Aaron Michels, MD, Associate Professor of Pediatrics & Medicine and Frieda and George S. Eisenbarth Clinical Immunology Endowed Chair at University of Colorado Anschutz Medical Campus talks about his professional and personal experience with Type 1 Diabetes, and a trial that is offering hope for the future.
Interview conducted by Ivanhoe Broadcast News in November 2018.
Give me an overview of what Type I diabetes is and how it differs from Type II.
Dr. Michels: In Type I diabetes, also called childhood onset diabetes or juvenile onset diabetes, the body’s immune system destroys those cells that make insulin. And insulin is really important for helping regulate blood sugars. People with Type I diabetes can’t make insulin which is why there are insulin injections, insulin pumps and a lot of checking blood sugars. In type II diabetes the situation is you can make insulin you just can’t use it well enough. And for those people there are many medicines that can be used to help people use their insulin but Type I really is a disease of not enough insulin, the body has destroyed the insulin producing cells.
I think a lot of people think that it’s always genetic, that’s not always the case.
Dr. Michels: It’s not, so actually I have Type I diabetes too, but about eighty five percent of all those people that come to see us in clinic that are newly diagnosed with Type I diabetes will not have a family history. And so there is a genetic component to it but most cases are sporadic in terms of not having a family history and then unknowingly come with high blood sugars and need to be treated with insulin.
When do they play a role, is it a specific molecule you can talk about, when does that impact your risk of Type I?
Dr. Michels: Certain genes predispose risk for developing diabetes. I wish it was as simple as you have a gene and you get the disease but it’s not that easy. I usually say if you have the right genes it’s kind of like stacking up dominos. And then something else has to come along to knock those over before you get to Type I diabetes.
And what are some of the genetic risk factors?
Dr. Michels: A lot of studies, great studies, have been done looking at these and there are HLA genes that confer risk. Suffice it to say that about fifty to sixty percent of everyone with Type I diabetes and those at risk have one specific gene and it’s called HLA DQ8. If I throw in another one (HLA DQ2) it can get to nine out of ten people with Type I diabetes having one or two of these genes.
So it has the gene but it doesn’t mean that oh, you have it so all your siblings have the same risk that you do.
Dr. Michels: That’s correct. So many more people will have the gene that don’t develop diabetes than those that do, but if we look at all of those with diabetes these genes are overly represented.
Specifically tell me about the DQ8 molecule, what that is.
Dr. Michels: This is a gene that’s involved in the function of the immune system. Most genes end up making proteins. And this protein product is on very specific immune cells. It plays a role in Type I diabetes by activating T cells, T lymphocytes, to go and destroy those insulin producing cells in the pancreas.
If you have the DQ8 molecule what’s the risk of getting this?
Dr. Michels: Good question. If you have DQ8 you are eleven times more likely to develop type one diabetes than someone that does not have it.
But you might not get it, you could have the DQ8 molecule and not get it.
Dr. Michels: That is correct. And so I give the example if we put twenty people in a room and you tell me they all have the HLA DQ8 gene, one will develop Type I diabetes and the other nineteen walk away and will not develop it the rest of their lives.
So take me in to the research, what is this research that we’re talking about?
Dr. Michels: The research I and my lab does is really on why people develop diabetes and what can we do to prevent diabetes. Type I diabetes today in 2018 is predictable. We can measure markers in the blood and these are antibodies. They’re directed against different parts of insulin and insulin producing cells. And if you have two or more, that’s not really a question of if you develop diabetes but when. And so if a disease can be predicted it really should be prevented. When we started looking for new and novel therapies we wanted to target this HLA-DQ8 molecule. It’s common, it’s prevalent in Type I diabetes and it plays a role in people getting the disease.
How did you find a drug that could do this? Because this wasn’t easy: oh, let’s try this.
Dr. Michels: No, this is years of work. But DQ8 has been studied a lot as a gene and protein, t and there are really fine pictures of DQ8. And so we took one of those pictures and then we started to take drug like molecules, think things we could take orally that might go and block its function. And that’s where we started with this super computer putting pictures of molecules in DQ8.
And what did you find?
