Raghu Mirmira 2018 Transcript

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Freed: This is Steve Freed and we’re here at the 78th Scientific Sessions from the American Diabetes Association. And we have a special guest here, who’s presenting, and it’s Raghu Mirmira.

Mirmira: That’s right.

Freed: Did I get that right?

Mirmira: Yes, you did.

Freed: Okay. First try, that’s very cool. But anyways, maybe you can start off with telling us a little bit about yourself.

Mirmira: I’m the Director of the Diabetes Center at Indiana University and I am also a physician and a researcher. And I lead a lab that studies both type 1 and type 2 diabetes, very basic aspects of how the disease develops and then potential treatments that we first conduct in animal models. And then we also have a group within my center that does clinical studies. I was trained as an endocrinologist and have been doing diabetes research for about 30 years now.

Freed: And what’s the title of your presentation?

Mirmira: So, the title of my presentation tomorrow, Monday, is Type 1 Diabetes is More Than Just an Autoimmune Disease.

Freed: And maybe you can kind of give us a quick over view of that. (This won’t go out before your presentation.)

Mirmira: Sure, sure. Well, what I’m doing is participating in a what is maybe sort of lightheartedly called a debate against one of my colleagues who takes a stronger position that type 1 diabetes is really just an autoimmune disease. And my perspective is, “Well, that’s part of the story, and that there’s more to type 1 diabetes than just autoimmunity.” And I think that that’s reflected and the fact that a lot of trials for type 1 diabetes that have targeted the immune system have had really only modest success. Some drugs work modestly and other drugs don’t work at all, raising the possibility that maybe we’re missing a part of the disease that we aren’t really targeting with our drugs. And so, my presentation tomorrow will focus on the evidence that would suggest that we should be really looking at other aspects in addition to autoimmunity.

Freed: So, you probably have a lot of information or you’re an expert when it comes to autoimmune issues. And maybe you can talk briefly about why beta cell transplantation has not really taken off and been that successful and has a lot to do with autoimmune treating that.

Mirmira: Yeah. So, again, it depends on who you talk to. The people who really advocate for beta cell transplantation certainly have an argument to make that despite the fact that sort of the gold standard, being insulin-free, isn’t achieved long-term with transplantation, that there are other benefits to transplantation such as protection from severe hypoglycemic episodes for example. And that’s true. That’s true. But part of the reason it hasn’t entirely taken off is not just because of autoimmunity, and I think that’s maybe a very small aspect of it. It’s what we call alloimmunity. You’re taking cells from somebody else and putting in somebody else. You have to use immune suppression. And those immune suppression agents also have a tendency to impact beta cells and their survival. And then there’s of course alloimmunity, that is your immune system seeing cells that are not part of you and want to reject those. And then there’s another component, of sort of an instantaneous loss of beta cells right after transplantation. It has nothing to do with immunity but what we call compliment activation, so it’s just the body’s way of just causing immediate lysis of cells, so it’s kind of complex. And really for transplantation purposes, I think we have to think about more than just autoimmunity but these other components as well.

Freed: So, what is your feeling about the regeneration of beta cells because I think recent research has shown that for type 1s that there’s still beta cell activity in some way, shape or form?

Mirmira: Yeah. And that’s actually one of the comments that I’m going to be making in my talk tomorrow. It’s that the traditional perspective that in type 1 diabetes you don’t have beta cells at all largely arose from studies in mice, right, in animals. But when we started analyzing humans we started to see that there are actual beta cells there, maybe they don’t function normally or maybe there’s not enough of them. But it certainly provides hope that maybe there’s the potential to regenerate some of these cells. And the other thing, I guess, you should ask is if we study those residual cells in somebody with type 1 diabetes, can we learn something about the cells that are most resistant to autoimmune attack and maybe those are the cells that we really need to kind of increase the amount of. And if there’s ways we cause those cells to regenerate which is possible, that might be a really more promising approach in the future.

Freed: So, if they asked you to look into the future from your knowledge — a cure for type 1 is around the corner, my personal feeling. We’re doing so much research and we’re learning so much. And it’s kind of simple, you replace the beta cell with a bunch of beta cells and you’ve cured it. Type 2 is another type of disease. It has to do with obesity. And education — and there’s just so many things involved that it’s a whole nother disease. Technically, they shouldn’t even be called diabetes, the same, because they’re completely different. So, where do you think the type 1 cure may come from?

