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Mark Huising Transcript

Nov 18, 2017
 

To see this interview in full, click here.

Steve Freed: This is Steve Freed with Diabetes in Control and we’re here at the American Diabetes Association 77 scientific session 2017. We are here to present you some really exciting interviews with some of the top endos from all across the world. We have a special guest with us and I’m going to let you tell us a little bit about yourself and what you do.

Mark Huising: Okay so my name is Mark Huising. I am a basic scientist. I work at the University of California at Davis and I study physiology of pancreatic islets.

Steve Freed: You presented a symposium here and the title is “Neglected Delta Cell: The Difference Delta Cells Make in Glucose Control.” I consider myself fairly knowledgeable about diabetes but between the alpha and the beta cell, and know we are getting to the delta and maybe the gamma…what is the delta cell?

Mark Huising: So the delta cell is really nothing new and all of us and probably some of the folks watching also will know delta cells and they know that they are endocrine cells that sit in islets and around 1 to 10 percent of the islet cells are delta cells and they make somatostatin and that’s where we’ve stopped knowing and learning about them. Somatostatin was discovered actually right here in the San Diego area in my former lab back in the 70’s and back in those times when it was established that somatostatin is a really powerful way to inhibit insulin secretion from beta cells and glucagon secretion from alpha cells. But we haven’t really followed up and tried to understand how this works in a normal healthy person and potentially how the control afforded by delta cells breaks down in diabetes. In the last couple of years, we’ve really started to make inroads, to be able to understand those aspects of delta cells that we’ve not known before.

Steve Freed: So maybe you can describe some of your research interests. I know that when it comes to diabetes, most people involved are very passionate about what they do and a lot of people have diabetes.

Mark Huising: Right.

Steve Freed: Let me ask you, do you have type 1 diabetes?

Mark Huising: I have no personal connection with diabetes.

Steve Freed: Then what generated your interest?

Mark Huising: So, the way I started in this field is I was at the lab that discovered many of the peptide hormones that I work with. The lab was headed by Wiley Vail and he discovered, as I said, somatostatin but he also discovered a peptide that’s called urocortin 3 that is becoming better and better studied for reasons that we will talk about. Urocortin 3 is a wonderful way to mark mature beta cells. Basically, if a beta cell makes and expresses urocortin 3, it’s a real beta cell and we know this now. When we started this, we didn’t know this though. We discovered this peptide urocortin 3, not knowing anything about it, and it turned out that one of the main sites that expresses urocortin 3 is the beta cell, and the pancreas and the question became “well if the beta cell makes large amounts of this urocortin peptide, what is it doing?” and that’s what I’ve been studying ever since.

Steve Freed: So obviously you presented here. What were the most important points of your presentation that you wanted people to take away?

Mark Huising: The most important points are that delta cells are there for a reason. They participate in the accurate control of insulin secretion from beta cells and glucagon secretion from alpha cells. If you do not have delta cells and the direct feedback they provide, minute to minute, second to second, beta cells and alpha cells don’t know when to stop secreting. Like everything in biology, what comes up has to come down, and the feedback by delta cells helps beta cells come back down after they have secreted insulin, after insulin has told the body to store glucose away and keeping insulin secretion high will be detrimental, so it needs to be shut down and delta cells are important to help beta cells timely attenuate insulin secretion.

Steve Freed: What percentage of the beta cells are delta cells?

Mark Huising: So, in mice it’s about 60 to 70%, in humans 50 to 60% of the endocrine cells are beta cells and depending on the islet, between 1 and 10% of the endocrine cells are delta cells. Now the big difference here is that beta cells have to release enough insulin to serve almost every other cell in the body, so they need to release a lot of insulin for the insulin to reach basically all the other tissues in the body. Delta cells have only to supply enough somatostatin to target the beta cells in the same islet. So there is a reason why there are not as many delta cells. Their audience, if you will, is more limited to the cells in their immediate surrounding.

