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Carla Greenbaum Transcript

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Steve Freed: This is Steve Freed with Diabetes in Control and we’re here at the American Diabetes Association 77th scientific session 2017. We’re here to present you some really exciting interviews with some of the top endos from all across the world. And we have a special guest with us, Carla Greenbaum, MD. First, tell us a little bit about what you do, your type of practice.


Carla Greenbaum: Sure, thanks for asking and I’m thrilled to be part of Diabetes in Control, which is a great service I think to the community. I work at the diabetes program at the Benaroya Research Institute, which is Seattle. So my job is primarily clinical research. I do see patients but primarily my job is really doing research and I’ve been doing that for almost 30 years now. The whole idea is that for many years we’ve been looking to find ways we can predict who is going to get type 1 diabetes and what we can do to prevent people from getting the disease, and that’s our area of research.

Steve Freed: Type 1?

Carla Greenbaum: Type 1 diabetes is our focus. Benaroya Research Institute is all about immune diseases. We actually study across autoimmune diseases, so type 1 diabetes, multiple sclerosis, rheumatoid arthritis because what we learn from one disease is very applicable to another. So that’s our entire research focus of our entire institution.

Steve Freed: What’s the title of your presentation here?

Carla Greenbaum: I was talking about disease modifying therapies in type 1 diabetes.

Steve Freed: I always like to say “when are we going to have a cure?” and the answer is in 5 years.

Carla Greenbaum: And 5 more dollars right? That’s what it is.

Steve Freed: And they’ve been saying that for over 50 years.

Carla Greenbaum: Sure.

Steve Freed: But your research isn’t about a cure for diabetes.

Carla Greenbaum: Well, it’s actually related.

Steve Freed: Yeah it is related. It’s how to prevent type 1 diabetes, which is almost because in 100 years there won’t be anybody with diabetes so I guess in one way it’s a cure for diabetes but not for those that already have it.

Carla Greenbaum: Well, I’d like to just if I may correct you a little bit on that.

Steve Freed: Sure, absolutely.

Carla Greenbaum: You know for people that are living with diabetes who may not have enough of their own beta cells, there’s of course a tremendous amount of work where people are trying to make more beta cells. But this simultaneous problem that has to be solved is how to keep the immune system from destroying them. So all the work that we are doing in prevention is really saving beta cells that people already have. The same problem is going to be coming when we give people new beta cells back. So really it’s the same thing. We’re still all working for the cure. It’s just a different population of people that we are testing in. In some ways it’s a much easier population. They already have their beta cells. We don’t have to go out and give them some.

Steve Freed: My question is nothing to do with anything and that is, I don’t know if you’re familiar, this goes back at least, I don’t know 12 years ago, and there was research, it’s called INGAP by Dr. Aaron Vinik. And he sits on our board and [is a] great guy and they are still doing research, and the philosophy of that at the time was basically how to keep the bucket half full. You know where the immune system is going to attack it but hopefully this drug, this INGAP drug, would keep filling it up halfway so that you know you wouldn’t have type 1 diabetes technically. And then a lot of research has gone to say that beta cells aren’t really dead, they’re just inactive. They’re in suspended mode and if we can bring them back to life, it may not be 100%, it may not even be 80%, but we don’t need 80%. Where is your research relative to all that?

Carla Greenbaum: Well, I think it’s important to know, we’ve known forever right? That type 1 diabetes is a disease both of the beta cell and of the immune system. Like all other immune diseases though, immune therapy does change the course of those diseases. So while we’re looking to try to find agents that actually support the beta cells and make them happier and make them last longer, we’re still going to have to keep the immune system at bay. So ideally we will apply combination types of therapies. When Dr. Vinik’s INGAP gets to be something that we can test, we would be eager to do it. What we’ve done so far… I’m chair of Type 1 Diabetes Trial Net, which is a large (your tax dollars) NIH-funded international clinical trial network, and our job is to identify people who are going to get clinical type 1 diabetes and try as many trials with the different therapies as we can to see if we can slow and stop that disease. If we had a therapy that we could test that we think focuses on the beta cell, we’ll be right there doing it. At the moment, most of the trials have some form of immune modulation or immune therapy because that is a part of the disease.

Steve Freed: So, your research, like you said, is not so much per se for a cure for those people that already have it. It’s really meant in some way to help be able to prevent type 1 diabetes. Would that be from the womb? Would that be, you know after 3 years of age? Do we even have an idea when that will take place if you’re successful?

