← Diabetes Core Update
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- [00:03]
A
Welcome to this special edition of Diabetes Core Update, where we're going to discuss an update on beta cell function. That's right, the old beta cell that we learned about in medical school, sitting right there in the pancreas. And I know you're asking what could be going on new there. Well, it turns out a lot. This special edition of Diabetes Core Update is sponsored by Sanofi. I'm your host, Dr. Neal Skolnick, professor of Family and Community medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. And this series on beta cell Update is being sponsored by Sanofi. Joining us today to help us to understand and to update us on beta cell biology and function is Dr. Melina Bellin. Dr. Bellin is a of pediatric endocrinology and Surgery. She is co director, Total Pancreatectomy and Eyelids Auto Transplant Program and the Albert D. And Eva J. Cornea Chair, University of Minnesota Masonic Children's Hospital. Welcome, Melina.
- [01:19]
B
Well, thank you, Neal, for having me today. I'm really happy to be here.
- [01:23]
A
Melina, let's level set. Before we talk about what's new, let's first go over the basics of the pancreas, silent cells, and the beta cell. Can you lead us through those basics?
- [01:35]
B
Absolutely. So I think, as your audience is probably aware, the pancreas has two different components, the exocrine component and the endocrine or the islet component of the pancreas. When we look at a pancreas on imaging, we're largely seeing the exocrine portion or the digestive portion of the pancreas that makes up roughly 98% of the pancreas mass. And it's composed of the acinar cells that make digestive juices and, you know, the trypsinogen, trypsin lipase, and then the duct cells that secrete those digestive juices into the gut. And of course, the the area of the pancreas that we're interested in as endocrinologists and I think your audience is interested in are the islets. And the islets are clusters of cells. They vary in size. So roughly, you could think of an average islet being about a cluster of a thousand cells. They're scattered through the pancreas. And and there's different cells within those islets. The ones that we think of probably most often in the diabetes world are the beta cell that makes the insulin and also C peptide, which is part of the pro insulin molecule. And then we also oftentimes think about the alpha cells that make glucagon in response to hypoglycemia. And there's a few other cell types in there that we maybe think less about, like the PP cells that produce pancreatic polypeptide. And that whole eyelid has a basement membrane or sort of a collagen structure around it to hold it together. And it's highly vascular, so it also has vascular cells.
- [03:04]
A
So let's just think for a minute about type 1 and then type 2 diabetes and remind us of what happens to those islet cells. Two very different phenomena.
- [03:15]
B
Yeah, yeah, you're absolutely right. So the, the thing that is common to probably all forms or most all forms of diabetes, including type 1, and is that there's some component of beta cell failure in either of those settings, but that beta cell failure is different. Right, so we're Talking about type 1 diabetes or autoimmune diabetes. Right. There's an autoimmune destruction of the beta cell. And so people with type 1 diabetes lose virtually all of their beta cell function over time. Now, you could say that if you looked sensitive enough, right, you might see very tiny amounts of insulin, but probably not clinically meaningful. In type 2 diabetes, by contrast, there is an insufficiency of the beta cell, meaning that the beta cell can't produce enough insulin to meet all the demands of the body, the metabolic needs of the body. And that might. And that is really heterogeneous in terms of like, there's a lot of heterogeneity in different patients within that population. Some individuals may be very insulin deficient, have a severe insulin deficient form of type 2 diabetes where they still make some insulin, they make some C peptide and insul insulin, but it's low levels. And then you have, you know, the spectrum of what people might classically think of with a very obese, insulin resistant type of person who actually might make high levels of insulin from their beta cells. But it's not enough. It's not enough to meet the demands of the body. And so there's still an insufficiency of the beta cell even in that setting.
- [04:43]
A
Great, that's so helpful. And we're going to come back to some of that toward the end of our podcast. Now let's transition and talk about some of the exciting things happening with regard to beta cell measurement, preservation, regeneration and replacement. That's a lot going on. Let's start with beta cell preservation.