Dr. Michels: We found molecules, and then we took those into the lab for testing. Remarkably we had success. And then we went back to ask the question, there are lots of drugs that are already out there prescribed for many different reasons, could we get lucky and one of those have an off target effect to block DQ8. We did and that’s how we found methyldopa.
Tell me about your first study, just twenty people in that right?
Dr. Michels: Yes.
Tell me a little bit about that, how was it given and what the results were.
Dr. Michels: Sure. A lot of work went in to studying methyldopa in some animal models. But eventually with it being a common and approved drug we wanted to see would this work in people with Type I diabetes. So here at the Barbara Davis Center we designed the study and we recruited twenty newly diagnosed patients and they all had the DQ8 gene. This really is now getting to be personalized medicine. You have the target of interest and we want to treat and see if we could block that target in a small number of patients. And fortunately we were able to do that.
But these are people that already have the disease?
Dr. Michels: Yes.
So this was to see if this would work in patients who had this molecule?
Dr. Michels: Yes. These were people in the honeymoon period that still make some of their own insulin shortly after being diagnosed.
What did you find in the study that you know that this inhibits?
Dr. Michels: First it was safe and it was tolerable which is always important when we do trials with patients. But it also blocks DQ8, it blocked its function. It was a short term trial only over three months but we also measured markers of blood glucose, average blood sugar over time and then someone’s ability to make insulin. And that was all consistent over those three months which was good to see.
Did it block the DQ8 molecule in everybody?
Dr. Michels: It blocked the DQ8 molecule in seventeen out of the twenty individuals we treated.
Are you trying to figure out why not the other three?
Dr. Michels: We are and we’re also trying to make sure we can block DQ8 well enough and over a long enough period of time so we can try to prevent and delay the onset of the disease.
Tell me what methyldopa is.
Dr. Michels: Methyldopa is an oral drug and it’s used to treat high blood pressure. It’s been around a long time; it’s been in clinical use over sixty years and it was actually one of the very first blood pressure lowering drugs that was ever approved. It’s not used as much any more as you have to take it multiple times a day. With a drug around that long it’s really, really well characterized. We know its side effects, we know what to look for and so it made doing these studies in people a lot easier. Whereas if you make a brand new drug there a lot of unknowns, a lot more time and safety testing have to go in to that and fortunately that was all done in the past.
How surprised were you when you saw, wait this really old blood pressure drug blocks it? Were you expecting something like that, did you know enough about that drug that you thought maybe this would work?
Dr. Michels: I had no idea we were going to find methyldopa, there is a little bit of luck and serendipity and then as we tested and worked with this we were excited in knowing that we could this in to humans and test the hypothesis could we block DQ8 in people with Type I diabetes.
In the study, was it one pill a day?
Dr. Michels: Good question. Since it can lower blood pressure and actually didn’t lower blood pressure in any of the people we treated, which was good to see, they took the medicine twice a day for a while and then we upped the dose to three times a day and then we increased again to kind of a higher dose but the medicine had to be taken two to three times a day.
What’s the next step, where do we go from here?
Dr. Michel: There’s a couple next steps. Since methyldopa is very safe we want to do a larger trial especially in those at risk. These are now people that are on their way to developing diabetes and needing insulin but not yet there to see if we can block DQ8 and slow down this disease process. I know living with diabetes is a lot of work and it’s a lot of work that doesn’t go away. So any amount of time we can have a child and their family not having to deal with the burden of Type I diabetes would be fantastic. So that’s one goal. And then our next goal is well we’ve done all this work but let’s improve on it, let’s make it so we can take the drug once a day. Maybe we can block DQ8 better and even remove that side effect of eventually lowering blood pressure.
Are you currently recruiting for the next study?
Dr. Michels: It’s set to start soon and this is now a multicenter trial through the National Institutes of Health.
How many centers?
Dr. Michels: It should be ten to twelve.
So just kind of scattered around the country?
Dr. Michels: Yep, all in the United States.
That will be great. And I need to get that list of centers.
Dr. Michels: It is on www.clinicaltrial.gov (NCT03396484) so it is there and it’s through the NIH sponsored Type I diabetes TrialNnet. This is a large network of diabetes investigators that come together to do these trials.
Who are candidates for this, do you have the genetic markers or do you have to be tested first?
Dr. Michels: You do need to be screened and have the HLA-DQ8 gene.