Carla Greenbaum: Sure, so I think it’s very important to recognize that one of the biggest advances since long before my grey hair, has been that now that we follow people for so long, we can actually put people into different stages of disease. So we know that type 1 diabetes starts at stage 1, which is when people have 2 or more antibodies. Now why do we say that? If you have 2 or more antibodies, we now know you will develop clinical type 1 diabetes. Before, we used to say you have 2 or more antibodies, you have a 40% risk over 5 years, etc. But now we’ve followed enough people long enough that we actually know that is a start of disease and we need to treat that just like we treat hypertension. You know we treat high blood pressure. Why do we treat high blood pressure? It’s to prevent stroke or heart attack. We can treat islet autoimmunity. We want to prevent people from getting clinical manifestations of type 1 diabetes. So stage 1 is when people’s glucoses are still normal completely but they have multiple antibodies. Stage 2 is when the glucose is abnormal but not diabetic and they’re not symptomatic and again with multiple antibodies. Stage 3 is what we used to call new onset diabetes. And so all the trials are identifying the people at those early stages. We’re not preventing disease. We’re treating that early disease to prevent having hyperglycemia. Now many of our studies involve children as young as 3 and in fact our natural history study, where we’re following people to see if we can stop and prevent their disease, they can be screened as young as 1. And we can test them for these markers. The different drugs depend on what their ages would be appropriate to test. So study results that will be announced later this week, involved a study that involved children as young as age 3 up to adults in their 40’s. So, we really know that since type 1 diabetes encompasses all ages, that we really need to have a breadth of therapies to try.

Steve Freed: So, let me ask you a question. What is disease modifying therapy and why is it needed for type 1 diabetes?

Carla Greenbaum: Well, I should ask you, right? I mean it has been 95 years and we’ve been treating diabetes the exact same way, right? With insulin. Better insulin, shorter insulins, faster insulins, better ways of delivering insulin. But it’s insulin. I mean that was 1922, right? That’s when women got the right to vote. We’ve come a long way, but not in type 1 diabetes. And you have to ask yourself why is it? And partly it’s because we’re a result of our own training. Endocrinologists are very comfortable with handling insulin pumps, are very comfortable with CGM, and yet we don’t have much experience. When I talk to young people and fellows starting out in their career and they want to talk about how to prepare for the future, I tell them they should marry a rheumatologist because they know how to use these kinds of therapies and that will be important. But let me flip the question back to you. Why do we need disease modifying therapy? What we have isn’t very good. And you can take the analogy of juvenile arthritis, also affects young [people], it’s about the same incidence as type 1 diabetes, same number of people have it. We still don’t know what the cause is. We know there’s a long preclinical period of time. And for many years symptom therapy was what was used. Better pain control, better crutches, better wheelchairs for those kids, right? And what changed it? It’s when disease modifying therapy has made it so where now the joints don’t erode, they don’t have the disabilities. And the analogy in diabetes right now, we treat symptoms, we treat the glucose. We’re not treating the disease, which is what we need to move to. So that’s what disease modifying therapy is all about and that’s what I think we need to do.

Steve Freed: What about gene therapy? Are we at a point where we can look at a person’s genes at birth or at a year old and say you’re at risk for type 1? Have we reached that point?

Carla Greenbaum: We have the ability to screen and identify people who are going to get diabetes for sure. We can do that. That’s the fruits of worldwide research for the past 3 decades or so. We don’t yet do it as a public health measure because we don’t yet have a therapy. But when I talk to people who talk to me and say “well how are we going to find the people?” you know we screen every baby at birth for a whole variety of things with a heel stick. You can do the same thing here. I’m absolutely confident that we can institute screening people and really prevent this disease once we have the therapy.

Steve Freed: So, because we don’t have a therapy, what’s the sense is what you’re saying?

Carla Greenbaum: Well, I think there is a sense. Let me say one other thing though. We know, so in diabetes trial net we screen relatives, because a relative has a 15 times increased risk of getting diabetes than someone in the general population. So, we need to screen thousands of relatives to find enough people who will develop the disease. Even if they choose or are not eligible to be in a trial to see if we can slow or delay the onset of disease, we know that closely monitoring will prevent DKA. So, somebody has an antibody, we monitor them every 6 months and we will find glucose abnormalities long before they have any symptoms and that would be a huge benefit. So, just being in monitoring alone is very important.

Steve Freed: But we’re not doing that at birth, are we?

