In this Exclusive Interview transcript, Lisa Letourneau talks with Diabetes in Control publisher Steve Freed during the ADA 2018 convention in Orlando about genetics and diabetes, and how monogenic diabetes differs from type 1 and type 2.
To see this interview in full, click here.
Freed: This is Steve Freed. We’re here at the American Diabetes Association, 78th Scientific Sessions, here in Orlando. And there’s at least 20,000 people here, all about diabetes. And today, we have one of those 20,000 people, who’s very interesting and has an interesting type of job that she does as research. So, maybe we can start out with and you can just us a little bit about yourself.
Letourneau: Sure. My name is Lisa Letourneau. I am a dietitian by training but primarily a diabetes researcher nowadays. I work at the University of Chicago. I’m the Diabetes and Genetics Clinic Research Manager there. And my day-to-day job is basically overseeing and managing all of our studies related to kind of how genetics and diabetes are related to each other.
Freed: But you’re involved with monogenic diabetes.
Freed: And I think today if we could, number one, define what monogenic diabetes is, because I think most medical professionals, they know about type 1, they know about type 2 but monogenic is something new. And maybe you can just tell us, number one, what is monogenic diabetes.
Freed: And what can the medical professional do to help diagnose monogenic diabetes, because right now it’s either going to be one or two. And if you’re monogenic, you’re somehow going to fall into one of those.
Freed: And we know that with treatments, it’s more specific and there’s better things you can do if you’re diagnosed with monogenic. So, why don’t we start out with it and just tell us what is monogenic and then what is the best way to diagnose it. If a patient comes into your office and their blood sugar is elevated, you don’t immediately have to put them on insulin.
Letourneau: Sure, yeah. So, I think the best way to think about monogenic diabetes is just starting by kind of breaking down the words. So, mono meaning single and then genic having something to do with genes. So, basically it’s where you have a single gene mutation or abnormality in some gene that’s important for either beta cell function or glucose regulation. And that single mutation is enough to cause someone to have hyperglycemia. So, it’s kind of different than type 1 or type 2 which are polygenic diseases. So, although type 1 and type 2 both have a genetic component, it’s not just a single gene mutation that causes those conditions. It’s kind of having multiple genetic risk factors that together give you an increased risk to develop those sorts of things.
Freed: So, a patient comes into your office, they have elevated blood sugar, a fasting blood sugar, and A1C, the word monogenic never comes up in that process. They’re usually put on oral medication, if they’re type 2. If they’re type 1, they’re put on insulin. So, what should you be looking for when that patient is going through the different tests, or should there be another test to determine whether it’s elevated not because of obesity but because of genetics?
Letourneau: Yeah. Those are great questions. So, to kind of answer them separately, so clinical features that people can look for, the first one is the easiest and that’s diagnosis age. So, if people were diagnosed with diabetes under the age of one, so under about 12 months of age, we would encourage them to have genetic testing done to determine if they might have neonatal diabetes which sometimes can be treated with other medications besides insulin like oral medications. So, anyone diagnosed under age one should definitely get genetic testing. For people that are diagnosed after age one, there’s kind of a different set of criteria that you can look for. So, things that rule out type 1 and type 2 diabetes are helpful to start with. So, for example, if you have a patient who you might think otherwise would have type 1 diabetes but they were antibody negative at diagnosis, maybe their insulin requirements are pretty low, those might be reasons to think that they could possibly have this condition. If you have a patient who has a type 2 diabetes diagnosis or even pre-diabetes, if they don’t really have an elevated BMI, if they have incredibly stable fasting blood sugars that don’t really ever go above maybe 140 milligrams per deciliter, A1Cs are incredibly stable, and as well as the family history. So, we look for family histories primarily with people diagnosed under the age of 30 or so. So, they should have a linear family history. So, the patient might have diabetes diagnosed under age 30 as well as one of their parents, one of their grandparents, et cetera. So, that’s kind of the clinical features.
