Key:
NZ Nahida Zaman
DS Dr Desmond Schatz
DL Dr Robert Levine
MA Dr Mark Atkinson
NZ Good morning, hello and welcome to Diabetes Radio, I am your host Nahida Zaman. My guests today on the line are Dr Desmond Schatz, Dr Mark Atkinson and Dr Robert Levine. Doctors, a very warm welcome to Diabetes Radio. The question today, is it time to mow the GRAS in type I diabetes. Dr Desmond Schatz, you are Associate Chairman of Paediatrics and Medical Director of the Diabetes Center at the University of Florida in Gainesville. You have been involved in type I diabetes research since the mid 80s and have published over 200 manuscripts. Dr Robert Levine, you are a type I diabetes research advocate who has focused attention on the importance of taking a patient’s interests first approach to the discovery, development and delivery of life changing therapies for the prevention and cure of type I diabetes and its complications. Finally, Dr Mark Atkinson, you are the American Diabetes Association eminent scholar under a faculty member of the Department of Pathology at the University of Florida. Doctors, a very warm welcome. Dr Schatz, can you please begin by giving the Diabetes Radio listeners some information on your background, your research focus and some of the key trials you have participated in
DS I am a Paediatric Endocrinologist with an interest and passion for type I diabetes. Like my colleagues who are participating on this call, I have been involved in type I diabetes research for over 25 years and focused on the genetics, prediction, understanding of the mechanisms related to the prevention and ultimately the cure of type I diabetes together with my colleagues, we have been involved in studies aimed at interdicting the course of the disease, have been very much involved with studies such as the diabetes prevention trial, multi centre studies in the United States and in the world, in TrialNet as well as other investigator initiated studies, all of which are using agents aimed at trying to reverse the suicidal process that leads to type I diabetes and that is sort of a summary if you will of the kinds of work, studies that I and my colleagues at the University of Florida have been involved with for the past few years.
NZ Dr Levine, what is your professional background and how did you become involved in patient centred diabetes research advocacy?
RL Thank you. I am professionally trained as a Cardiologist but like so many individuals who get involved with cause advocacy, I made a promise to a loved one, in my case it was my wife, that I would do all I could including using my professional insight and standing to define and validate new approaches to relieve her of the burdens of type I (Diabetes) including ultimately finding a cure.
NZ Dr Atkinson, what is your research focus at the University of Florida and how long have you had an interest in type I diabetes?
MA Like my colleagues, I have been working in the field of type I diabetes research for a period just over 25 years and I suppose I could sum up my research interest in saying I have been working on the addressing of three questions (1) what causes type I diabetes, (2) can we find ways of predicting the years in advance who in the population is at high risk for developing this disease in the future and (3) can we find a way to prevent and/or cure the disease and those three questions have resulted in many programmes being designed that, for example go out and screen populations through blood tests to try and find combinations of genetic and serological markers that will identify individuals again months to years before disease development, to studies to try and examine those individuals looking at what in the environment might help cause the development of the disease say agents such as vitamins and vitamin D3 to bacterial constituents and viruses and finally I am happy to serve with many people here who are trying to do these type I diabetes prevention and reversal trials. Here we have worked with studies ranging from pre-clinical, using animal models with the disease to identify candidates that would be potentially applicable to humans to the actual efforts in human clinical trials.
NZ Dr Levine, your combined extensive experience in the area of type I diabetes culminated in the publication of one of the most important editorials we have seen a while. It appeared in the November 2011 issue of the ADA journal ‘Diabetes’. The editorial was titled It’s Time to Mow the GRAS in Type I Diabetes and Diabetes Radio would like to encourage anyone with either a clinical research or healthcare policy interest in type I diabetes to read this particular article. Dr Levine, what motivated your team to write this editorial?
RL I think we got to the intersection of need from the standpoint of patient need and knowledge, expanding knowledge base in terms of the pathophysiology of type I (Diabetes) and frustration frankly with relative failure of conventional approaches to solve the difficulties associated with type I diabetes and its complications and solve them in a way that is useful from a clinical perspective for treatment over an individual’s lifetime so it seems that the timing was right to put this idea into play, it is an idea that the three of us have shared for many years but now I think as I said, the need, knowledge and level of frustration was at a point where it was appropriate to put these ideas out there and see what reaction we would get.
NZ Dr Schatz, in the editorial you urge for the large scale clinical testing for generally recognised as safe, otherwise known as GRAS-like agents in settings of type I diabetes. You gave an example of a simple experiment which demonstrated improved diabetes management. Can you please recap this story for the benefit of our listeners?