Carla Greenbaum: There are studies which follow at birth and again trial net is following people once they are 1 year old. It’s not a public health [measure]. It’s not clinical use yet. It’s really only as part of a research study. But you know the American Diabetes Association, actually clinical practice guidelines, do recommend that people be referred to be screened and tested in the research studies.

Steve Freed: So, what are the stages of type 1 diabetes? And why does it matter?

Carla Greenbaum: Yeah. So I talked a little bit about that the first stage is when you have multiple antibodies and normal glucose and you feel fine. The second, multiple antibodies and abnormal glucose, and stage 3 is new onset. It matters because when we’re doing therapies there, we are treating disease and not preventing the disease. We’re preventing further manifestation of the disease, but we’re not giving therapies to healthy people. We’re giving therapies to people who are already ill.

Steve Freed: Speaking of the diabetic healthcare provider, due to advance disease modifying therapy in type 1 diabetes, what can we do?

Carla Greenbaum: Yeah, that’s a great question because one of the challenges we have is that we know that even experienced diabetes healthcare providers, don’t seem to know that the risk, once somebody has diabetes, is 15 times greater. So, the first thing they need to do, every time they have someone who has diabetes in their family, they need to tell them. The other family members are at increased risk and they can refer them and get them tested. We now have [ways] people can sign up and do this online. Go to Diabetestrialnet.org and people can read about the studies, decide whether they want to participate. Or even instituting hopefully by the end of this year where people have kits at home and they can test finger sticks and send us a blood samples at home. So I think from a healthcare provider standpoint, you should be aware that these studies are going on. You need to let people know that their risk is increased, refer them for the studies and not be so scared about immune therapy. These are used in many, many, many diseases. 80 million Americans take immune therapy and it’s very effective in changing the course of their disease and we need to offer that to people with diabetes.

Steve Freed: I know there’s research going on right now about developing a vaccine. How far do you think that’s going to progress? I mean from your personal experience?

Carla Greenbaum: You know I think in terms of a vaccine when people talk about it, I think they’re mostly imaging the idea of soon after somebody’s born, before antibodies are developed can we do what we call primary prevention or actually even stop antibodies beforehand. And there’s a lot of work going into it. We haven’t seen fruits of that yet. Someday I hope that will be the answer.

Steve Freed: I know they’ve done studies to people that are at risk that gives them insulin and that didn’t show very positive results. I think that was a couple years ago.

Carla Greenbaum: Right actually in the 1990’s we did a study called the Diabetes Prevention Trial or DPT1, and we had two actually different trials. One trial was using injections of insulin. The idea was that we could rest the beta cells and they would survive the immunotech better. Unfortunately, that wasn’t effective. We did a second trial using oral insulin. Now you know of all people that taking oral insulin doesn’t affect your blood sugars at all, but what it does is that it decreases the immune response. Just imagine the kid, right, the kids on the floor are eating dirt or my kids did, you know they crawl around, and when you eat that, your gut’s immune system down regulates the response, you don’t want to respond to everything. And so we take advantage of that by this notion of oral tolerance. So, the DPT1, the diabetes prevention trial oral insulin study tested that and overall the results were negative, right? It didn’t have an effect. However, there was a subgroup that had quite an effect. So, trial net has now repeated that study and those are the results that you’ll be hearing about soon.

Steve Freed: You know it used to be called juvenile diabetes. And we changed the name because we’re seeing more people with adult onset diabetes and I had a patient come into my pharmacy with a prescription for sulfonylurea and I said, “When were you diagnosed?” And he said, “About 15 minutes ago. I just came from the hospital.” And I said, “How did they diagnose?” And he said, “Well, I went in for a physical and my blood sugar was 675.” and I said, “So wait, let me get this straight…”

Carla Greenbaum: They’re giving you a sulfonylurea.

Steve Freed: I sent him back to the hospital.

Carla Greenbaum: Good for you.

Steve Freed: You know so what about adult onset diabetes?

Carla Greenbaum: Yeah, that’s a great question. So among the other things we’ve learned over the years is that you know the paradigm (it was primarily developed in the 80’s, right?) of type 1 and type 2 has been very helpful, but in general what that is, is we’re putting a box in a continuous variable in a category. And we know that immune mediated diabetes can occur at any age and it is often misdiagnosed in adults because people are so used to people having type 2 diabetes. And of course now since we don’t have other therapies, the goal of all therapies is to reduce your glucose so it’s not so critical to know. But the most interesting thing we’ve been learning recently is that if you were diagnosed with diabetes as a child, type 1, as compared to adult, you have a very different clinical course. So people who are diagnosed as children have a much more rapid fall in their insulin secretion. They lose beta cells much more rapidly. We now know certain immune and genetic characteristics are different. So it’s certainly possible that someday we will change the name just like in arthritis. So there’s juvenile arthritis and there’s rheumatoid arthritis that’s in adults. They’re actually two different diseases. There are two different therapeutic pathways. Drugs are developed separately. We may get there, so it depends whether you’re a lumper or a splitter, but you’re correct. Certainly immune disease can happen at any age.