- [05:02]
B
Yeah, you're right. That is a lot going on. And I think it highlights how diabetes management and treatment may be very different. You know, 10 years from now than it is now. And so I think if you think about diabetes now and how we're all taught to practice for diabetes, we look at, you know, glucoses and deterioration and glucose control, right? And then we start insulin or maybe a different type of drug therapy, and it's all focused on sort of treating the end of diabetes. And I think where the field is moving and I think particularly right now in type 1 diabetes, and I think this is maybe going to come in the future in type 2 diabetes, but in type 1 diabetes is how do we intervene earlier, right, to protect that beta cell so we don't lose the beta cell function and then have to replace it with insulin therapy. So what can we do to keep that beta cell healthy? And so, for example, within type 1 diabetes, a lot of the research over the past 10 and 15 years, you know, multicenter research through, supported by NIDDK and other institutions, is to really look at who's at risk for getting type 1 diabetes. How do we identify type 1 diabetes when it's pre symptomatic, meaning there's autoimmune disease. So this is what we call stage one or stage two type one diabetes. Now there's autoimmune disease that's active and you either have normal blood glucoses or you have some impaired beta cell function, but your glucoses don't meet diabetes standards. And so how do we catch people at that phase? And then hopefully, ideally in the future, how do we intervene with immunotherapies to or other therapies that will kind of halt that process of losing the beta cells?
- [06:43]
A
Boy, that, that just as you say that, that is just so exciting and amazing to think that we can even begin to think about catching things so early on. Tell us a little bit about beta cell regeneration and replacement.
- [07:03]
B
Yeah, so there. I think most people will think of this most classically as transplant therapies. That's kind of the classic form of beta cell replacement therapy where you're giving islets back. There is also some work in regeneration, sort of how do we make new beta cells without having to give a transplant? I think that maybe is not quite as close to the clinic yet. So I'll talk a little bit more about the actual beta cell replacement, because that is something that actually, although many people may not be aware or think of it much, is available to some extent, clinically. The really kind of classic beta cell replacement therapy that's been around since the 1960s actually is whole organ pancreas transplantation. Right. There are some patients with type 1 diabetes and type 2 diabetes who oftentimes need a kidney transplant, who get a pancreas transplant. Right. And they can replace those beta cells through pancreas transplantation. And it can work and it can restore insulin independence and normal glycemia. But obviously it's been very, very limited because it requires immunosuppression and a major surgery. Right. So there's only a certain number of patients with diabetes who have been treated with pancreas transplant. Now, more recently, although it's mostly under research trials, there are islet cell transplants where you're not giving the big surgery of giving the whole pancreas back, but you're just isolating those islets and giving those islets back. And interestingly, how they do that is they actually infuse them into the liver so they go into the portal vein and they make a new home in the liver and they can produce insulin. And the surgery is a very simple surgery. It can be actually done by an interventional radiology approach and people can come off insulin after this form of beta cell replacement therapy. But it's still been very limited. So for one thing, in the US it's limited to mostly clinical trials. Up until very recently, it requires still anti rejection medication. So these are islets that are coming from a deceased donor. And so it has all the issues of any type of organ transplant where you need immunosuppression. And because they've been like, from a deceased donor, you can only get so many of those islets. And so there aren't that many deceased donors who are appropriate to donate a pancreas to islet transplantation. So it's been a very limited field. It's been mainly people who have severe hypoglycemia. So think of the type of people with type 1 diabetes in particular who might pass out or have seizures because they're very brittle or labile. Those are the people who've really been treated with islet transplants and, or people who have a kidney transplant and then they get an islet transplant after a kidney transplant. So that beta cell replacement therapy actually is done to some extent right now. It's just done on a very small scale. And I think the future looking approach would be finding ways to overcome those barriers of cell supply and immunosuppression to be able to replace cells and more, more people than we can right now.