Your other question about what type of testing we could do, the only way to diagnose monogenic diabetes for certain is to do genetic testing. So, the problem with that is that it’s very expensive and insurance companies aren’t always willing to cover the cost of it. It’s not always cost effective to perform that testing on patients. And so, a few different groups including ours have looked at what situations make it cost effective. And so, there’s been some papers published on that. But if a patient has enough of a suspicion to think that they may have this condition, then it can be cost effective in some cases to have that testing done.
Freed: So, a parent comes into the office with a young one-year-old and elevated blood sugars, most medical professionals would say most likely, depending upon the A1C, that it’s type 1 diabetes. And they might do genetic testing, they might not. And then, another patient comes in, and I’ve seen this many times, where it’s a thin person with elevated blood sugars and it’s not type 1. They assume it’s type 2. And it isn’t, and yet the treatment for monogenic is completely different in most cases than you would normally treat somebody.
Freed: So, what is the most likely treatment for monogenic?
Letourneau: So, it really depends on what type of monogenic diabetes they have. So, for neonatal diabetes. like I’ve mentioned before. people that are diagnosed usually under six months of age but sometimes under 12 months of age, about half of those patients who have monogenic causes usually have a mutation in one of two genes that responds really well to oral medications like sulfonylureas. And so, that’s nice because they’re really cheap medications and they often have better blood sugars taking those medications than they do taking insulin as well as less hypoglycemia. So, that’s one example of kind of personalized treatment. Some others, so if a person has GCK-MODY, they don’t usually need any treatment at all. We’ve seen a few cases of people with GCK who were misdiagnosed with having type 1 or type 2, including one person who was misdiagnosed as type 1 and on an insulin pump for many years who didn’t need that treatment at all. He was able to come off of his pump entirely once he had a genetic diagnosis. So, it really depends on the type. Some types of monogenic diabetes still require insulin but it just kind of depends on which type is found.
Freed: Do you see anything unique about their blood sugars? You know, because it is a unique disease, you would think that their blood sugars are elevated all the time or they’re fluctuating all the time, especially if they’re being mistreated as far as in the type of medicines they’re given.
Letourneau: Yeah. So, there is one type of monogenic diabetes that has a very distinct phenotype. And so, I mentioned before in the kind of clinical features to look for if someone has incredibly stable fasting blood sugars, so always somewhere between a 100 and 140 milligrams per deciliter. Their postprandial blood sugars are usually under 200. Their A1C never really goes above 7.5% to 8%. That’s pretty characteristic of GCK-MODY. So, the problem is that some people with type 2 diabetes can kind of overlap into that category. And so, it can be a little difficult to sort those out. If the person with GCK-MODY is also a little bit overweight, it’s hard to kind of differentiate them sometimes. But that’s one example of the type of monogenic diabetes that has very consistent blood sugars. Other types, not so much. So, there’s HNF1alpha MODY, that’s also called MODY 3. People with that type of MODY can have pretty aggressive blood sugars where most of them don’t present NDK because they tend to still have a little bit of their own insulin production still, but they can have A1Cs up into the 10% and higher range. So, it really just depends on the type.
Freed: So, a person is diagnosed with an elevated A1C, are there ways to eliminate the monogenic, to know that it’s type 1 or type 2? The only way from what you’re saying is through genetic testing. So, is it recommended that we do genetic testing for people that are diagnosed with elevated A1Cs?
Letourneau: So, not for everyone because it wouldn’t be cost effective. Monogenic diabetes in general is pretty rare. It only affects about 2% of all people with diabetes. So, for the neonatal forms that are under age one that’s a pretty easy category to just test all of those people. For people who are diagnosed later and might have MODY it becomes a little more challenging to decide who to test and who not to test. What we usually tell providers is they’re the expert of their own patients. And so, if they feel like their patient just isn’t quite fitting with their usual type 1 and type 2 pictures, that might be reason enough to discuss that case further with a center that has expertise in this area. So, we’re certainly happy to do that. We talk to health care providers very frequently via email or phone. There’s other institutions in the world that do this type of research as well, but we’re always happy to help review cases. I would say if at least a few of those clinical features that I mentioned before are true then it might be worth giving them another look, so negative antibodies, normal BMI, and a strong linear family history.
Freed: Now, you’re at the University of Chicago and they have a monogenic diabetes registry. What is the purpose of that and does the university pick up some of the cost of the genetic testing if you participate?
