Series 3 episode 5. Andrew Lotery and Amanda Stride: Glucokinase MODY – a mildly raised fasting glucose for life that should not be treated

In this episode we talk to Andrew Lotery about how he was found to have a raised fasting glucose on an insurance medical. He was treated as Type 2 diabetes but he questioned this as he was young. slim and physically fit. A chance reading of a research funder’s newsletter led him to the Exeter team and a diagnosis of glucokinase MODY.  

Amanda Stride worked as a research registrar in Exeter.  She showed that in glucokinase MODY the fasting glucose was raised from birth and remained stable and regulated throughout life with treatment not changing the blood glucose. 

Anna Steele showed in her PhD that patients with glucokinase MODY did not get complications affecting the eye or kidney even after 50 years of raised glucose.  So in glucokinase MODY treatment with insulin or tablets is not needed and does not work; patients should be discharged and not followed up.

Transcript

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This is One in Six Billion. A podcast about diabetes and genes with me Maggie Shepherd and me Andrew Hattesley. It didn't matter whether you were on insulin or tablets, it just didn't seem to make any difference to the blood sugars.

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Welcome to the One in Six Billion podcast. Today we're going to talk about a special type of MoDi or maturity onset diabetes of the young known as glucokinase. And it's a pleasure to welcome two guests, Andrew Lottery and Amanda Stride. So welcome, Andrew. Thank you for coming and joining us on the podcast. I wonder if you could introduce yourself to our listeners. Thank you for having me. So I'm Andrew Lottery. I'm currently a professor of ophthalmology.

at the University of Southampton. And prior to that, I worked at the University of Iowa, where my gluco-cione story really started. we jumped straight in there. And maybe if you could tell us how you first picked up as having a high blood sugar. So as I say, I was working at the University of Iowa and I'd just had the birth of my twin sons. And I thought it was about time I got life insurance.

I was in my early thirties. So as part of getting life insurance, I had to some blood tests done and that included a blood glucose measurement, which came back to me very surprisingly as high. And so it looked like I had diabetes. Interestingly, there was no feedback from the insurance company to just sent me to blood test results and actually didn't change my premiums or anything, but it

did provoke me to go and seek medical attention at the University of Iowa. And so the doctors there initially thought I had insulin dependent diabetes and wanted to initially think about putting me on insulin, but I was very fit and well. And they couldn't really understand why my blood sugar was high. no family history of diabetes. I wasn't overweight.

no symptoms. I just had this high blood sugar. And so was a bit of a puzzle. I managed to persuade them not to give me insulin because my sugars weren't too high. And they then started me on the drugs for people for type 2 diabetes mitformin. But my sugar levels just stayed the same and they weren't really sure what was going on.

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So can I ask you, Andrew, what were you thinking at this point in time when they were querying the type of diabetes that you might have and for you it had come completely out of the blue? Well, it was all a bit depressing really the thought of needing insulin injections. And, you know, I think I even was sent off to get a prescription of insulin and at the local Walmart pharmacy. And it's also, of course, quite expensive.

in the United States to buy all these medicines. And I was checking blood sugars, was doing thumb pricks to measure blood sugar. So that was all a bit unpleasant as well. So it was all a bit depressing really to have this. And I was puzzled why the sugar was this high. then your blood sugars didn't go super high as they would in type one diabetes. So that

wasn't the case. And so then you were switched over to type 2 diabetes as your diagnosis. Yeah, well, again, my understanding of type 2 diabetes in a young person is they're generally overweight, not eating a very healthy diet. And I was going to gym, I was running a lot, I was not overweight, was just reasonably fit and cycling a lot.

I was really surprised why I would have type 2 diabetes when I had a normal weight and was otherwise healthy. So it was a puzzle. So they'd started you on some medication, presuming you had type 2 diabetes. Did you find that made any difference to your blood sugar at all? No, didn't. And again, my doctors were puzzled by this as well.

So initially started off with a GP family doctor. wanted to give me insulin and then talked about that. And then I ended up seeing a physician with us, an endocrinologist, I guess, with special interest in diabetes. And again, they were puzzled why I didn't have the normal risk factors. Why, why I had a elevated blood sugar. So did you stay in America under the kind of private health care system or did you come back to the UK?

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So I came back to the UK to my current job as Professor of Ophthalmology at University of Southampton and I received grant funding from the Wellcome Trust and I was getting their research news bulletins and I came across Andrew's research on glucokinase mutations and just a Wellcome Trust magazine about the research they funded.

