Trying to Make a Difference for Those With Type 1 Diabetes

Interview by Rona Williamson
Mark A Atkinson is currently an Eminent Scholar for Diabetes Research at the University of Florida (FL, USA). The author of more than 300 publications, Dr Atkinson is beginning his 29th year of investigation into the field of Type 1 diabetes, and has been the recipient of multiple scientific- and humanitarian-based awards for these efforts. He has also been active in a leadership service to the Type 1 diabetes community, with active administrative or advisory service to the Juvenile Diabetes Research Foundation (JDRF), the American Diabetes Association (ADA), the NIH, the Immunology of Diabetes Society (IDS) and a variety of companies from the pharmaceutical and biotech industry. He is a charter member of the NIH's Immune Tolerance Network Scientific Advisory Board, a member of the External Scientific Advisory Board to the NIH Beta Cell Biology Consortium and a member of NIH TrialNet. He is also the executive director for the Network for Pancreatic Organ Donors with Diabetes (nPOD). Dr Atkinson is an internationally recognized authority on multiple aspects pertaining to Type 1 diabetes, with particular interests in disease prediction and prevention, the role for environment in the initiation of the disease, stem cells and pancreatic regeneration, pancreatic pathology, clinical trials seeking to prevent or reverse the disease and the identification of markers of tolerance and immunoregulation.

What Lead You to Specifically Focus Your Research Efforts on Type 1 Diabetes?

This question is a great one to start with, and for 25 years, my answer has always remained the same.

Type 1 diabetes is a terrible disease; a disorder in need of a cure. I believed then, and remain in belief until this day, that my efforts have the potential to have a positive impact for those with this disorder.

The story behind how I came to that conclusion had a somewhat peculiar start. In the early 1980s, I had what I now look back on as representing a 'premature mid-life crisis'. In other words, I was a 20-something- year-old looking for a career that would combine my curiosity for research with a strong desire to help others. Through what could be described as either divine intervention (to the spiritually faithful) or plain dumb luck (to the agnostic), I ended up as a graduate student at the University of Florida (FL, USA). The road to that situation started by my retrieving, out of a trash can, an advertisement for the program. When arriving at the University of Florida as a new graduate student, I had no intention of becoming a Type 1 diabetes researcher, yet I was drawn to the passion for understanding this disease as exemplified by an individual who eventually became my mentor at that institution, Dr Noel Maclaren. Noel was quite well known to the Type 1 diabetes and endocrine research communities at that time for a number of his investigational 'firsts', ranging from studies involving islet cell autoantibodies to the diagnosis and classification of polyendocrinopathies. During the process of my choosing a laboratory home, Noel noted a requirement that I spend time at a childhood camp for those with Type 1 diabetes. He suggested that to really understand what it would take to make a difference in the lives of those with the disease, given my lack of knowledge regarding the disorder, I must spend time living shoulder-to-shoulder with children with Type 1 diabetes. Hence, armed with sunscreen and mosquito repellent, I attended my first diabetes camp. To call it impactful, in retrospect, would be an understatement. I had no idea of the challenges that individuals with the disease face 24 hours a day, 365 days a year. When meeting with Noel following that trip, he asked about my newfound thoughts on the disease as well as what level of commitment I would provide to research in Type 1 diabetes. To this day, I still remember his advice during that session. Namely, "If you were to pursue three things – find out what causes Type 1 diabetes, identify a means to predict … years before symptomatic onset those destined to develop the disease, and identify a way to prevent and cure it – you will have done a good thing and had a successful career in diabetes research." Now, nearly 30 years later, I still follow those three goals put forward that day.

In terms of meeting those goals, the news has been both good and bad. Good in that a community of investigators, one that thankfully includes myself, has made impressive progress toward that second goal. Type 1 diabetes can, through a combination of genetic, metabolic and immunologic tests, be predicted years in advance (i.e., risk for disease determined). The bad, perhaps even sad, news is that much work remains on the first and third goals. These goals do, however, form much in the way of major research interest and activity for me as well as many others.