Mirmira: So, that’s a great question. I think one of the things that we have to sort of temper in some respect on our enthusiasm is that as you pointed out that type 2 is kind of complex because there’s so many variables in type 2 diabetes. One of the points of my talk tomorrow is really sort of emphasizing that type 1 diabetes is probably as just as diverse and complex in many ways, because all of the things that we thought about the disease, being an autoimmune disease, an attack on beta cells, is really not entirely true across the board. And so, different individuals exhibit different what we call phenotypes. So, the reality is that it turns out that one size will probably not fit all in type 1 diabetes. And so, this big push internationally for personalized medicine, I think applies as much to type 1 as it does to type 2. And so, where will the cure come from? I think that one thing is sure and that is that we do need more beta cells, at least more functional beta cells in type 1 diabetes. And if we’re talking about a real cure, I think it will come from two angles. Angle one would be how do we increase the numbers or functions of beta cells that remain, and then the other angle is how do we keep the immune systems at bay. Once it gets activated, it’s going to — every time there’s new beta cells it’s going to see them. So, really the question will be the two approaches. We’re going to have to think about beta cells and how we can hide them from the immune system. And we’re going to have to think about the immune system and how to keep it at bay. And that’s really the point of my talk tomorrow is that it’s more than just the amount of autoimmune disease. We’ve got to think about the beta cells.

Freed: It’s interesting. I appreciate you sharing that information.

Freed:  So, how does having type 1 today differ from 15, 20 years ago?

Mirmira: Well, I think that our treatment of type 1 diabetes has advanced quite a bit. I think many people would look at it and say, “Geez, we still give insulin.” That’s true. We did that beginning in 1923 when insulin was discovered, but what we have now are many new things. So, we have different types of insulins that can be really used in a very personalized way. They have different kinetics of action. And then the second thing is we have different modes of delivery. So, now we have pump systems and we’re developing closed-loop systems. There’s also people that are studying different types of insulins that might be smart insulins, so to speak, that only act when the blood sugar is high. And some of these prototypes, if you will, are already out there, so there are a lot of people that are using different types of insulins today that didn’t exist 15 years ago. And then, certainly the pump and drug delivery technology has improved substantially. So, I think for those reasons there are — it’s a very different disease in the way we treat it today. And I think for that reason it’s not the disease that’s so easily treated by a general practitioner whether it’s a pediatrician or an adult practitioner. I think it really does require specialized therapy that not even your average endocrinologist can do. I think there really is a new field of diabetology. And I think a lot of these more advanced systems requires multidisciplinary care with diabetologists, nurse practitioners, nutritionists, social workers, so it’s a very different disease in that respect.

Freed: And what are the new concepts emerging in type 1 diabetes today and how may they change the way we treat diabetes now and into the future?

Mirmira: So, as I said that, apart from the technologies which I think are really beginning to move rapidly, the area that I think is really quite exciting is the area of induced pluripotent stem cells. I think that’s exciting because it can potentially get over one big barrier that exists in transplantation of beta cells today and that is this concept of alloimmunity, recognizing a cell that’s not coming from yourself. So, that we can take your blood cell or your skin cells and then convert them into beta cells, I think means that there is the potential for an endless supply of your own beta cells. And I think that’s going to be a very important tool going forward. But the other thing that I think has been emerging in the last few years is understanding that the islet is made up of more than just the beta cell. There are alpha cells, pancreatic polypeptide cells, and some anastatin producing cells. So, I think we’re going to need to be able to recapitulate that little organoid, understanding the complex interplays between the different cell types. So, I think going forward I’m really excited about induced pluripotent stem cell technology. I think that it really does offer the potential for a cure. If only that somebody requires transplantation every six months of their own cells, I think most people would find that acceptable if they could be insulin free in the interim. And then there are other — with that in mind, there are other encapsulation technologies to preserve the longevity of these cells. So, I think apart from technology, I think our understanding of how to create new cell types using your own cells as assort is really an exciting avenue.

Freed: And a lot has been said about the role of ER stress in diabetes.

Mirmira:  Yeah.

Freed:  What is ER stress? Is it a good thing or a bad thing?