And I was reading this and thinking, well, maybe I've got a glucokinase mutation that maybe would explain things. So I contacted Andrew by email and he very kindly responded right away. And we had a bit of a conversation and he helped me organize genetic testing for glucokinase mutations. And lo and behold, it came back as positive that I had this unusual

form of diabetes, if you like, with a glucokinase mutation. So if I hadn't read that Welcome Trust magazine, I probably still would be none the wiser why I had this change in my blood sugar. So it sounds really fortunate that you happened to pick up that Welcome Trust magazine and read about Andrew's work and you picked up from that yourself the potential of you having this glucokinase change.

So how did you feel when you got that result? Well, it was very reassuring to know that there wasn't really a risk of long term complications of diabetes. Another interesting thing that happened was my GP registered me as being diabetic. And so I kept getting chased by the diabetic eye screening service to have my annual eye screening.

Being a professor of ophthalmology, can get someone to look at my eyes. Then the eye departments have never gone to the eye screening, but it's virtually impossible to get off that. Being chased for diabetic eye screening, but it was really reassuring to know that I wouldn't have the potential risks of diabetes, which can affect your eyes, your kidneys, your nerves, your heart, et cetera. It was very helpful to know that. And I think it was also interesting to me that

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diabetic experts in the United States didn't seem to consider this. mean, the research was just coming out, I guess, in the early 2000s, but it never dawned on any of the specialists that I saw with the high blood sugar that this might be an explanation. Yeah, it's very interesting. We'd been doing research in Exeter since 1995, but actually the diagnostic testing on the NHS had started around 2000.

And so we were still in the early days of spreading out. And one interesting thing was that lots of our early patients that we picked up, like you, had had glucose tested for some other reason, like an insurance medical. There was no reason for them to think their blood sugars were high, but also they were often health care professionals. And I think what that meant was that they were able to say, this doesn't make sense.

and question the system and keep looking for an answer because they had more power to get people to think about them. And so I don't believe that doctors and nurses are more likely to have glucokinase. I think it was just, especially in the early days, those were the ones who were making it to our door to get the testing. So I wanted to ask you, Andrew, when you got the diagnosis of glucokinase, Modi, I presume you were told to stop your type 2 diabetes medication?

Yes, over the years I've corresponded with Andrew and he's kept me up to date in the research in this about not being needed. And as I say, well, I measured my blood sugar levels on and off the type 2 medication, which is metformin, and there really wasn't any difference on the levels on or off the medication. So, yeah, it was clear it wasn't affecting the blood sugar levels.

That's absolutely right. You were showing so many features that are typical of glucokinase. The incidental measurement, which happened to be for you for an insurance medical, often for women it's being tested in pregnancy, and then not having any symptoms, but having a raised blood sugar. And then the treatment making no difference to that.

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And actually when you stop it, the blood sugar remaining at the same level. And as you say, what we think this is, is you're born with a higher blood glucose. And actually that's been there all your life. The only difference that happened in your thirties was that a test was done rather than your blood sugar being any higher, which means things like age of diagnosis become a random thing. It's just going to be when you're tested. Probably at that point, we'll move over to

Amanda, because indeed she was one of the people doing work around that time. So welcome to the podcast, Amanda. Would you mind introducing yourself to our listeners? Yeah, thanks very much for having me. I'm Amanda Stride. I'm currently a consultant at Torbay Hospital. But in the early 2000s, I was working in Exeter with Maggie and Andrew as a research registrar. And I'd come from Birmingham before I was working in Exeter.

and my friends from Birmingham had got in touch with me and said there was this really smart registrar and she wanted to do research in diabetes and I should definitely find her a job. And I was certainly not a person who was ever going to deny Tim Harvey if he said something should happen, it should happen because he'd been enormously supportive throughout my time in Birmingham. And so Amanda had come to join us and actually one of the first things that we

had to do was for the very first time we'd got European funding. And this was interesting because at that time there was a lot of competition still going on between the centres that were supposed to be collaborating together. there were people from France, people from Sweden, Denmark and Spain. And Amanda was given the task of trying to bring these people together with the research.

Yeah, it was an interesting task as a very naive young registrar to be given. And we actually met for the first time close to where we're recording the podcast today in a room at the back of a pub. And Andrew had to use all the skills he had to persuade people that they wanted to give us as much data as we could get out of them so that we could really look at what happened to fasting glucoses and then after.