Another 'legacy' gift, if you will, provided by Noel during my period of training was his pattern for having research efforts occur with families be highly relational and personal, not merely one of labor. With this, both I and other young trainees at the time (including current colleagues Dr Desmond Schatz and Dr William Winter [University of Florida]) learned to extend inordinately large amounts of time related to studies involving family members of those with Type 1 diabetes who did not themselves have the disease. This set up an environment of 'trust' and a degree of relationship that over the years since has lasted to this day. Indeed, many of the children we saw with Type 1 diabetes in the 80s now routinely return to us as parents, with concerns over their children developing the disease.

As a result of this, my colleagues and I have been naturally drawn to volunteer for many lay organizations organized around the theme of Type 1 diabetes; most notably, the Juvenile Diabetes Research Foundation (JDRF) and American Diabetes Association (ADA). My first efforts with such entities began in 1989, and in the time since, relationships have formed with dozens and dozens of lay persons (both patients and their family members), most revolving around the notion of finding a cure for Type 1 diabetes or improving the lives of those with the disease. These relationships have resulted in countless interactions allowing for expressions of joy and laughter, as well as those of sadness and disappointment. Indeed, in what might be best be described as an example of 'social symbiosis', I believe my words/actions have provided hope to those individuals to keep pushing forward. In turn, their stories of need have inspired me to move forward. I have said it often: interacting with individuals with Type 1 diabetes and their family members is my favorite part of what I do, day in and day out, with respect to Type 1 diabetes.

Finally, I would be remiss if I failed to mention the support of my family to this cause. My children grew up in an environment where it was clear, 'Dad wants to help those with diabetes.' This continual support and affirmation has included many years of family sacrifices for Dad to pursue this cause.

Hence, the combination of four items: need, close colleagues, interactions with those with the disease and a supportive family have led to my having a passion for studies of this disease.

Would You Term Type 1 Diabetes Mellitus as an Autoimmune Disease?

Recently I coauthored my 300th research publication, and while I have not checked the accuracy of the statement I am about to make, I would believe it quite true. For those articles that I coauthored related to Type 1 diabetes (which are the vast majority), somewhere in the beginning prose would be a variation of the following sentence:

"Type 1 diabetes is an autoimmune disease that results from a cell-mediated destruction of the insulin-producing pancreatic β cells."

With surety, I am not alone in making this statement. Indeed, I would venture to guess that more than 90% of articles related to the pathogenesis and natural history of the disease pose some variant of this declaration. It is, in short, dogma … likely the biggest dogma associated with Type 1 diabetes, perhaps only surpassed by some form of a statement that individuals with the disease must take exogenous insulin replacement therapy (the most obvious of declarations).

However, the timing of the posing of this question is profound in that at perhaps no other time in my Type 1 diabetes research career have I been more confused as to how to answer the question.

Do I believe there is autoimmunity in Type 1 diabetes? Without question.

Do I believe autoimmune mechanisms contribute to β-cell destruction in Type 1 diabetes? Again, without question.

However, based on a series of events … individually small but collectively large, I am being induced to quietly perform an intellectual 'self-assessment' of my beliefs to the specific notion as stated in the question.

Support for an autoimmune nature of Type 1 diabetes is found in many places. Associations with genes that are the major regulators of immune responsiveness (e.g., MHC), autoantibodies against β cell self-antigens (e.g., insulin, glutamic acid decarboxylase, IA-2 and so forth), inflammatory infiltrates within pancreatic islets cells and beneficial (even if only temporary) metabolic responses to immune-mediated therapies all point towards an important role for autoimmune activity in the disease. Beyond this, if one takes into account studies of animal models, the evidence supporting a role for autoimmunity is even stronger, as experiments have been designed to directly show the autoimmune nature of the disease.