Steve Freed: You know, so getting back to my original question, a possible cure or what you’re talking about, preventing, you’re involved with that on a day-to-day basis.

Carla Greenbaum: Absolutely.

Steve Freed: So, how comfortable do you feel in saying that we most likely, not that we will, but most likely, could have a possible treatment or cure, what you’re doing for type 1 diabetes. I always thought that diabetes type 1, the knowledge that we’ve gained over just the last 5 years, is probably equivalent to what we’ve learned over the last 50 years. So if you extrapolate that to the next 5 years, okay, it’s unimaginable what we’re going to learn with all the studies that are going on. So, how much more comfortable do you feel saying that we should have it within 5 to 10 years?

Carla Greenbaum: You’re never going to catch me on tape saying it’s going to be 5 years. But I will say this. You know I’m not certain we’ll have a cure in 5 years, but I’m confident that we will be able to start using other types of therapies, which will change the course of disease. It may not make it go completely away. People with arthritis and multiple sclerosis etc. do much better on these kinds of therapies, but it hasn’t cured that disease either. And we need to say stepwise progression means something. You know you still score runs if you’re hitting singles all the time, right? And so I think we just need to sort of look at this as we are now in the stage of applying this tremendous amount of knowledge we’ve gained over the last few years. Applying it means doing trials. And many trials will be negative and we have to say, okay let’s do another trial. How do we make cures and advances in cancer? How do we do it in any other disease? Hundreds and hundreds of different things were tested. I’m not saying we need to do that many, but we do need to do more trials and I’m confident if we take that approach, we will certainly have new therapies for people with type 1 diabetes.

Steve Freed: Not if the government takes away 50% of the money going to research. That’s going to make it tougher.

Carla Greenbaum: Yeah, I guess I’m not one of these people where the sky is falling. As you know there’s strong bipartisan support for medical research in Congress and it’s really Congress that determines the dollars.

Steve Freed: and I always thought that type 1 diabetes should be a lot easier than looking at type 2 because with type 1 you know exactly what you have to do. Somehow you have to prevent the destruction of the beta cells if you really want to find a cure. There’s no other way to get around it unless you replace those beta cells. With type 2, you know, I always tell people, nobody likes me to say it, we already have a cure for type 2. It’s called duct tape. People get mad when I say that because it’s not always the patient’s fault.

Carla Greenbaum: I think the way I would consider it and I’m confident this will happen in 5 years, both diseases start with a lesion of this problem with the beta cell. If [you have]the lesion in the beta cells when you’re young and you have the right or the wrong immune genes, you will get a manifestation of the immune system accelerating that destruction. But people with type 2 diabetes have a beta cell lesion. Just because you’re overweight or sedentary does not give you type 2 diabetes. It may unmask something earlier than the other would and we know for sure you can do treatment with aggressive exercise and therapy. At least for a while, but that fails. It doesn’t fail because the person failed. Their pancreas isn’t working and I think it’s very important to remind people. We have this image out there you know that somehow type 2 diabetes is somebody’s fault. It’s just not, right? They have a disease. A disease of the beta cells.

Steve Freed: And how did you generate this interest in getting involved in what you do because I find that most people that have diabetes have it in their family. We’re somehow motivated to find a way to treat it in some way that would better the lives of people with diabetes. Do you have any diabetes in your family?

Carla Greenbaum: I did not have diabetes in my family, although my training was actually as a family physician and I worked for a number of years in the Indian health service. I saw a lot of people with diabetes in that sense and recognized I wanted to learn and understand more, and that’s when I went back in for more training. But like you said, almost all of my staff, not all of my staff, most of my staff either personally or had a family member who was affected with type 1 diabetes. And these are all very talented people that can make a lot more money doing other things, but they bring incredible passion to work every single day and it makes a big difference.

Steve Freed: I want to thank you for your time.

Carla Greenbaum: Yeah, this was fun. Thank you so much for inviting me.