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oral glucose tolerance test where you drink a sugary drink to see what happens to your sugars. And we wanted to get data from all of the centers and pull that all together. So we had a big group of patients that we could look at what happened to their blood sugars. But we sat in a back room battling that out and asking people to give us their data when they didn't really want to to start with. Was this data relating just to patients with glucokinase or different types of genetic diabetes? So we were also asking them for

data for other types of genetic diabetes, in particular HNF1 alpha. But this was the first time there'd been big numbers for these conditions because each of us only had a few. So it did make sense to put all the data together. And how many patients did you get data from in the end? It was over 400, wasn't it? I think the thing that I still remember as being really interesting was we got different data from different countries. So the French had a lot more

patients who had a glucokinase mutation because they do a lot more screening, particularly in pediatric clinics. Whereas the teams from Scandinavia had a lot more patients with H and F1 alpha because of how they follow up patients with diabetes in their clinics. So that was really fascinating to see the different information coming in from the different centers and the format they sent it to me in was interesting from the different centers as well. And what did you find about the patients with glucokinase particularly?

So they had a higher fasting glucose level, but when they did the oral glucose tolerance test, so when they have the sugary drink, their blood sugars didn't really rise any more than you'd expect somebody without glucokinase to. So effectively when you drew out the graph, there was a normal shaped graph doing exactly what would happen just at a higher set point to people without glucokinase. So really that fitted with this idea of a higher set point throughout life.

And what happened with age is you just had a range of ages in that group of patients. so glucose did go up a little bit. Fasting glucose did go up a little bit with age, but exactly in line with what you'd expect in the normal population, because we see that glucose goes up anyway as people age. So it was absolutely mirroring what happens to people without diabetes. And the fasting glucoses that you found were pretty stable, weren't they? Yeah, so not changing really at all for a long time.

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and within a really narrow range around 5.5 I think it was. Yeah I think if I remember it right, only 2 % of patients had a blood glucose below 5.5 and when we went back and asked them to recheck it then they were all over 5.5 when they were rechecked which really suggests that you could use a fasting blood glucose cut off of 5.5 as being a very good way of picking up people that had

glucokinase as the genetic cause for their raised blood sugars. Because you had this big data set, normally we'd expect things like how heavy people were, which we measure as their BMI, to alter what their blood sugars does. Did you find that happened with glucokinase? No, there was no link with way to tour. Which is completely different from type 2 diabetes, where it's a major determinant. Absolutely.

Did you find any difference between the results from the different countries? No. You did go ahead and publish that paper and got the authors from all the different countries to be on it together as a joint effort, which was a real first for European diabetes research at that time. It did take 33 drafts of the paper. Yes, we did get there in the end, which was amazing.

So Amanda, you then went on to do some research looking at treatment in glucokinase? Yeah, so it was something we talked about quite often in our meetings and we recognized that people with glucokinase had really stable blood sugars and that didn't matter what treatment you seemed to give them, it didn't seem to make any difference to their blood sugars. And Andrew talked about it when he was talking about his diagnosis, but the treatment that you ended up getting seemed to depend on what age you were

diagnosed. So if you were young and you were slim, everyone worried that you had type 1 diabetes, so you went on to insulin. But if you're a bit older and slightly overweight, then you went on to treatment for type 2 diabetes. But it didn't matter whether you were on insulin or the tablets, it just didn't seem to make any difference to the blood sugars. And we'd kind of recognized that and we wanted to capture that information as well as we could, but it actually proved quite difficult. So we started by looking back through the

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referrals that we'd had for genetic testing and looking at what treatment they were on when they were referred to us and then seeing if any of them had had follow-up blood sugars afterwards having stopped their treatment and to look and see if there was a difference between them. And it was really interesting because when we looked at how many patients were on treatment when they were referred in for testing, it was about 21%, so about one fifth who were on some form of treatment, which just struck me as quite interesting that

that many people were willing to keep taking medication that wasn't making any difference. And Andrew was talking about if you're in somewhere like America where you're paying for treatment, that's really significant, isn't it? Yeah. And so what you were finding was that the overall blood tests, which is measured as glycated hemoglobin, was exactly the same in the 750 patients who had no treatment compared

So they're just under 200 who were on either insulin or tablets. Now the trouble with that data was it didn't prove that the treatment wasn't working because it was possible that they'd only had it because their blood sugars were higher. So how did you try and tease out whether it really was working or not? Yeah, so we were able to follow a small number of patients. It was 16 in total who were referred on treatment and get them to stop the treatment and do a follow-up.

blood test after they'd been off treatment for three months. So we took some consecutive referrals that came in at that point and did a mini study, really it was small numbers, but asked patients to stop treatment and had a blood test before and after they'd stopped their treatment. And it didn't change at all. There was no difference when patients were off or on treatment. 6.3 % on treatment, it was 6.3 % on average after treatment. Yeah.