DS Conventionally we have used immunotherapies, immunomodulatory therapies, immunoregulatory therapies, immunosuppressive therapies to again try and reverse the process of these two type I diabetes and again these are being conducted in multi centre studies and in fact are ongoing. I, as a Paediatric Endocrinologist get approached all the time by motivated families and by asking what they can do, should they change their diet? should they change their patterns? what can they do to help ease the burden of diabetes? what can they do to reverse it? and unfortunately there are no therapies as has already been discussed which have been shown to really change the course of diabetes. We always get told anecdotal stories and what I did was to explain to one of the children that as a science project they should try different things and I had heard that grapefruit or really grapefruit extract really improves the postprandial, meaning the blood sugars after one eat. in individuals with diabetes and I urged this family, in fact I urged several families to do this experiment and what they did was they obtained grapefruit rind, they crushed it up and they took it. The child who was 12 years old took the grapefruit rind and then measured blood sugars after he had eaten compared to his own control in which he did not take it, grapefruit rind, and found that his blood sugars two hours afterwards were far superior which suggested in fact that grapefruit rind may have an impact on improving blood glucose control and any therapy which is safe, any therapy which makes the lives of any patient or family with type I diabetes is in my mind, is in our minds, great strides forward and so yes he did not do a double blind controlled study but he did it a single study and suggested that a very benign therapy, a GRAS therapy would in fact improve blood glucose control suggesting to us that maybe we need to do more of these studies and that is part of the impetus for this editorial.
NZ Dr Atkinson, from your viewpoint as a Pathologist what else has convinced your group that it was time to re-address this issue of large scale clinical testing for grass like agents in type I diabetes?
MA I can actually address your question in two ways, first is a notion that we are currently running on behalf of the juvenile diabetes research foundation the world’s largest programme directed at obtaining organs from individuals who have a diagnosis of type I diabetes. This programme operates around the clock 24/7, 365 here in the United States and our goal is to use the organ donor network within this country to try and identify individuals again who have a diagnosis of type I diabetes and one of the notions that we have seen in our four year history is that examination of the pancreas of individuals with type I diabetes or a diagnosis actually is quite heterogeneous and so one of the notions that drives us to think that we need to be more diverse in our therapies is that if you only use therapies that say target as Dr Schatz said, the immune response, there may be people whose disorder might not fully be affected by an agent that would only target the immune response so if we could use therapies that were multi-component and perhaps would not only target the immune response but other constituents say such as the beta cell, they think that would be a good idea. The second reason is from more I would say of not just a pathology but more of a pathoepidemiology perspective, meaning that in the United States, in any given period of time the second reason is not only a pathology based notion but an epidemiology based notion in that we believe that in the United States approximately one to one and a half million people have what has been termed type I diabetes. Most intervention protocols currently are targeted at a very select population meaning that we also believed that in a given year, approximately 20,000 individuals are diagnosed with this disorder and if most trials that are ongoing in the United States examine people who are at the point of diagnosis or within three months of diagnosis, that means that only about 5,000 individuals or less at any given period of time are being subject to much of the in care based investigation in the United States. That is like I said 4,000 to 5,000 people. Meanwhile there is much larger population of over a million type I diabetes patients out there who are not the subject of cure or improved based therapeutics and even of those there is a good percentage that we believe actually have some residual beta cell function in year two, they are not being the subject of much in the way of the investigation so I guess to summarise things, we think one of the other driving issues underlying that must be related to the number of people that would benefit from a GRAS therapy that have a diagnosis of type I diabetes.
NZ Dr Schatz, from your viewpoint as a clinician, other than the ability of these agents to enhance glycaemic control, what other expected benefits could we potentially expect?
DS Ultimately we are talking about improving the lives, the quality of lives of patients with diabetes and that may mean that their regimens are simpler, are easier, yes we have learned about the benefits of the DCCT, of EDIC, their tight control both reduces complications and delays the progression of complications but if we could make it easier as you point out clinically, that would be a great benefit because it is not easy to maintain tight control with multiple insulin shots, with pumps, with multiple blood glucose testing, etc so if we could reduce that burden with a safe drug that would be a major victory. But in addition to that, it is possible that some of proposed GRAS agents may have an effect on the immune system, so to use one of them as an example, the Trichuris suis ova which are really the ova of a pinworm, this may alter the immune system such that the immune system is switched from a more damaging immune system to a more protected immune system. What we believe is that there may be an alteration in the immune system, one from an offensive immune system to a protective immune system and it is possible that we could switch from what we call a TH1 response which is thought to be involved with the destruction of the pancreatic islet beta cells to a more protective TH2 response and by the administration of a benign parasite such as a pinworm it is possible that we could alter that immune phenotype and induce protection.
NZ Dr Levine, many GRAS like agents have been tested in type I diabetic patients in various trials, for example co-enzyme Q10, garlic, magnesium and chromium. The benefits were often neutral or negative, so what has changed, why are you calling for the scientific community to revisit their potential use?
