Transcription:
Understanding the Mechanisms and Preventing Complications of Diabetes Adolescents and Youth

Dan Simon, MD: Hello, everyone. My name is Dr. Daniel Simon. I am your host of the Science at UH Podcast sponsored by the University Hospital's Research and Education Institute. This podcast series features University Hospital Health System's cutting edge research and innovation. Thank you for listening to another episode.

Today, I am happy to be joined by Dr. Rose Gubitosi-Klug, Division Chief of Pediatric endocrinology at University Hospital's Rainbow Babies and Children's and Vice Chair of the Treatment Options for Type 2 Diabetes in Adolescents and Youth Study to talk about her latest research findings in the area of pediatric diabetes.

Rose, tell me little bit about yourself. Where did you grow up and what inspires you to be a physician? How did you decide that you wanted research to be a part of your career?

Dr. Rose Gubitosi-Klug: I grew up right here in Cleveland area. During high school, I loved my math and science classes. I had many teachers who planted the seed that engineering or medicine might be enticing fields for me. My parents encouraged me and I even had an older sister who also pursued medicine and pediatrics, and she really inspired me.

So I started out as an engineer and quickly wanted to apply all these problem-solving skills I learned to improving the health of people. Following engineering school, I went on to medical school and I fell in love again. This time with seeing patients, hearing their stories and always finding more problems that needed to be solved in order to advance treatment. So research really became an important part of my career following my medical training.

Dan Simon, MD: What attracted you to pediatrics and, specifically, to diabetes? As a successful physician-scientist, what career advice would you have for young investigators, especially women who want to pursue research and this career path?

Dr. Rose Gubitosi-Klug: So my parents were both teachers. So I started with inheriting that desire to impact the future by caring for and improving the lives of children. I've also had, like many others in the field of diabetes, many family members affected by diabetes and it's complications, the triopathy of diabetic retinopathy, neuropathy, nephropathy, and even macrovascular disease.

So, you know, the hallmark of medicine and especially pediatrics is prevention. So I began my training in pediatric endocrinology here at Rainbow. My personal connection to diabetes and desire to prevent these really devastating complications of diabetes for all children steered me into research and diabetes.

So your second question, any success that I've had is really the reflection of some extraordinary mentors and the support that my family and colleagues have provided. It's a lot of time and dedication. I've been in good company, especially I'll start with my husband who has shared this dream of performing academic research with me for the past 30 years. As well, I had mentors who really sensed my passion for research and they helped to guide me really from the start, advocating that I have the lab space, the technical assistance, time, et cetera, to pursue a physician-scientist career.

When I look back, I had several mentors, not just one, and I really blended their lives. I wanted to emulate the clinical compassion and efficiency of one mentor, presentation skills from another, and then, you know, always work-life balance from a third mentor. So, I was really fortunate to have several role models and we met periodically as I transitioned from mentor to independent research. And we still meet periodically today. When I reflect, it was one of my mentors who early on said, "Just keep doing what you love in a place you love and you're happy and you will do your best work." And I found that here at UH. And I might add that I hopefully inspire others around you to do the same, and it's really nice to have a community of physician-scientists. And I really try to find those individuals passionate for research and help them along this path.

Dan Simon, MD: You know, I think one thing, Rose, that a lot of people don't appreciate is just how long this actually takes. You know, I remember I short tracked in residency into a scientific career and spent several years in the lab and then, you know, did a post doc. I think my fellowship seemed like it was forever. And I guess the one thing I would say is you have to be really patient. Did you ever look at the clock or did you just say, "It'll take what it takes and we'll just move along slowly"?

Dr. Rose Gubitosi-Klug: No. As a woman, a clock is what I thought about when I'm trying to balance all of this with a family and wanting to have my own children and everything. And I kept hold of the one thought, was that "I know where I want to get to, and it may take me a little longer, but I want to be happy in the end." And that's when I got to fellowship and, you know, every step of the medical journey, life gets better and, you know, the balance gets better and what you're doing, you're getting more focused and you're getting that level of expertise. And I always wanted to work at sort of the highest level of academic medicine. You have to be patient, you see people graduate and go on to their careers and you're still in the lab doing research. But it's all worth it. And we all have our different tracks. And we really need people who are cutting edge and want to find new discoveries and lead to new treatments.