- [10:02]
A
And then this summer, I remember reading about stem cells. Where does that fit in?
- [10:08]
B
Yep. So that, that really fits into the, the future looking Approach. Now, stem cell derived islets are in clinical trials right now. So not in clinical practice, but in clinical trials. But they are being done in, in people with type 1 diabetes. Now, I want to just emphasize here that there aren't any treatments for type 1 diabetes where there's actual stem cells being put in. And so these stem cell therapies, sometimes people refer to them as stem cell therapies. What they really are is they're manufactured islets. So you're taking a stem cell, you're making it into either sort of an islet precursor or a nearly mature islet beta cell outside the person in vitro, right? And then you're transplanting that, that pancreatic progenitor cell or that immature islet cell into a person. And so they're actually trying to remove all the stem cells before those products go into people so that you don't have some of the, like, off target growth risk and stuff like that. But the amazing thing about those cells is that once you have a stem cell line, you can make many, many, many, many islet products, right? Kind of almost an unlimited number of islets to treat many patients who have diabetes. So as opposed to having to try to find someone, you know, who died and didn't have diabetes and could donate their pancreas, now you can take these cells that are actually manufactured in a standardized way and be able to give them to people. And so what's happening right now is the, there's various clinical trials that have gone on in this realm. There are ongoing trials where these islets, these type of islets are actually being transplanted with immunosuppression. There's upcoming trials where they'll be done without immunosuppression because of genetic editing. There have been trials where these type of islets have been transplanted in encapsulation devices to try to protect them from the immune system. That's had some challenges. Those islets haven't worked to a great extent. They may have some islet survival, but not a lot of islet survival. Because once you try to package the islets into something that hides it from the immune system, it gets hard to get good oxygen supply and good, you know, glucose exposure and insulin out. And so I think, you know, some of the genetic editing technologies where you can actually change the way the islets look to the immune system so that the immune system doesn't react and try to attack them, might have some real potential. And the goals there are like, okay, we can do it with the immunosuppression right now, but that's still a big risk for a lot of people. What if we can change these islets to where we can give them without immunosuppression or with very little immunosuppression? And now all of a sudden, we can take all of these people, Right. Many, many people with type 1 diabetes and give them back their cells.
- [13:07]
A
This is so amazing to listen to, because I live in a world where most of us in primary care are still trying to fig, do you give metformin first or an SGLT2 or GLP1? And that's challenging enough. And just to hear this whole other line of research and potential for incredible therapies in the future is just honestly amazing.
- [13:34]
B
Yeah, I would say it's a real. It's really transformative. Right. In terms of how that would affect the field. And I think when you're talking about thinking about all these different drug products, that's a lot of that's in the type 2 space. Right. The type 1 patients mostly just get treated with insulin. These cell therapies right now are being developed and tested in type one, but that's partly because that's an easy patient population to test these therapies in. And so when we give an islet transplant and we want to know, is that working? Right. The way we look at that is to measure C peptide as a marker of insulin production. And people with type 1 diabetes have undetectable C peptide. Right. If you were to measure it in clinic and someone who has 10 years of type 1 diabetes, you're probably going to get something that looks like zero in your lab. And so if you give them cells and then all of a sudden you see C peptide levels of 4 or 5, you know that that's the cells you gave back. So it makes it very easy to study. But I think once you have a treatment that's really successful in type 1, then people are going to start taking that and saying, like, okay, so what can we do for people with type 2 diabetes where it might be because people with type 2 make their own insulin, it's a little harder to measure a C peptide and say, did that C peptide come from that person or from the islets you gave them? But once we know the therapies work, we can start moving towards, you know, that form of diabetes as well.
- [14:54]
A
Yeah. So you mentioned measurement. Let's move on now and talk about testing beta cell function first, the how, and then we'll talk about when that might be applicable in practice.