RL As I indicated earlier, we have learned a lot more about type I diabetes and its cause and importantly about some of the pathophysiologic origins of the complications of diabetes, both type I and type II and I want to add to what Dr Schatz has just said with regard to the potential benefits of these agents and from the perspective of a cardiologist, not simply about the beta cell, of preserving beta cell mass or easing glycaemic control in patients with type I, it is also about protecting individuals with type I diabetes from the progression to life limiting and life altering complications. Most of the burden of type I diabetes is in fact the early occurrence of such severe complications as kidney failure, heart disease, vascular disease, retinopathy, blindness and neuropathy. So part of the motivation for putting out this concept of investigating GRAS like agents and supplements that have demonstrated some pathophysiologic potential benefit is around our new understanding of inflammation. Inflammation as a role in the cause and consequence of type I diabetes, both from the perspective of the beta cell and beta cell vitality as well as the development of the macro and microvascular complications of type I. You can look at data from Dr Bramley’s lab here at Albert Einstein, Dr Holmgren at Karolinska, Dr Bruce Freeman here at Pittsburgh, all around agents such as Glutathione or nitro fatty acids or a form of a thiamine vitamin which demonstrates potential salutary impact on the inflammatory pathways which contribute to the development of type I diabetes complications.
NZ Dr Atkinson, does the favourable safety profile of GRAS like therapeutics and agents approved over the last decade also have a role in your call for further research into its role?
MA I believe so and although it is not type I diabetes, I think the diabetes community in general has been really sensitive with the issue of safety as a right, meaning that the products that are on the market that have been subject to re-evaluation and review by regulatory agencies, FDA and EMEA and the like, there has been a number of drugs in the type II space that have been pulled off the market because there are issues of safety. On the type I diabetes side, specifically we have concerns because again this order used to be called juvenile diabetes and it is still in some circles is referred to as such but when you are intervening in juvenile populations you always want to be safe when you are intervening in juvenile populations you especially want to be sensitive to issues of safety so I think that the notion of do-no-harm or trying to minimise the harm that would be caused that we are talking about a disorder that is largely occurring in juvenile populations for which they are many, many years ahead of time, in front of them as well as just some of the cautions that we have seen when you intervene in the endocrine system, I think that they all call and support a notion that if you have therapies out there that are safe and have a history and profile about them, that it makes a strength for our cause that we have been putting forward.
RL And just to add to that, if you look at the large portion of patients affected by diabetes type I but also type II globally and then you look at the fact that diabetes is a chronic disease which individuals have to live with hopefully well for the entirety of their lives, the issues of access, adoption, clinical acceptance, tolerance on the part of patients and cost of medications that have to be taken over individual’s lifetime have to be a primary consideration in what gets evaluated so safe therapeutics that are accessible, affordable and well tolerated over the lifetime of individuals has to be a filter through which we make our decisions about the types of therapeutics which we evaluate.
NZ Professor Schatz, your editorial made a strong case that having a GRAS like initiative is warranted. What would you test and in which populations?
DS One marker that we could test is called C-peptide. C-peptide is a marker of residual pancreatic islet beta cell function and it is known that subjects who have retained C-peptide have reduced complications, both short term such as hypoglycaemia, ketoacidosis as well as a reduction in microvascular, such as Dr Levine has already mentioned, blindness, kidney failure, nerve damage as well as macrovascular heart disease, strokes, heart attacks, etc so any effort aimed at retaining C-peptide would in itself be beneficial so a study which was developed to look at retaining the inevitable loss of pancreatic beta cell function that occurs in type I diabetes would in itself be beneficial. With a design of looking at C-peptide, one could then look at many corresponding variables such as quality of life, reduction in these said complications.
RL I would just add to that that if you look at vascular complications as one area of concern, young adults with type I diabetes, that a very high percentage have some clinical evidence of macrovascular disease even early in life, even as early as their 20s and 30s so developing a study protocol which looked at carotid intima thickening over the course of the years from post adolescent to early adulthood so from age 18 for instance to age 35 and investigating the efficacy of GRAS like agent in arresting the progression of carotid intima thickening would be another sort of trial that could be undertaken to demonstrate prevention of future vascular complications.
NZ Dr Levine, launching a large-scale clinical trial represents a massive challenge. Are there any existing efforts whose design provides a network of type I diabetic patients or subjects at increased risk for the disease and potentially amenable to GRAS base testing?