So in new units, it would be 46 millimoles per mole on treatment and then 46 millimoles per mole off treatment. And I think for me, what was interesting was what it told us about doctors. I remember going to Switzerland and a lady explaining to me that her patient did respond to treatment, but she needed to keep increasing it.

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So what would happen is that the Hb on C would be 6.5 % on one occasion and she would add a new treatment. And then she'd measure it again, it would be 6.3%. And so she would be pleased that the treatment had worked. And then through kind of natural fluctuation at some time, then again go up to 6.5%, at which point another treatment would be added. So the person was now on two drugs.

And then again, it would come back down again. It would fluctuate a bit, but as soon as it went back up again, then a third treatment would be added. And when I saw her, she had a person on three drugs and was thinking of starting insulin. And it was really interesting to me, because for me, it was clear that this was just the normal fluctuations in the measurement, but it was being seen as treatment response. And I think it's a really hard idea for doctors to get hold of, but there is a time where

treatments don't alter it. And what I say to them is, well, just think if you haven't got diabetes, then actually your blood sugar would just come back to its normal level if you took a drug, because you'd have to take insulin continually to keep it down. Because as soon as you take even a little bit, your own body shuts off its insulin and you keep the blood sugar at exactly the same value. But it is interesting how hard people found that result to accept.

So we know from work that Anna Steele did during her PhD that individuals with glucokinase don't go on and develop the complications that we typically see in other forms of diabetes. And that's something that Andrew mentioned previously. So that was a really important finding for this group of individuals, isn't it? Yes, I think now we're in a situation where Amanda's research has said that the treatment doesn't make a difference. And Anna Steele's work has shown that

there isn't a adverse consequence of the high blood sugars. And so really the most important thing is you have something that is really not diabetes. And I think one of the things we're trying to do is to remove that label. And sometimes people can get in a right pickle as their HPLC is near the cutoff for diabetes. But actually with people with blood glucose is raised because of a change in the glucokinase gene.

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They do not get complications. They do not need treatment and they do not need testing for complications. And it's quite a big step to persuade doctors to let go and discharge people from clinics. you think they need to have annual blood testing, Andrew and Maggie, HbA1c even? No, I wouldn't. In the same way as I wouldn't take someone who's got a normal blood glucose.

and test to see if they might develop type 2 diabetes in the future. So why should they do it with somebody just because they start off at a higher level? I can't say they won't get type 2 diabetes. I don't have any reason for thinking they will have it any more than somebody of a similar age and similar BMI. And in fact, we know that around one in a thousand people in the population have this change in the glucokinase gene. And most of them are going around and just have never had that.

incidental blood glucose tested as Andrew was until he went and had that medical for his insurance test. So most individuals with the glucokinase change actually are not having routine testing anyway. We have now been able to look in UK Biobank at around 200 people there who have a change in the glucokinase gene and show there are no adverse effects compared to the people who don't have that change.

So this long-term blood glucose really doesn't matter. So it's really interesting because we've got a genetic condition that is really good news. It's really good news because you've been told you've got diabetes and then you've been told that actually this is glucokinase raised blood sugar and you don't have diabetes. What we've started to do is to have a general letter that we will write.

not only to the doctors to get them to discharge the patients, but also to insurance companies to remove any weighting at all. Because sometimes, because people think they have type 2 diabetes, there's been an increase in premiums. So that's given us an overview of glucokinase and how it impacts. So Andrew, hearing Amanda's work, is there any reflections or questions that you've got? Well, it's very reassuring.

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to hear about the lack of complications with this. I guess one question I have is I've got three grown up children now, three young adults. So I guess they have a 50-50 chance of having this gluco-cannes mutation in each of them. So what should I advise them to do about either being tested or warning them about what to do if they do?

have a blood glucose measurement for some reason. I have told them about my diagnosis and so that they don't go down that same path of being mislabeled as type one diabetics needing insulin, whatever. But what's your advice about families, about what they should do about testing other members in the family? So we don't recommend family testing.

routinely in people who are not thought to have diabetes of some type. We do recommend that anybody who has been found to have a raised blood glucose, which might include gestational diabetes, or being labeled as having type two diabetes, that all family members who've got that should be tested. Because in that situation, finding out that it's glucokinase is really good news, because it means that they can stop treatment and normally their blood glucose will not need to be.

monitored after that. In contrast, if you have people who don't have a diagnosis, like your children, then we wouldn't recommend that you give them one, even if it's a benign diagnosis, because it's not of any benefit. And all that could happen is they could end up getting caught up in some system and called up for screening. And you just don't need that. So it's best to avoid it.