- [15:08]
B
Yeah. So the, the, the very basic answer to how is that if you want to look at beta cell function, you're looking at either insulin or C peptide levels and usually looking at those in the context of what the glucose is, right? Because if the glucose is high, then your insulin and C peptide secretion should go up. If someone's hypoglycemic, even if they don't have diabetes, they're going to have low insulin and C peptide. And a lot of times what we like to use is actually not the insulin level, but the C peptide level. Because once you start getting patients who are taking insulin shots, right, Once you have someone who's on exogenous insulin, all of a sudden it becomes more difficult to interpret those insulin levels. So if you measure an insulin in the blood and someone's taking insulin, it depends on what type of insulin assay your lab is using. But sometimes it's going to pick up some of those insulin shots they're taking, right? But the C peptide. And so just take a step back for those who might have not thought about this for a long time. What the C peptide is is that when the beta cell makes pro insulin, which is kind of the precursor to insulin, right. It cleaves that apart into insulin and C peptide and then co secretes insulin and C peptide. And so when you look at C peptide, you're looking at the insulin someone's own body is making and you're not picking up any of the insulin they're taking. So that's really how we look at it in the clinic and the research setting. We can do a lot of specialized stimulation tests to kind of try to like, test certain, certain beta cell responses. But in the clinical setting we're usually just talking about maybe taking a fasting or a postprandial C peptide level.
- [16:47]
A
And let's talk about when we might do that. And let's start with type 2 diabetes first. Let's say that adult who comes into the office, their sugar's high, maybe they have a random sugar of 250. We'll make this a 40 year old gentleman who has a BMI of 27. Right. And so he doesn't fit perfectly the profile of our typical type 2 person with diabetes. Is there a place for C peptide testing in that, that individual? We're concerned obviously for our listeners about lada.
- [17:29]
B
That's right. And absolutely. I think that right now is probably the most, one of the most common scenarios where someone might use C peptide testing when they're trying to figure out Is this type 2 diabetes or is this like type 1 diabetes or a version of type 1 diabetes with latent autoimmunity or LADA where you might not need insulin at the onset, but you're going to progress because you have autoimmunity. Right. And so I think for those patients who just don't fit your typical profile of type 2 diabetes are not quite as obese as you'd expect. Maybe there's a, they're a little bit younger, they lack some of the insulin resistance features on clinical exam. There's a role for testing both autoantibodies, you know, to look for autoimmunity of type 1 or of LADA and then also testing the C peptide. And so if your patient that you just described has a low C peptide, you're going to be inclined, especially in the context of the glucose you described, right? So, you know, the glucose is 200. Now maybe your C peptide comes back as, you know, 0.5 for, you know, something below your, your normal range in your assay. You're going to think, well, this patient has insulin deficiency. This is more characteristic of type 1 diabetes or a blada. And, and within, within that LADA population, specifically where they may not need insulin at onset, there are some guidelines where if the C peptide level is, is quite low, is, is below. And I will say the caveat on C peptide levels is they'd have different units. And so you have to interpret this in the context of the units your, your, your lab is using. So if it's below about 0.3 nanomoles per liter, or in the U.S. more often, we're looking at nanograms per milliliter, so about 0.9. That's kind of a, a low C peptide level where you may, your first treatment choice may be insulin, right. When you start to get higher C peptide levels, it may be more appropriate to use the medications that you might follow for routine type 2 diabetes, but continue to follow that patient quite closely.
- [19:37]
A
That's so helpful and that's really a great example of where this is clinically useful. What I will do for our listeners in the program notes that are on the, that are with the podcast, I'll put a link to the management of Latent Autoimmune diabetes and adults consensus statement that was published in diabetes in 2020 because there's a ton of there and there's actually a really nice helpful algorithm to walk that through. We had talked in a previous podcast about screening for early type 1 diabetes. Is that another example where we one screen and we'll talk in a moment about how to screen. And then is that where beta cell preservation becomes, again, clinically meaningful?