Yet, as noted recently, I have been impressed by findings (by ourselves and many others) that at least open the door … if only a small crack, that mechanisms related to the β cells themselves may contribute to their own demise. To be clear, this is not a novel notion on my part … indeed, a famous article published in the 1980s put into play the concept that Type 1 diabetes may be the result of 'suicide' of the β cell, rather than 'homicide' induced by the immune system.^[1]

My increasing doubts regarding the strict autoimmune nature for Type 1 diabetes have been fed by findings in the pancreases from persons with the disease, as well as organs examined from those prior to disease onset (i.e., autoantibody positive yet nondiabetic). These efforts suggest that persons with, or at increased risk for, Type 1 diabetes have smaller pancreases than age- and BMI-matched subjects, their pancreatic islets are rife with unusual characteristics (e.g., decreased glucose transporter expression, increased MHC class 1, decreased glucokinase, diminished expression of glucose transporters and so forth), as well as vascular changes (both exocrine and endocrine) that combined, at least in my mind, support a potential causal role for b cells or the pancreas itself to induce the disease.

With these findings, I would predict that much in the way of effort will be extended by researchers over the next few years to understand the contributions of autoimmunity, as well as b cell abnormalities, to the formation of Type 1 diabetes.

What has Been the Greatest Achievement in Your Career so Far?

If allowed, I would note a 'tie' for two activities that I am particularly proud to have been a part of. One is scientific … the other humanitarian.

On the science side, I am honored to have been associated with the establishment of an organization known as the Network for Pancreatic Organ Donors with Diabetes (nPOD). This effort began in 2006 following nearly a year of planning and is one for which I continue to serve as its Executive Director. nPOD, with financial support from the JDRF, supports research utilizing transplant-grade human tissues obtained from organ donors for the purpose of better understanding the causes of Type 1 diabetes, as well as to identify ways by which the disease might be cured. nPOD collects tissues (i.e., pancreas, spleen, whole blood, serum, lymph nodes, pancreatic lymph nodes, skin and bone marrow) from a variety of patient groups including: Type 1 diabetes (from recent onset to any duration); autoantibody positive but nondiabetic; Type 2 diabetes; cystic fibrosis-related diabetes; pregnancy; bariatric surgery; childhood obesity; and, of course, 'controls' (persons without any form of diabetes). Logistically, nPOD is quite difficult to operate (24 hours a day, 365 days a year).

Seeing nPOD form was, in a way, the result of a long research journey. By the mid-2000s, I and a number of other researchers, along with the JDRF, became of the belief that one of the major reasons Type 1 diabetes was a disease without a cure revolved around the notion that the vast majority of research studies on that topic involved the use of animal models for the disease. To be clear, I have nothing against animal models. I myself use them routinely. It was just that due to a variety of factors (e.g., lack of funding, organizational challenges and logistics), researchers did not have a straightforward means to study these tissues. When nPOD began in 2006, our original effort provided tissues to six projects. As of the time of this writing, nPOD now supports over 120 projects worldwide. While I consider nPOD a success, my rationale supporting this belief finds its basis in many ways. First, nPOD has a goal of changing the way Type 1 diabetes research is performed through increased collaboration and improved communications. Thus far, a profound level of success has been seen in both areas. Second, I firmly believe nPOD has the chance to 'rewrite the textbooks' on how Type 1 diabetes develops. Thus far, nPOD is making steps toward that notion.

For more information about nPOD, our award-winning website may be of help.^[101]

On the humanitarian side, I would posit my recent efforts attempting to see insulin become available to those in third world countries is also an effort worth noting, if only for the purpose of increasing awareness with this article.

This portion of my career emanated from a truly serendipitous start; I took my first medical missions trip to a third world country (Haiti) some 15 years ago. This was a life-changing experience and one that year after year, increasingly gains my attention and effort. Indeed, in the years since, I have not only been to Haiti some 15 times but, have been to impoverished areas within a number of nations (e.g., the Philippines and Nigeria).