So I kept my head to the ground. I really just loved what I was doing. And fortunately, again, I had those mentors who kept telling me, "It's going to be worth it. You need to hang in there. You're doing great work. Just hang in there."

Dan Simon, MD: Yeah, that's really great. I think all of us really owe so much of our success to our mentors. So a large focus of your research has obviously been type 1 diabetes and, you know, with the discovery of insulin now over a hundred years ago and the advancements in diabetes or really technology today, how has modern diabetes management really impacted the development of diabetic-related complications?

Dr. Rose Gubitosi-Klug: This is a great story. With the discovery of insulin, you know, type 1 diabetes was no longer a fatal disease, but a chronic manageable disease. I've had the opportunity to be involved in the Epidemiology of Diabetes Interventions and Complications Study, which is the long-term followup of the Landmark Diabetes Control and Complications Trial.

This study funded by the National Institute of Health is now in its 40th year. So 40 years ago, the study enrolled adolescents and young adults into a trial to determine if intensive management, meaning multiple doses of insulin per day to regulate blood glucose in the near normal range, could prevent the complications of diabetes. Indeed, we continue to see the benefits of intensive diabetes management on a reduction in all of the complications of diabetes. The study set the standard of care for diabetes management, and we discuss these important findings with our patients and their families recently diagnosed with type 1 diabetes from day one. Yet achieving and maintaining such careful normal range glucose is challenging for many individuals. Daily management carries the burden of multiple glucose checks and insulin injections. Fortunately, these burdens are slowly being reduced with advancements in diabetes technology like automated insulin pumps and glucose sensors, also known as the artificial pancreas systems.

Furthermore, while it's always best for children and adolescents with new-onset type 1 diabetes to intensively manage their diabetes from diagnosis, our recent analysis demonstrate that improvement in management over time continues to have long-lasting effects decades later, thus a hopeful message and encouraging message to our children, youth living with type 1 diabetes, that it's really never too late to seek help in reaching and achieving their diabetes goals.

Dan Simon, MD: What do you feel is still the most limiting factor for patients in reaching their diabetes management goals? I mean, it's got to be pretty tough.

Dr. Rose Gubitosi-Klug: It is and this hasn't changed. It's hypoglycemia and the fear of hypoglycemia that remain the limiting factor for success in diabetes management. Our parents of children with type 1, I mean, they tell us from the time that their child's diagnosed, their sleep has been more restless due the worry of a low blood glucose occurring overnight and the risk of seizure.

Having too many low glucose levels can lead to unawareness or lack of the usual symptoms like a raising heart rate, sweating and hunger, these protective reflexes. We found that the greatest risk factor for having recurrent severe hypoglycemia, meaning when an individual requires treatment assistance, is having experienced a first episode of severe hypoglycemia. And adolescents were found to have a higher rate of severe hypoglycemia.

As well, our recent report described that recurrent severe hypoglycemia increased your risk of cognitive decline and accelerated rate compared to the general population. Thus, we discuss hypoglycemia management and prevention routinely with our patients and their families, the revolution in diabetes technology with systems that can turn off insulin delivery, prevent hypoglycemia, provide these exceptional tools for families.

Our next challenge though is making sure that these devices are available to all families and that we can provide the educational support to optimize management, use these systems every day, regardless of socioeconomic status.

Dan Simon, MD: Well, it's really great to hear, Rose, that technologic advances are going to help our patients and their families. I mean, this has got to be just really tough for parents with young children. I want to congratulate you on your recently published paper in the New England Journal of Medicine and, you know, while type 1 diabetes is still the most common form of diabetes in childhood, what research has been made recently in youth-onset type 2 diabetes?

Dr. Rose Gubitosi-Klug: Yes. And most notably in pediatrics, we've come to recognize the development of type 2 diabetes. Traditionally only occurring in adults, we've now reported in youth as young as eight to nine years of age. As part of the treatment options for type 2 diabetes and adolescents and youth in today's study, we investigated how best to treat type 2 diabetes when it presents at such a young age and we monitored for the development of diabetes-related complications. And through today, we demonstrated that the clinical course of type 2 diabetes, when it presents in youth is much more aggressive with more rapid loss of function or failure of the beta cells to overcome the weight-associated insulin resistance.