- [20:26]
B
Yeah, that's absolutely spot on. So the early detection of type 1 diabetes, there's, there's two reasons why we have been more proactive about recommending screening for relative, you know, people who have a relative with type 1 diabetes or people who might be at risk because they have autoimmunity. And some people say maybe we should even be screening the general population. Right. And one of the reasons that we want to pick up type 1 diabetes at the early phase is because, you know, realistically, we can reduce the rates of, of decay by quite a bit. Right. If you know that you're at risk and you're monitoring closely, you can detect hyperglycemia earlier. But the other reason that you're getting at that's, that's going to be, I think, even more and more important over time is that we may have ways to protect those beta cells, protect that beta cell function that they have right now to either slow down or prevent the progression to symptomatic type 1, what we like to call stage 3 type 1 diabetes. Now, in the type 1 diabetes field, there's a single agent that's available right now that's actually FDA approved for that, a drug called toplizumab that targets T cells and depletes the T cells that are attacking the islets. And that's given at a very specific phase where you have antibodies and you have kind of pre diabetes range glucoses, but you don't yet have full diabetes where you need treatment. But I think that's just setting the stage to more and more of those type of therapies coming out in the next five or 10 years. And so we'll have more opportunities to not just wait to give someone insulin, but identify them early and intervene to prevent them from needing insulin.
- [22:07]
A
It is just so amazing. And can you just remind us again of the different stages? Because I think it's something that we're not all as familiar with, those pre clinical stages of type 1.
- [22:19]
B
Yep. So there, there are actually four stages to type 1 diabetes, and two of them are preclinical. And so stage 1 type 1 diabetes is the stage at which the autoimmune process is active. And so that what we can measure in the blood is autoantibodies. Right. There's also cellular autoimmunity attacking the beta cells. But what we can measure is things like GATA and insulin autoantibodies and zinc transporter 8 and Ia2. And at stage one, the glucoses are perfectly normal. So if you put a CGM on someone, you do an ogtt, you wouldn't be able to separate them from someone without diabetes. They look the same, but they have this active marker of having two or more autoantibodies to signal type 1 diabetes. Okay. Then those individuals you can continue to follow closely with intermittent OGTT or continuous glucose monitoring and eventually, eventually they'll progress to what's called stage two, type one diabetes. And stage two is that you have mild abnormalities in your glucose. It's not normal. So you might have impaired fasting glucose, you might have impaired glucose tolerance on an ogtt, you might even just have a spike up to kind of two hundreds post meal and come back down. And so there, I think there's a lot of to be worked out in exactly how to classify that, but that's stage two. And then stage three is you actually need insulin treatment. So you've damaged enough beta cells where you have a 1C 6.5 or higher fasting glucose right above 126, 126 or above, or random glucose above 200 with symptoms. And it's kind of classically what people think of as diabetes. It was stage three. Stage four just means they've progressed to destroying all of their beta cells. So within a few years someone goes from stage three to stage four diabetes because they no longer have any beta cell function.
- [24:14]
A
You know, it's interesting as you're saying that I'm thinking of on the other podcast that Ada does diabetes day by day, which is patient facing. About a year ago we had a physician on who both he and his wife have type one and they told this terrifying story of even as knowledgeable as they are, A number of years ago, driving on vacation, their daughter was very tired. And you know where this story is going, she had to go to the bathroom a number of times during this very long drive. And at one point she just looked terrible. And they said, you know, why don't we just check a blood sugar? And sure enough, it was very high and they went right away to an emergency room. She was quite sick and she did fine, thank God. But just how terrifying a story that was. And the idea of being able to have that sort of early detection for a number of reasons, one, so that someone doesn't present in dka, as you said, and then to potentially delay onset. Remind us of, I know you mentioned it briefly, but who are the potential candidates for screening and how to screen?