Letourneau: Oh, that’s a very good question. (Laughs) So, the purpose, the registry was formally started in 2008 and so it’s our 10-year anniversary this year, so the purpose is really to follow patients that have these rare forms of diabetes over time, so that we can learn more about what are the best clinical features to look for, what’s the best treatment for them. So, it’s a longitudinal study that tries to address all of those things. We are able to provide a limited amount of research-based genetic testing for people free of charge. So, we do try to reserve that funding for people who are uninsured or whose insurance companies won’t cover the cost of their genetic testing. So, we have the funds to do that through combinations of research grants and grateful patients –we have a foundation where people can donate. So, we are able to do limited amount of testing. And our registry has over 3,000 people in it at the moment; about 900 of them have known monogenic form of diabetes. And some of those people we’ve tested in our lab, I would say maybe a third to half, and then the rest of them were able to get genetic testing done elsewhere.
Freed: What percentage of people come to you after being misdiagnosed with type 1 or type 2 and then you do the genetic testing and you find out that it’s monogenic diabetes and you change their treatment, and then they walk out the door very happy?
Letourneau: Yeah. So, unfortunately it’s a pretty high number of patients who have that situation. Something I think that’s really interesting is that about 50% of our referrals to the registry come from health care providers and then the rest come from patients themselves. So, we do get a lot of patients who are kind of their own advocates. They recognize that their condition isn’t quite like type 1 or type 2. They feel like they’re a little bit different. And so, they can also contact us directly and kind of be their own advocate. So, we have had many situations where people were misdiagnosed as something else. We’re able to help them get genetic testing and they end up having one of these forms that can be treated with a different medication, so that happens, not infrequently.
Freed: Diabetes is a worldwide disease. So, how is monogenic diabetes treated from other countries?
Letourneau: I think one of the major hurdles for most places, including in the US unfortunately, is being able to get the genetic testing done. So, some people will diagnose monogenic diabetes clinically by saying, “They meet all of these clinical criteria. I think they have MODY,” but we really encourage people to get the genetic testing done to be sure. So, even in the US insurance companies aren’t always willing to pay for it. In some other countries like in the UK, they have a really strong — I think it’s from the Welcome Trust that helps fund all of their genetic testings, so they have pretty good access to that. Certainly places like the continent of Africa, we don’t know a whole lot about monogenic diabetes there. We actually have a collaborator that’s from Nigeria, and so we’re trying to work with him on finding cases of atypical diabetes in Africa and just trying to scratch the tip of the iceberg of what could be going on in Africa with monogenic diabetes because it hasn’t been looked at very much.
Freed: What are the biggest negatives in trying to get the information out because it’s fairly new, not very well-known? I’m sure there’s a lot of stumbling blocks as far as getting the information out to the medical community. What are some of those?
Letourneau: Yeah. So, I’ve been pleasantly surprised. We deal with a lot of health care providers that we talk to that know a little bit about monogenic diabetes or are very willing to learn, which is great. But then of course there are many others who might not be so knowledgeable or don’t have the resources to be able to learn about it. So, we try our best to be a resource for health care professionals. So, if people have questions, we’re happy to answers those. Like I said, we spend a lot of time over email and phone talking to people. So, just that one-on-one interaction is certainly the major way that we reach out to health care professionals. And the other way is conferences like this, so being able to give talks and present posters is helpful. And then, we’ve been trying to increase our efforts at doing more broad dissemination of our work and our findings. So, something we haven’t done quite yet but are thinking about is like mailing materials to major academic centers in the Midwest and maybe seeing how that goes. And if it’s fruitful and helpful for health care professionals, then we would expand to other areas. So, we also have a website that I think provides information for people pretty readily. But, yeah, it’s definitely a challenge. And it’s rare, so I think a lot of providers think that it might not apply to them or that they don’t have patients in their clinic that have this condition. And we would challenge that by saying, “Maybe you just haven’t found the patients in your clinic that have this condition.” So, it’s definitely a challenge but we’re happy to try and work on it.