If allowed, I would like to share a very personal encounter that has, with time, served as the ultimate interface between the 'book work' of caring about those with Type 1 diabetes and truly caring for those in the third world. What do I mean by this? Take the example of Marie. Marie was (as I recall) a 24-year old Haitian … bright eyed and energetic, whom I met in a Haitian hospital I would not, in my worst fears, wish on my enemies – dark, without much in the way of professional care, with an arid stench that burns into one's senses. Armed with but one leg, Marie was ebullient about life, its future and most importantly … the blessings of having a sibling in Miami who would continue to supply (through circuitous means) insulin to keep her alive. Oh, and if I failed to mention this, my meeting with Marie was mere hours before she was to have a second total leg amputation for her battle with diabetes.

Let me repeat this. 24 years old. A (soon-to-be) double total amputee with Type 1 diabetes. But joyous … with infectious nature, to be alive?

How does one deal with this?

One seeks opportunities and trust me, they are out there. Indeed, I truly believe there are a number of settings where individuals at various settings in diabetes care … have the opportunity to change lives at a global level.

Indeed, as shared with me recently, the number 1 killer of persons with Type 1 diabetes is lack of access to insulin.

The number 1 killer.

Is it me, or is this amazing? In 2013, nearly 100 years following the general availability of insulin, people die for lack of access? Hence, when you ask what I am proud of, it is my efforts seeking to draw more attention to this need.

To achieve this, I would note two efforts that are of potential interest to the community at large. There are many organizations globally that are tackling the issue of insulin access – many organizations and all worthy of praise. However, there are two that predominate in that cause. Both, interestingly, have their origins in Australia. The first is Insulin for Life; the second, Life for a Child.

I would encourage all in your readership to review these efforts in total. However, for the purposes of this interview, I would note the intention of Insulin for Life USA to join with its global partners, to identify a means to provide insulin to 100% of the worlds population in need of this life-saving drug by 2022; the 100th anniversary of general availability of this agent for those with the disease.

For this, I am incredibly proud, for the notion of working with many, to make a difference.

Are There Any Groups of Researchers/Institutions That are Conducting Work That You Admire?

Without a doubt!

But first, to be clear, I am extremely proud (and blessed) to have what I believe are some of the best researchers and clinicians in the Type 1 diabetes community as my colleagues at the University of Florida. On the basis of any of a number of metrics (e.g., research funding, ranking for the quality of clinical care such as US News and World Reports, the impact of publications, number of clinical research trial, and so on), our Type 1 diabetes research program has both a national and international reputation. Beyond this, its impact extends beyond the local walls. University of Florida physicians and researchers have active leadership positions in a variety of government-supported organizations (e.g., NIH National Institute of Diabetes and Digestive and Kidney Disorders TrialNet, NIH National Institute of Allergy and Infectious Diseases Immune Tolerance Network), not-for-profit/private foundations (e.g., the JDRF, ADA, the Helmsley Trust) and for-profit entities (i.e., pharmaceutical and biotech company scientific advisory boards). Finally, our staff excel at making Type 1 diabetes patients and their family members priority number one. My colleagues and I continually take phone calls, answer emails, provide lay lectures and participate in face-to-face meetings with such individuals all for the purpose of providing answers (when possible) to important questions and most of all, provide hope.

Extending beyond the University of Florida, I find encouragement in the work of many in Type 1 diabetes research. Naming such persons in an article like this is a bit challenging in that, just as can happen at the Academy Awards when an awardee 'slips' and fails to say thanks to a person responsible for a particular accolade, I fear making such a mistake here. With that caution, I will take a moment to mention a few individuals and groups that I admire, in particular.

