding research along these lines. One of the concepts we are looking at is whether or not a virus causes type 1 diabetes. And if there a limited number of viruses accounting for type 1, could we develop a viral vaccine, similarly to the polio vaccine?
Another approach would be something we mentioned before: babies born via C-section have a different microbiota. Are there ways to reset or stimulate microbiota induced immunoregulation so that it is more robust so these babies wouldn’t get allergies or wouldn’t get autoimmune diseases? It’s speculative but this is a direction we are pursuing and we are trying to get other groups to do so as well to leverage our resources.
We know type 1 diabetes is an autoimmune disease that targets the beta cells. A third approach might be to teach the immune system to tolerate and regulate itself to the beta cell autoimmune response with vaccines. We are trying to develop beta cell antigen immunoregulatory vaccines.
DiabetesCare.net: Can you tell us where we are with the artificial pancreas project (APP) today and what the expectations are for the coming years?
Insel: There will be continuous developments within this field. Today, we don’t have closed loop systems; we have devices that comprise a glucose monitor that is speaking to a pump, based on rules and algorithms. But this requires human intervention.
We have low-glucose suspend pumps that, if blood sugar goes low, they stop pumping insulin. These devices are available in Europe and hopefully they will be available in the United States in the near future.
The next generation of devices will be able to predict if you are going to go low, and if you are, they will suspend insulin. Those devices are being tested and look quite interesting. We will see those in Europe in the next year or two.
The follow-on generation of devices will not only predict lows and suspend insulin infusion but if you are going high, it will pump insulin and keep your glucose in a particular range. These devices are going to become more sophisticated to where you will be able to target the high and low range.
We have tested these systems in the hospital setting and have now moved to outpatient and out-of-hospital experimental settings. We can get excellent control overnight. The problem is with mealtimes and the bolusing of insulin. We don’t have systems that completely anticipate mealtimes and correct for such.
Directionally that is where we have to go. We believe it is going to be a long time before you have a “set-it-and-forget-it” type system. We will see, however, increasing functionality that will impact individuals with the disease with each new generation of devices.
DiabetesCare.net: With the artificial pancreas project there are some interesting critiques being heard from people online that research should be geared for cure therapies only and not for this particular project. Why is the AP project important?
Insel: To be very candid, a cure is not at hand. But we continue to make good progress toward a cure. While working on it, we need to keep people with T1D healthy. It is a very difficult disease to manage, and if we can help people live a better life today and decrease some of the burden of living with type 1 and prevent complications, that would be absolutely fantastic! And, we think devices have the ability to do such.
I do want to stress the majority of our funding is on cure therapies and not with the artificial pancreas. We are steadfast in our commitment to curing this disease. Most of our budget, time, and people are focused on a cure.
DiabetesCare.net: Are there any particular areas of research where decisions could be made that you are excited for in the coming year?
Insel: Recent release of the final regulatory guidance for artificial pancreas systems from the FDA is very exciting because it provides feedback to the companies about what they need to do to get these products on the market. I think having a low-glucose suspend system in the U.S. in the next 1-2 years is conceivable.
The other major development is that for the first time we have a diabetic eye drug that can be used to stop the progression and improve the condition of people with diabetic macular edema.
DiabetesCare.net: Will there be any developments in the islet cell field?
Insel: We are launching some major programs for encapsulation. We will announce them within the next year, and they will encompass a team-based approach to work on islet encapsulation and in delivering second and third generation encapsulation approaches, but will take some time to fully develop.