- [25:31]
B
Yeah, so the. I think it Depends a little bit on how you ask. Actually, anyone could get screened. There are research studies, the ask study that anyone can get screened, screen for antibodies if they want to. But the people that we right now sort of target for screening and highly recommend screening are people who have relatives who have type 1 diabetes. Now particularly first degree relatives. If you're a kid or even if you're a kind of a young adult up into age 40 to 45, that if you have a first degree relative with type 1 diabetes, you have about a 5% risk of having type 1 diabetes. That means you still have a 95% risk of not Right. But your risk is much higher than the normal population. So that's a group we strongly recommend at least discussing screening and offering that option. Now kids who have a second degree relative are also eligible for screening and some people might also consider it for people who have other autoimmune diseases like celiac disease, where you share some of the high risk genetic features. So that would kind of be the tier in terms of screening the first degree and then second degree relatives and then other autoimmunity.
- [26:39]
A
Okay. And it's. And you screen with the usual auto antibodies that we would.
- [26:44]
B
Yeah. So there, there's a few ways you can do it. There's, there's a couple research trials where people can get screened. If they do have a family member with type 1 diabetes, they can get screened through the, the Pathway to Prevention or it used to be called the Natural History study through trial net. There's this other research study asked that's a just general population screening that, that is open. But yes, you can also, if you have a patient in your clinic and you're drawing blood and they have a parent sibling child, you know, with type 1 diabetes, you can order, in your clinical lab you can order GAD antibody, insulin autoantibody, IA2 and zinc transporter 8 and those would be the sort of top four that we would use. Sometimes people also order an islet cell antibody titer as well.
- [27:32]
A
And if they were positive, we would refer them to one of our endocrinology colleagues.
- [27:38]
B
Yeah, I think that's correct. Right now it's really an interesting question because right now if someone has autoantibodies that are positive, they do get referred to us, particularly in the pediatric endocrinology world for sort of further assessment for the dysglycemia that would qualify them for teplizumab treatment and sort of discussion and monitoring. I think future looking, you can imagine a standard of care where everyone who has a relative with type 1 diabetes or maybe even the general population is being screened. And there may be enough people who are positive with autoantibodies that there isn't capacity to refer them all to an endocrinology clinic. And so at some point in the future, it may be that even people in the primary care clinic are getting that result back and then doing, you know, an oral glucose tolerance test or some screening to identify when to refer. But I think you're correct right now with kind of where we're at and this being relatively new, if you're picking up someone who has auto antibodies, picking up at least a phone to your endocrinologist colleague is probably your best next step.
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A
Yeah. And then remind us the, the results of giving toplizumab. What's the benefit?
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B
Yeah, yeah, so. So the results of giving toplizumab. Right. So I should say that right now, the way that toplizumab is given and it's based on the clinical trials that were done is it is given as a single, I'll say a single dose, but that dose is over 14 days. So a single course, I guess I would say of teplizumab therapy over two weeks and then there's no further treatment given. So it's very short term immunosuppression. And if you do that, you can delay the, on average, delay the onset, the time to go into symptomatic stage 3 type 1 diabetes by several years. I think there's like an open question about, you know, could there be options to repeat treatment or add other treatment or something else that would, would delay things. But that's the treatment right now is just a one time treatment and it's not thought to entirely prevent it, but to be able to delay it.
- [29:51]
A
Yeah, just what a fascinating discussion. We're just about out of time. Any final thoughts you have for our listeners?
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B
I just encourage people to stay tuned and be watchful of this field because I think it's really going to just change how we think about and treat diabetes over the next decade.
- [30:17]
A
I am looking forward to further discussions. Dr. Melina Belin, thank you so much for joining us.
- [30:24]
B
Well, thank you, Neil, for having me. This has been really a delight.
- [30:27]
A
And most of all, of course, thanks to our listeners. Thank you for joining us on this incredible discussion about beta cell function. Cutting edge area. This special edition of Diabetes Core Update is sponsored by sanofi. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.