If ever your children ever want to know without having a genetic test, they can just test their fasting blood glucose because that's a very simple way of knowing. Generally for those that are men, we wouldn't recommend that they go looking for it. If you have a daughter, certainly prior to pregnancy, would be worth probably knowing that the glucose is raised because as you'll hear in subsequent podcasts, we've made real advances

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in managing it during pregnancy. And if you know that you've got a glucokinase mutation, we can test the fetus and treat the mother correctly as a result of that. So I think for your daughter at the time that she's thinking about children or when she first gets pregnant, then that would be a good time to test the fasting blood glucose. But we try to keep people away from doctors. We certainly have seen situations where they've gotten quite a muddle and actually made things worse.

Thanks, that's really helpful. I mean, I haven't advocated for any of my children to be tested, but I've just warned them if they, for some reason, like a medical insurance thing, kind of high blood glucose, that this would be something they should check out just to make sure. So they don't go down that rabbit hole of investigations and treatment that wouldn't be helpful. Thank you. So thank you, Andrew, for sharing your story of your diagnosis, finding out that you've got this change in the glucokinase gene.

And thanks to you, Amanda, for sharing your work that you've done in this area. Thank you for joining us. Thank you. Thank you. Thanks for unraveling this mystery too. It was great to hear from Andrew about his story and you could see why it would be so baffling for him to be told that he has diabetes when he feels completely well. then after they ruled out that it was

likely to be type 1 diabetes, then to be told it's type 2 diabetes when he's going to the gym and he's fit and he's slim. It really made no sense. Yeah, absolutely really confusing and how fortunate that he was looking at the Wellcome Trust newsletter and reading about your work about glucokinase. Yeah, that's really interesting that none of the professionals that he was seeing in America, even at a university hospital,

were considering the possibility that it could be glucokinase. But really once you got in touch and you said, well, it's incidental, high blood sugars, and it's just stayed stable and the treatment hasn't made any difference for me, that became kind of diagnosis you could make immediately. And we know so many times we've heard from other patients how they've either been picked up through routine screening, as you say, the women in pregnancy, the men.

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at routine medicals quite often or children with incidental hypoglycemia. That's such a frequent presentation. And also if I sometimes hear a story of someone saying about borderline diabetes, that always makes me think, could this be glucokinase? Then it was really interesting from Amanda how she did the research that really established that whatever the change in the glucokinase gene,

that you had a very similar level of blood glucose that was raised from the day you were born to the day you died and really stayed very stable, just getting slightly higher as the decades went past. But whenever you ate a meal, if it went up, it came back down again to that reset higher level. And I think it's such a simple message, isn't it, for healthcare professionals that raised fasting glucose above 5.5.

and the very stable HbA1c. I know with a number of patients we've tracked back over their records over a number of years when they've been treated as supposedly having type 2 diabetes and having a very stable HbA1c that really only fluctuates a very small amount. Yes, and that's helpful for diagnosis, but also interesting that you can then ignore whether they're on treatment or not because it was Amanda's work.

that really established that it didn't have any effect. And it's always hard to prove that something doesn't make a difference. It's actually much harder than Ewan's work, say, of proving how good HNF1-alpha responded to sulfonylureas. And I think it was interesting, your point about healthcare professionals finding it difficult to let some of the patients with glucokinase go out of their system, if you like. They are often retaining them on the diabetes.

annual reviews, which really Anna Steele's work showed that they're just not at risk of those complications of diabetes, so they don't require that follow-up. I do have some sympathy for them because when you've made a diagnosis of glucokinase, even now, it's still, I love being able to diagnose monogenic diabetes and to know that what I should do is having made that diagnosis is immediately discharge them from my clinic, so I can't tell anybody else about the

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diagnosis I made is a little bit disappointing but I guess I just have to live with that for the patient's sake. So we hope you've enjoyed this episode and if you'd like to hear more about glucokinase we'll be following on with the story about glucokinase in pregnancy. So join us again in two weeks time to hear the continuation of the glucokinase story.

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