I have the pleasure to welcome Dr. Dilan Athauda, who is the main author of the paper to this edition of the MDS Podcast. He's an academic and neurologist working at UCL Queen square Institute Of Neurology and the Francis Creek Institute. Welcome to the podcast, Dilan. And thank you very much for your time.
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[00:00:55] Dr. Dilan Athauda:
Thank you having me.
[00:00:56] Dr. Eduardo de Pablo-Fernández :
So we are gonna discuss your paper on the impact of type two diabetes in Parkinson's disease. There's been a lot of literature about the association between these two conditions. And this goes back a few decades. Recently there has been growing evidence from different fields of research, epidemiology, clinical studies, that have added more evidence to this association. And, more recently, diabetes has been included as a risk factor for prodromal Parkinson's disease. What is the association about? Is this more than just peripheral hyperglycemia driving more cerebrovascular disease? Are there any other mechanisms involved?
[00:01:34] Dr. Dilan Athauda:
Yeah, I think that's a really interesting question. And I think to answer that you'd have to look back at the epidemiological data that's been shown over the last few years. And as you rightly mentioned, there's growing evidence to say that diabetes is a newly identified risk factor for the development of Parkinson's. When you look back at the epidemiological studies and the meta analysis of these studies, you'll see that if you have type two diabetes, you're around 40% more likely to develop Parkinson's disease than if you don't have type two diabetes.
And interestingly, one of the first things that people often question rightly is, is this all due to an increased vascular risk? So people with type two diabetes and hypertension tend to have other vascular risk factors and they tend to have more cerebrovascular disease. that's what's thought. And often that's been thought to be the main link between these two conditions.
However, these epidemiological studies have mostly confirmed that not to be the case when they've accounted for people with vascular risk factors and use these confounders and the link between type two diabetes, and Parkinson's disease is still strong. Once you exclude all the people with vascular disease, or account for them, which means there's other mechanisms that are probably playing a part.
And there's a few competing theories into what are links type two diabetes and Parkinson's. One thing that I'm particularly interested in is the insulin resistance links between these two diseases. Type two diabetes is characterized by peripheral insulin resistance. And there's now a lot of evidence to say that a form of insulin resistance occurs in the brains of people with Parkinson's as well. And also the brains of people with other neurodegenerative diseases, such as Alzheimer's. And we think that this development of insulin resistance is thought to be the common link between these two conditions. Other potential theories include an increased risk of glycation, whereby if you have type two diabetes, then there's an increased risk of an irreversible chemical reaction called glycation that occurs on some of the proteins that were involved in type two diabetes called alpha Synuclein. And at least it leads to a more aggressive aggregated form, And that leads to more inflammation, and more disease process. And that might also be linking these two common conditions.
[00:03:37] Dr. Eduardo de Pablo-Fernández :
This is very interesting that shared mechanisms between these two apparently different conditions, not that they have like a common role central nervous system.
We will go back to the mechanisms a a bit later, but now focusing a bit more on your paper, there's been a lot of epidemiological studies showing that predating type two diabetes is a risk factor for Parkinson's disease, but it seems that also having type two diabetes can modify the phenotype and the disease progression in Parkinson's disease. And that's what you are, addressing with your study. Tell us a bit about the evidence type two diabetes is a disease- modifying factor and the aim of your study.
[00:04:18] Dr. Dilan Athauda:
Up until our paper was published, there's been a few smaller studies suggesting that if you have type few diabetes, you tend to have more severe Parkinson's. So you might have a bit more severe motor symptoms. And these studies have tended to be using smaller numbers of people with Parkinson's and type two diabetes, and looked mainly at the motor symptoms. The studies up to now have shown that if you have type two diabetes, then you might have more tremor, more rigidity and concentrating on the motor aspects of Parkinson's.
What we wanted to do was to see whether having Type two diabetes actually altered the disease progression, altered the course of Parkinson's if you have type two diabetes.
So what we did was, we used the publicly available data set called Tracking Parkinson's Cohort, which is led by Donald Grosset and Huw Morris, and it comprises around 2000 individuals with Parkinson's who were recently diagnosed with Parkinson's. So everyone enrolled in the study had Parkinson's on average around 12 to 15 months before they were enrolled. And they've been followed up for around six to eight years. And the advantage of this cohort is that it had a large number of Individuals with Parkinson's, and also, each individual had a lot of descriptive data either about their age, their medication, but also about their Parkinson's, but also about other conditions such as type two diabetes. There was lots and lots of data about the types of symptoms they had. Not just the motor symptoms, but also the nonmotor symptoms.
And we used this data set to look at the association between Parkinson's and type two diabetes. And we did two main analyses.