RL There are a number and two that come immediately to mind, we have the great benefit individuals here in the US of some considerable wealth have decided to deploy that wealth for the benefit of others in the area of finding cures for diabetes and so the Helmsley Trust has created a multi-centre collaboration called the type I diabetes exchange where I think it is as many as 60 medical centres here in the US and elsewhere to recruit individuals who are willing to participate in trials and pre-qualify them for trials so that investigators who are interested in pursuing such trials have a kind of ready made group of individuals who have been profiled who have their medical records in place and biological samples available for looking at those individuals’ progression of disease over time. Similarly the Sandford Health System that is funded Mr Danny Sandford is the largest integrated not for profit healthcare system in the Mid West here in the United States. They have a commitment to deploying GRAS like across their network. That is just two, I am sure that there are others in the age of social networks and mobile technology, self-organising groups of clinicians and their patients would be imagined to be able to come together quite readily if the right proposal was tabled. I did not mention the BREM correlation which is another effort but also it is important to mention organisations like the Juvenile Diabetes Research Foundation which has put together global networks for clinical trials, the National Institute of Health has funded TrialNet similarly is put together and is now much more aware of the potential for GRAS like agents so I think it cuts across the sectors of public and private sector interests in organising the networks of individuals and clinicians who are interested in doing clinical trials relevant to finding cures and new therapies for type I diabetes so we should not limit the consideration to just one or two networks, it should be understood that really it is a global interest and developing these sorts of networks.
NZ Dr Schatz, would changes need to be made to the design of randomised control trials?
DS I that this is an opportunity to perhaps develop more novel trial designs and I think particularly of a study that is being conducted by the research team at Brigham and Women’s Hospital at Harvard Medical School over the next several years. This is a study in which the investigators are using vitamin D and fish oil supplements to ask the question as to whether they would prevent cancer, heart disease and stroke and this study is called the VITAL study. Although it is a large scale randomised clinical trial, what they are doing is they are doing this by mail so it simply involves a survey before and afterwards, patients are sent their drugs in the mail and there is very little involvement other than completing these surveys and keeping up to date, so what it is doing is it is reducing the burden on participants and I think that for a study that has a minimal side effect and is not a burden to frankly the individual or the investigator and offers benefit, we can think of more provocative designs which will also be cheaper as we move forward in performing such studies.
NZ To Dr Atkinson, a significant hurdle to your proposals will shortly be the intellectual resistance and perhaps fear amongst healthcare professionals. Is there a chance that individuals agreeing to such a cause would be considered unprofessional?
MA This is one of our major concerns and as you noted a hurdle that we believe will be present and is currently present in terms of trying to bring GRAS therapies to practice, meaning that it would be one level to make an argument that something that would be simple or common place or maybe something that derived from traditional medicine might be used because there might be a degree of scepticism there but when you add on top of that that the capitalistic market place which we live in which is exceptional, it does allow opportunity for people to make promotion of products, they are free to do that and unfortunately many of the GRAS like compounds or things that would be rightly or wrongly and I will say sometimes wrongly consider this GRAS compound will be touted on in commercials. You will see them pop up on your computer screen, you will see them in what they call infamously infomercials on television and so there is with all of these types of activities there is a sense of if I go forward with this when there is the essentially entirety of the medical pharmaceutical industry out there that I will be somehow perceived as less than professional or unprofessional so it is not that we that think it is an issue that cannot be overcome, nothing will overcome doubt like success, there is certainly examples out there that we think could be used to argue for the case and so we recognise that this is a challenge but we are not letting it dissuade us from moving forward.
NZ And one last question Dr Levine, would healthcare policy and research funding priorities also have to change on some level?
RL The healthcare policy and research funding priorities do have to change to a degree and I think that is why I got involved in advocacy. It really does come from the community of patients affected by type 1 diabetes and its complications and their loved ones and clinicians like Dr Schatz and basic sciences like Dr Atkinson and the group at University of Florida and groups similar to them all over the world who take a person-centric view who sit down across the table from their patients and say alright, what are the challenges of type I diabetes and the complications, how does it affect day to day, what can we possibly do today that we know is safe that we can then try to out to see if it is in fact efficacious in improving lives and what shall we be looking towards tomorrow based on our expanding knowledge base of mechanistic cause of type I and its complications and as Dr Atkinson said, where there are not commercial interest there is often less commercial interest or frankly academic interest from the standpoint of standing in an academic community so one of the things we have to do as individuals who are involved in leadership in academic centres is persuade our colleagues that this is important and that their careers will be enhanced by investigation utilising agents that are in this arena so it is about advocacy, it is about academic interests, it is about people’s careers, it is about commercial application but at the end of the day it is about what we can do as individuals, as scientists, as family members to improve the lives of our loved ones and do it in a fashion that is replicable across large scale populations of patients.
NZ Dr Levine, Dr Atkinson and Dr Schatz, that you so much for taking the time to speak with Diabetes Radio today, we wish you all the best with your research.