So you have to have the DQ8 molecule. How does somebody know they have that, is this just someone who will have to have a sibling or a parent or grandparent with Type I and the family just wants to know?
Dr. Michels: We want subjects that have DQ8 and antibodies against insulin producing cells. And a lot of the time there are now studies both research and general population studies screening kids for those markers trying to raise awareness and really prevent diabetic ketoacidosis which shows up when people present with Type I diabetes.
This is adults only, the study eighteen and up?
Dr. Michels: It will be children, adolescents and adults, eight and up.
That is great. What does this mean for people?
Dr. Michels: This would be a personalized therapy that could be used in children to delay the onset of Type I diabetes. Which would be fantastic and a major milestone in the field.
So even delaying it is a big success, it could possibly prevent it from ever happening?
Dr. Michels: I would like to hope so but having lived with diabetes for over twenty six years anytime that you don’t have to go through this even if the child and family is young if we can push it out of teenage years those are I think really, really reasonable next steps. But you’re right it’s not bad to hit a homerun when you’re up at the plate and prevent it from ever happening.
When did you go to school knowing I’m going to research this disease?
Dr. Michels: I grew up with Type I diabetes so I went and saw my pediatric endocrinologist every three months like a lot of kids and families do. Eventually I went to medical school wanting to be a doctor that’s what led me to medicine. And then something happened, so when I was diagnosed and this was in the early nineties there was a lot of excitement. Type I diabetes it was supposed to be cured it was supposed to be gone. And I’m now going to medical school, I’m still taking insulin shots and checking my blood sugar all the time, I wonder why this hasn’t happened. Maybe I can do something to help and that’s really what drove me to be a physician, endocrinologist, and then a scientist studying Type I diabetes.
How old were you when you were diagnosed?
Dr. Michels: I was twelve, right before I turned thirteen.
When you went through medical school you knew that this is the path you were going to go down.
Dr. Michels: Yes.
Pretty driven then.
Dr. Michels: I was, yes very well driven.
Why was this so personal for you?
Dr. Michels: I’ve obviously lived with diabetes myself and then we all grow up and I have two beautiful daughters and unfortunately my oldest daughter also has Type I diabetes. We knew at the age of two that she had all the markers and then we started treatment with insulin at the age of five. And so it’s hard. I obviously know a lot about diabetes myself but now being a father that’s a really, really different perspective and things really do need to be done to lessen the burden for patients and their families. Especially children with diabetes.
I feel like it would completely change the disease in your head to be the parent of a Type I.
Dr. Michels: It is, so I obviously had a lot of perspectives on diabetes both as a patient and as a physician. But the one as a parent, that’s a lot different. Because now it’s not you, it’s not your choices and especially when they’re children so young it all comes back to my wife and I helping her live and learn to live with Type I diabetes.
Your other daughter does not have the DQ8 molecule?
Dr. Michels: She does not.
So she wouldn’t be a candidate for your research?
Dr. Michels: No not right now.
But your older daughter may eventually have children that do have DQ8 so that must be in your head somewhere that this might help the next generation in your own personal family.
Dr. Michels: Yes, obviously I look at it’s great that Type I diabetes is predicable, this is fantastic. And if we can eventually prevent the disease it will go away although I do hold out a lot of hope for a cure. You know taking those of us that don’t make any insulin and re-educating the immune system so we can have transplanted cells put in that make insulin so they can live life without insulin injections and pump sensors and everything that we have to do. And I’d really like to not have to see my daughter live with diabetes for seventy plus years.
Who can get these tests done, do you have to have a family member with this to get tested? Could you walk in to your pediatrician’s office and say hey, I’d like to have my kid tested?
Dr. Michels: There’s a NIH funded pathway to prevention so if you have a relative with type I diabetes you can get screened. And this is a research study free of charge so you can be screened for risks and for those antibodies.
And that was in most cities?
Dr. Michels: Most major cities across the United States. And then even here in Colorado now we have a program called ASK autoimmune screening for kids. Where we’re going out to pediatricians offices, health fairs trying to screen kids for these markers and Type I diabetes risk.
Did we talk about everything you wanted to talk about or is there anything we should restate?
Dr. Michels: I think that’s pretty good.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
David Kelly, PR
314-750-2318
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here.