So the first type of analysis we did was a cross-sectional analysis. So we looked at the severity of people's Parkinson's at entry into the study. And we compared people who had type two diabetes and Parkinson's compared to people with Parkinson's. We identified about 170 people with Parkinson's and type two diabetes. And we compared that to the cohort with Parkinson's. And obviously the number of individuals in each group is very, very dissimilar. So in order to counteract any biases from that, we tried to statistically account for that as much as possible by addressing differences in age of onset, body mass index, vascular risk factors, hypertension, other medications, and duration of Parkinson's, so that we could try to see whether the effects that we saw between these two groups were actually real.
And what we discovered was that people who had type two diabetes did indeed have a much more severe form of Parkinson's, looking at a snapshot of their severity of their Parkinson's. They had more severe motor symptoms. They had more severe problems with their walking. But also, for the first time that we've shown this, is that they also had more severe non-motor problems. So people with type two diabetes and Parkinson's tended to have more problems with depression, sleep problems and a lot of other non-motor problems. And they also reported a worse quality of life compared to people without type two diabetes. And that was a snapshot in time.
So the other analysis we looked at was whether having type two diabetes influenced how your Parkinson's progressed over time. And so when we looked at that, very interestingly, we found that if you had type two diabetes, you were more likely to have more severe motor symptoms over time, but also more severe mood problems, such as depression. And also, you are much more likely — almost twice as likely — to develop problems with your walking and also problems with your thinking and memory compared to people without type two diabetes. So this is one of the first studies that has shown this in a large number of people with Parkinson's and type two diabetes, that this seems to have an effect on the disease progress.
Now, one of the very first obvious questions about this is: well, we know quite reasonably that anyone who has two chronic diseases tends to do worse than people that have one chronic disease. So for instance, if you have heart disease but you have heart disease and liver disease, for instance, obviously if you have two chronic conditions, you tend to have a worse outcome than people that just have heart disease, for instance. So this is called an additive effect. But we think this effect of type two diabetes is not just an additive effect. It's not just a coincidence having two chronic diseases that you tend to be worse off.
Now, yes, type two diabetes can affect certain things like, you can get problems with the nerves that can cause problems with walking and also problems with tremor. But it also affects non-motor problems, which are a bit more difficult to explain. But also, when you look at preclinical studies, type two diabetes and Parkinson's shares a lot of pathological processes. So both of these conditions involve problems with mitochondrial functioning, inflammation, protein aggregation. And there's evidence that on a cellular level, these two conditions can overlap and influence each other. Preclinical studies have shown that in models of diabetes using mice, if you feed mice a high fat diet to induce a peripheral insulin resistance or type two diabetes, these mice develop degeneration of their dopaminergic system and develop Parkinsonism. Interestingly in humans as well, people with type two diabetes, but with no neurodegenerative disease or Parkinson's disease, when they undergo DAT scans and looking at their dopamine transporter uptake, they actually have reduced dopamine transporter uptake, And a subclinical degeneration of their dopaminergic pathways compared to people without diabetes.
So on a cellular level, there is an interaction between these two conditions. Therefore we do think that it's much more than an additive effect, that there is an interactive effect.
[00:09:38] Dr. Eduardo de Pablo-Fernández :
Interesting. One of the advantages of your study is the deeply phenotyped cohort that this is one of the first studies that addressed nonmotor symptoms a bit more in depth, and also, allowed accounting for a lot of potential confounding factors, such as vascular disease, BMI and so on.
So despite all of the adjustments it seems like the effect of diabetes on motor/ nonmotor symptoms and disease progression was still there. And you mentioned a lot of different potential mechanisms. The main goal of all these investigations in the association between these two conditions is to see whether there is any potential treatments for diabetes that could be repurposed at least for some of the population of people with Parkinson's disease.
You've been involved in some of these studies using Exenatide. And you have discussed some of these molecular mechanisms that are shared by these two conditions. How is this progressing?
Where are we at the moment? Do you think these medications will be approved soon to treat people with Parkinson's disease?
[00:10:43] Dr. Dilan Athauda:
Yeah, I think that's a really interesting question. So this all leads on from the work very, very early on a couple of decades ago, all the preclinical work from Nigel Greg at the NIH. He first showed that these class of diabetic medication called GLP-1 agonist seemed to be protective in cellular models of Parkinson's and in animal models of Parkinson's. And our group, led by Thomas Fulton at UCL and the National Hospital of Neurology, has led two Exenatide trials of people with Parkinson's, two rather small trials.
The first was an open label trial, and the second was a randomized control trial. And these trials have consistently shown that people who are prescribed one of these diabetic drugs called exenatide, which is a GLP-1 agonist, a drug that acts on the GLP-1 receptor seem to have better motor symptoms and non-motor symptoms compared to people who are not prescribed this drug. And these benefits were sustained well after the drug was stopped.