As well, youth develop the microvascular and macrovascular complications much earlier, within a decade of diagnosis. And that means it's resulting in debilitating medical conditions while only in their 20s at a time when these individuals should be entering the workforce. Yet there is hope as some of the today participants developed what we call durable control of their diabetes and were able to come off medications and essentially have their diabetes go into a sort of remission. This was associated with a reduced risk for the development and progression of complications. So we really need to understand the factors that lead to durable control, so that's really where the further research in youth-onset type 2 diabetes will be focused, is to understand these findings, what are the underlying mechanisms. And it's just really critical because we really have seen an increased number of diagnoses of type 2 diabetes amidst this COVID pandemic.

Dan Simon, MD: So Rose, how much of type 2 diabetes in the youth is secondary to obesity, inactivity and a more sedentary lifestyle?

Dr. Rose Gubitosi-Klug: Just like in adults, those are three critical factors related to youth-onset type 2 diabetes. Of course, there's always more to think about, especially in youth. What we do understand is it's this weight-induced insulin resistance, but then there is the physiologic insulin resistance of just going through puberty. So we have hypothesized that if we can catch kids early before they make it all the way through puberty and identify those that are really going to struggle with this combination of physiologic and pathologic insulin resistance, if we can help them ride that wave of insulin resistance and manage their glucose levels well during that time period, that we believe that those are the kids who will go on to go into diabetes remission. And so, we really need to catch these kids earlier. We also know there are high risk features, like if your mother had gestational diabetes, if you have a strong family history of type 2 diabetes, it seems that youth have this accelerated rate of developing complications, if you have these maternal and family factors. So whether it's genetics, epigenetics, a lot of other environmental triggers as well as likely psychosocial factors that contribute to youth-onset type 2 diabetes is something we definitely need to understand more and hopefully prevent.

Dan Simon, MD: That's terrific. So Rose, in a final question, what are the next steps? What are we looking for going forward now?

Dr. Rose Gubitosi-Klug: Yeah, no, there's always more. One question leads to more questions. And when it comes to research, I think the most compelling questions still come from conversations with patients, research participants and their families. And we keep this focus remaining on understanding the mechanisms and preventing complications of diabetes for millions of Americans living with diabetes.

For type 1, as we all age, we worry about our brain and our heart health and overall fitness. So we are embarking on what will be the largest assessment of cardiopulmonary fitness in type 1 diabetes. How we function in our world over time really relates to our fitness level. So we hypothesize that like our other long-term outcomes, that intensive management of type 1 diabetes will allow individuals to have fitness levels similar to the general population over time. They'll age similarly.

We will soon report on some novel investigations of the effects of long-term type 1 diabetes on brain structure, so actual structural changes that may relate to your history of glycemic control, and this is certainly a field of emerging interest in diabetes research.

We will also explore how impact of weight gain over time may lead to to insulin resistance and complicate the course of type 1 diabetes. So is there this element of a mixed picture of type one diabetes and now some elements of type 2 diabetes and study changes in the liver, which is where we can hopefully detect either early signs of liver fat that might signal some insulin resistance state in our patients with type 1. So really, the goal is to identify the factors associated with any decline in fitness or any development of liver fat and how that relates and how we can prevent these diabetes-related complications in future generations.

And then, as we discussed for youth-onset type 2 diabetes, we really need to turn back the clock. We need to identify children before the onset of type 2 diabetes to see if we can alter the progression of the disease. And again, here as well, insulin resistance study of the liver, study of the timing of hepatic fat and during puberty and its role in insulin resistance in children. Hopefully, a study like that will give us some clues.

Dan Simon, MD: Well, Rose, thank you so much for this great interview today. I learned a lot about especially type 2 diabetes in youth and really encouraged by the fact that early diagnosis may be able to actually reverse the course of the disease. Thank you for taking the time to speak with us today.

For our listeners interested in learning more about research at University Hospitals, please visit uhhospitals.org. Thank you, and have a great day.