The first among these is Dr George Eisenbarth, a long-time friend, frequent collaborator and oft coauthor. If pressed to say which individual in Type 1 diabetes was 'the most influential in the last quarter century', a number of names come to mind. However, even with this, I believe George would be the clear answer. George lost his life in November, 2012 following over a year-long battle with pancreatic cancer. In response to his loss, I authored an 'in memoriam' article for the journal Diabetologia.^[2] When agreeing to write that work, my initial thought was that penning my thoughts would take an afternoon … perhaps 3 h. The reality was far different; nearly three full days. I found myself engrossed in his history, writings, logic and accomplishments. Without question, he provided the model to explain the natural history and pathogenesis of Type 1 diabetes that nearly everyone, for a period of more than 25 years, has utilized. My thoughts are not singular here… other written memorials are in process, awards are being named after him, and honorary dinners being undertaken. Long after these pass, the impact of his research will last. Indeed, his insights are already missed.

George was also a member of a Type 1 diabetes research group that I particularly admire, the so-called 'Brehm coalition'.

Beyond this, there are at least two individuals from whom I have learned much – namely William Brehm and David Panzirer. Both have family members with Type 1 diabetes and have given much in the way of their time and resources to finding a cure for the disease while their professions could clearly take them elsewhere.

Currently, at the Diabetes Center of Excellence, University of Florida, an Innovative Clinical Trial is Being Conducted That Attempts to Preseve C-peptide in Patients With Long-standing Insulin-dependent Diabetes. Can You Give us a Little More Background Information on This Trial, Your Involvement and What Makes it Both Unusual and Important?

One of my past activities that makes me most proud is that working together with my colleagues at the University of Florida, I have been involved in the 'bench to bedside' or 'translation' of no less than seven therapies for those with or at risk for Type 1 diabetes. For many, seeing that happen once or twice in a career would be considered rewarding. However, by my laboratory maintaining a notion that everything we investigate must, at some point in time (even if theoretical), benefit the patient with Type 1 diabetes, we have seen an unusually high number of such events.

In the early 2000s, Dr Schatz and I put forward what at the time was an innovative, if somewhat controversial, notion calling for 'combination therapies' in approaches seeking to prevent or reverse disease. This was followed shortly thereafter by our movement to what is commonly called in the pharmaceutical industry a 'repurposing' of agents to identify drugs already subject to regulatory approval, and for which the safety profiles were already well established.

Through a process that involved what in some ways could be called a 'bake off' using combinations of up to nine different agents seeking disease reversal in the nonobese diabetic mouse model of Type 1 diabetes, we fell upon a combination that was particularly attractive: antithymocyte globulin plus granulocyte colony-stimulating factor. After establishing our strong interest in this combination, we were challenged by the aforementioned Helmsley Trust to design a truly innovative clinical trial that would benefit those with the disease.

We at the University of Florida participate in numerous clinical trials in Type 1 diabetes research. One of the established tenants for essentially all such efforts is the need to intervene relatively soon after disease onset (i.e., within 3 months or 100 days after diagnosis). While we understated the theoretical benefit of this form of intervention, we also know that many people with so-called 'established' disease (i.e., beyond 100 days) also desire to see therapeutic benefits from such interventions. Hence, the notion for our pursuing efforts in such individuals. Hopefully, by the end of 2013, we will see whether or not our pursuits were of benefit.

Finally, do You Have Any Words of Advice You Would Give a Young Researcher Entering the Field of Endocrinology and Metabolism?

First, while the pathway to where I am now has been far from a perfect one, if I had to say what activities helped keep me on the path, I would merely review some of the themes expressed above. Grow to understand what Type 1 diabetes is by spending time with those with the disease (i.e., do not let it be just a disease you understand from reading articles on the internet). Do not spend a lot of time on efforts that fail to have a clear pathway to benefit those with the disease; the rewards will be far greater. Build relationships … with many and carefully consider their counsel.

Finally, there is but one quote in my office … located on my desk. It is one I strongly believe in:

In order to achieve great things, you must be prepared to fail mightily.