So the question is, these trials were actually rather small, relatively speaking. So what we're doing now is, we are in the middle of a phase three trial using a lot more individuals with Parkinson's across different sites in the country to see whether the signal of effect we picked up in the two trials previously is still there in a number of patients, and in more patients with Parkinson's throughout the country. And I think that if that trial was to be successful or if it did show a positive signal that would lead to much more impetus and much more confidence in saying that these drugs may be helpful in altering the disease course in people with Parkinson's. I think the mechanism is less important if we show a clinical effect. Obviously the mechanism is crucial in terms of, we need to understand why these drugs work, but I think that that question won't entirely be answered by the time the trial will be over. And I think we're expecting results from our exenatide phase three trial in 2024, so far.
But there's also a number of other trials going across the world in France and the USA using different GLP-1 agonists. So other drugs in the same class in cohorts of people with Parkinson's, but also cohorts of people with Alzheimer's. And so It's a very exciting time to wait and see what these results will show. And they'll be coming in throughout the rest of the year and next year as well.
[00:12:52] Dr. Eduardo de Pablo-Fernández :
We are looking forward to those results. As you mentioned there is a lot of different mechanisms and, Parkinson's disease is, is thought to be very heterogeneous from a pathogenic point of view. Do you think that these antidiabetic drugs will be useful for everyone with Parkinson's disease? Only for people with diabetes and Parkinson's disease? What do you think?
[00:13:16] Dr. Dilan Athauda:
Yeah, I think that's a question on really how this drug works. I think at the moment we know from the small number of people that we've we've had on these trials there tends to be a, type of people who tend to be responding more than others with this drug. And that tends to be people who are certainly younger, who've had Parkinson's for a bit less. But, I think. the people are affected, it's either going to be a subset of people with insulin resistance or type two diabetes who may benefit the most. But I think in terms of seeing if this affects people without peripheral insulin resistance or even brain insulin resistance, I think that's the answer that this trial is hoping to answer.
And then when it's only when we do our analysis that we can see who benefits the most from these medications, that we'd be, able to give you that answer in full and in detail. one of the clinical implications from our paper is that it's shown that having prevalence of resistance or type two diabetes affects the progression of Parkinson's. So clinically, whenever I see someone in clinic with a new diagnosis of Parkinson's or even later on, I always send off a glycated hemoglobin, some cholesterol and metabolic markers. And in the time that I've been doing that so far, I've picked up a number of people with prevalence of resistance or prediabetes. And I think that's always important. And although that may be coincidental, I think that's always important to address through lifestyle factors and, and weight loss and exercise. And I think that's just a good mark of general health.
[00:14:34] Dr. Eduardo de Pablo-Fernández :
That's very interesting. And talking about clinical implications, there is a lot of evidence linking these two conditions and showing that diabetes may have a, a negative prognosis in disease progression and disability and quality of life. So when someone with diabetes comes to your clinic, and you make the diagnosis of Parkinson's disease, what do you tell these patients? Is the evidence robust enough to start discussing this association in clinic and this potential bad prognosis?
[00:15:06] Dr. Dilan Athauda:
Well, I do discuss the evidence that generally having control of diabetes will have a number of health benefits not just on Parkinson's, but on general health, in terms of reducing the occurrence of stroke and heart disease.
So I think that whenever I see someone with diabetes and Parkinson's, I always emphasize the importance of good diabetic control, and I make a point to write to the GP to ask that they ensure that their glycemic control or their blood sugar metabolism is really well controlled, not just for reducing stroke risk and secondary prevention, but also potentially that it may help their Parkinson's.
And I think that there's enough evidence to show that good control of diabetes can improve your outcomes in stroke and heart disease. And I think the evidence is starting to come forward now that it may affect your disease progression of Parkinson's as well. So having better control of your diabetes can only be a good thing. And I always write to the GP and also tell the person with Parkinson's in front of me, that healthy eating, exercise and lifestyle measures, and good blood pressure control are very important for managing type two diabetes, the complications that come out there of, but also it may have a secondary effect on their Parkinson's as well. So I think that that's that's good whenever you see a patient with these conditions.
[00:16:13] Dr. Eduardo de Pablo-Fernández :
Indeed. I think that approach is very important in treating people with Parkinson's disease. Well, thank you very much for your time and the interesting discussion. It's been a pleasure to have you here on the MDS Podcast, Dilan.
[00:16:26] Dr. Dilan Athauda:
Thanks very much for asking me to come speak to you today. Thanks a lot.
[00:16:28] Dr. Eduardo de Pablo-Fernández :
Thank you very much, everyone for listening and I hope you enjoyed the podcast. Bye bye.