Mirmira: So, ER stress is something that really came into vogue I would say, probably about six or seven years ago. Our group at Indiana and a few other groups around the country proposed that when a beta cell is exposed to certain environmental stresses, whether it could be pathogens such as viruses or other inflammatory insults, cells then begin to produce proteins within their cell that become misfolded. And because proteins run through what’s called the endoplasmic reticulum, these misfolded proteins trigger this whole pathway within the beta cells that causes the cells to ultimately die. And so, we now believe that this whole concept of ER stress probably accounts for how beta cells trigger autoimmunity, because they’re starting to produce these proteins in a sense that the immune recognizes as foreign, so that starts autoimmunity. But then this concept that ER stress proceeds means that the cells die, not as a result of autoimmunity but because it’s a sort of self-programmed death. So, ER stress is both a good thing and a bad thing. It’s a good thing because it’s really designed to allow the cell to try to recover while the insult goes away. It’s a bad thing because as we know in type 1 diabetes whatever that insult is doesn’t really seem to go away, and then so the cells are programmed to die. So, what we need to do in studying ER stress is identify the right points in the pathway that we can intervene. Small molecule drugs for example can preserve beta cells. And if we deliver those drugs perhaps early enough we can even prevent the initiation of autoimmunity. So, I think the whole idea of ER stress is a concept that really allows us to begin thinking about how we can begin treating the beta cell rather than the immune system.

Freed: What types of resources have been instrumental in advancing type 1 diabetes research?

Mirmira: So, in terms of resources, I think, there have been — I think clearly money is an important component. So, major advocacy groups like the American Diabetes Association, Juvenile Diabetes Research Foundation or JDRF, and a whole host of other organizations that raise awareness to diabetes that point out the importance of different aspects of not just treatment but lifestyle. And then, advocate for research at the federal level which is really where the majority of money comes from but also at the industry level, because particularly with type 1 diabetes it’s not a major focus of industry because the prevalence of the disease is not as great as type 2. So, I think in terms of resources, I think, advocacy groups research dollars from the federal government and then convincing pharmaceutical companies to consider either re-purposing current therapies or to really do research in this area, I think will make a big difference.

Freed: How long have you been engaged in diabetes research and what motivated you to commit your career to researching the disease? Because what I find in dealing with people with diabetes, they are the most active people that either have it in your family, okay, and as a little kid, your goal is to cure diabetes, or you have it yourself. It’s amazing how many people involved in diabetes all walk around with insulin pumps. So, what was your reason for getting involved?

Mirmira: So, I got involved when I was a MD PhD student back in the mid 1980s. And I got into this profession, sort of the physician, scientist, profession because I wanted to be able to leverage my passion for research into addressing a disease. And you know with many people who might select diabetes as a researcher, oncology, or neuroscience, many people have a personal story to tell. The truth of the matter is that I didn’t have a personal story. I wasn’t personally afflicted by the disease or had a family member. But for me, it was actually my mentors. So, I came in, I worked in a lab to do my PhD research. And my mentor who has since passed away, Howard Tager, was a huge advocate for type 1 diabetes, was an advocate for the JDRF, the ADA, the NIH at the time. And I think what he instilled in me was that we were still in our infancy in understanding the disease and then treating the disease. In my lab, his goal was to identify new insulins that could behave differently and so that’s what I studied. I studied making different insulin analogues. And lo and behold, almost 30 years later and almost everybody who has type 1 diabetes is being treated with an insulin analogue. And so, what drove me in this direction was the understanding that I could make a big different in a disease and it wasn’t just spending three or four years doing it. It was a career and that was really why I became a physician scientist, because I knew that I wanted to do something where my research could have an impact in disease. So, for these 30 years I did graduate research, I trained ultimately as an endocrinologist, and then I got a job in academics doing basic research, studying diabetes. And as I mentioned I study both type 1 and type 2 because there’s a little bit of overlap in both diseases. Probably the majority of my work is in type 1 diabetes and I’m still very passionate about it.

Freed: Is there anything you can point to where it was that moment in time when you discovered something or a new fact?

Mirmira: So, there were probably a couple of those moments. But if you ask me for a single moment in time, I think it was when I was a graduate student and I think this is true for most people, their formative years are going to be so very critical in convincing them that this is what they want to do. If it didn’t succeed then, then you go down a different path. And for me, I was a chemist as a graduate student. I was creating insulins and then I was testing them in cell cultures. And then, what happened was just as I was nearing the end of my graduate training my mentor told me, “You know, you have to begin to apply everything that you do chemically to a living being.” And so, what we then did was we did studies where we took these analogues that we had hypothesized based on our work in vitro and actually moved them into animals, so we did work in rabbits. And the amazing thing for me as a young scientist was seeing that all of the chemistry that I did really resulted in the biology that we expected. And that was sort of a defining moment because I really saw that the process of translating ideas into biological systems was possible. And then, really my whole career was defined a process of translation, getting ideas not just from the test tube into animals but getting them from animals into humans. So, we’re doing quite a few human studies now. So, for me at least it’s that progression, that process, and that initial set of experiments where we actually moved from chemistry to biology was really quite a defining moment.