Freed: So, why should health care providers refer patients to the University of Chicago and what should they be aware of as far as where they should send them, as far as if they’re having difficulties in controlling blood sugars? I mean, there’s got to be some specific things that the physician could say, “It’s time that I send you out to the University of Chicago where they’re very knowledgeable about this and you might have this.”
Letourneau: So, yeah, we’re happy to take clinic referrals anytime. One of the nice things about our research group and our registry is that we don’t have to see patients in person to be able to discuss cases with providers. So, we do a lot of de-identified case discussion. So, I would say really any time people have questions. So, if you’re a health care professional and you feel like you have one of these weird patients that just doesn’t quite seem to fit into type 1 or type 2, that would be the perfect time to email us or call us. Like I said, we’re happy to review stuff. We don’t mind if the case isn’t quite what we normally look for, that’s quite okay we try and think of it as a learning opportunity and help the health care professional know what to look for next time. So, we do take patients into our registry who have a known form of monogenic diabetes. And I think that’s something that’s not as well-known by the health care community. So, if you have a patient who has GCK-MODY and is doing great, not on any medications, we would still love to have them in our registry if the family is up for participating in research because that’s the way that we’re able to help other health care professionals, is by learning more information about all those patients. And then, if your patient is not able to get genetic testing covered through their insurance and you really think that they might have one of these forms, that’s also a great time to contact us. If the patient is eligible for our registry, they might be eligible for this research-based genetic testing that we do that’s free of charge to the patient.
Freed: What is the cash price for that type of genetic testing?
Letourneau: So, it depends on what testing is done. If you just do a single gene test, like let’s say for example if you really thought your patient had GCK-MODY, depending on the lab that does that it’s anywhere between maybe a few hundred dollars and a thousand dollars. One of the nice things about genetic testing is that there’s been so many advancements over the last couple of decades, now people can do next generation sequencing panels that cover multiple genes at the same time. Those run anywhere from $1,000 to $6,000 or $7,000, it really depends on the lab. So, it can be very expensive.
Freed: One of the things that I know about monogenic diabetes is that many times it can be treated with sulfonylurea, as you mentioned, which is a very inexpensive drug compared to what’s out there today. What percentage of patients did you see could be treated with sulfonylurea?
Letourneau: So, for the neonatal patients, people with KCNJ11 or ABCC8 mutations are responsive to sulfonylurea at pretty high doses which is sometimes surprising for health care professionals, even up to two milligrams per kilo of sulfonylurea for patients. So, they tend to be pretty responsive. For the MODY side of things, HNF1alpha patients are pretty sulfonylurea sensitive where they might only need a quarter of a tablet a day. And HNF4alpha patients can be sulfonylurea sensitive but usually not quite as much as HNF1alpha. And HNF1alpha mutations are the second most common cause of monogenic diabetes in our registry in the US, whereas in Europe they’re actually the most common cause. So, it’s a fair number of patients from our registry that use sulfonylureas instead of insulin or other medications.
Freed: Do patients that have monogenic diabetes react to nutrition and physical activity as other type 1s and type 2s? It’s so important for people with 1 or 2 type diabetes. How important is that for the monogenic patient?
Letourneau: Yeah. It’s still important. I think as we deal with patients with monogenic diabetes, the genetic testing and as you mentioned the medication really usually takes the forefront, but just like type 1 and type 2 nutrition and exercise can certainly help with control of high blood sugars. We’re not so sure about how much diet modification, how much of an impact that might have for people that have GCK-MODY. As I mentioned before they have these pretty stable mildly elevated fasting blood sugars and we don’t think that being on a very low carb diet would modify their blood sugars enough for it to be clinically meaningful. But to investigate that thoroughly they’re already actually starting a study on that at the moment, so we’ll have more information about that hopefully soon.
Freed: Well, in the end of the conversation, I know that nowadays if you want information, go to the internet.
Freed: So, I’m sure you have a website developed —
Letourneau: We do.
Freed: — an educational website. And where would people go?
Letourneau: Yeah. So, it’s www.monogenicdiabetes.org. There’s lots of information on there for health care professionals as well as for patients. And if patients are interested in signing up for our registry, there is a link to our registration form there as well.