Steve Freed: A person who has type 2 diabetes where he is insulin resistant and has glucose toxicity, the beta cells don’t work very well in that environment, does that also…I presume it affects the delta cells in a similar way.

Mark Huising: So, the way the delta cell feedback breaks down in somebody with diabetes is beta cells, as I said before, they express urocortin 3 peptide and every time a beta cell secretes insulin, which talks to liver, skeletal muscle, adipose tissue, they secrete a little bit of urocortin 3. This urocortin 3, instead of talking to cells elsewhere, just talks to the neighboring delta cells. Delta cells respond to urocortin 3 by secreting somatostatin, and somatostatin talks back to beta cell and helps the beta cell shut down stop secreting, provided that the insulin it gave off was sufficient to bring glucose levels back down. Now that’s how it works in a healthy individual. What happens early on in somebody even with pre-diabetes and they’ve shown this not only in mice models but in human donor samples as well as in macaque models of pre-diabetes, that even in a pre-diabetic macaques, we see this urocortin 3 disappear really quite early on, signaling that this local feedback, the normal feedback that helps attenuate beta cell function really doesn’t work appropriately anymore. And what happens then, there’s two things that happen, the loss of urocortin 3 means that the break of beta cells goes away so you allow more insulin to come out which is a sort of adaptation but what it also does is it contributes to these wild, volatile swings of plasma glucose. Rather than timely and pre-emptively inhibiting insulin activity from beta cells to make sure that you arrive just back down at your normal target for glucose, insulin is not timely released. It stays high for too long, glucose overshoots its set point and now it’s going to have to activate some kind of counter regulatory mechanism to come back up and you can actually see that if you apply glucose monitoring to mice, which we’ve done. You can actually see that really volatile pattern associated with the loss of urocortin 3 feedback.

Steve Freed: Now we can measure activity of beta cells.

Mark Huising: um hm

Steve Freed: Can we do that with delta cells?

Mark Huising: We can do the exact same thing with delta cells. We could do it with elective physiology where you basically stick a thin glass capillary in a cell and measure the electrical currents. It’s really hard to do. It’s really specialized. And recently, people have made wonderful tools available where we don’t have to do it that way anymore. We can actually look at fluorescent proteins that light up as soon as the cell releases calcium and calcium is an important second messenger and is a wonderful proxy for hormone secretion. So, rather than looking at hormone secretion directly we can actually take islets, put them under a microscope, and watch them behave in real time and look at the activation of delta cells, or beta cells, or alpha cells as we apply different drugs and then study the effect on cell activity. So, it’s actually very cool to do, but also very instructive because we can start to really figure out which drugs or which peptide hormones or which pharmacological agents work directly on beta cells and which ones work because they activate or inhibit a neighboring cell like a delta cell.

Steve Freed: Have you looked at some of the medications and how they react on the delta cells? For example, the GLP-1 drugs that were looking at possible regeneration of beta cells.

Mark Huising: Right, so delta cells in many ways resemble beta cells. There’s differences and we’re starting to appreciate them too. But the basic principle, the basic mechanistic building plan of the delta cell is the same as a beta cell and that is you need a way to sense glucose. That sensing of glucose causes the closure of what we call KTP channels. Sulfonylureas target those. So they will also target delta cells the same way that they will target beta cells and then the closure of KTP channels causes depolarization, the opening of voltage gated calcium channels, and these are again the same channels between delta cells and beta cells. The difference between delta cells and beta cells is more on the level of which receptors are expressed by the two different cells. For example, the incretin hormone, going through GLP-1 receptor, will probably also activate delta cells, but the incretin hormone receptor levels are much higher on a beta cell and then different receptors for example the receptor for urocortin 3 which is the same family, it’s a close relative to the incretin receptor, that one is not expressed by beta cells but it’s expressed by delta cells. The mechanisms by which they promote hormone secretion are actually the same between delta cells and beta cells so the main difference is the repertoire of the receptors that these cells have which dictate what signals they respond to and that’s how delta cells respond to different signals than beta cells.

Steve Freed: So, what do you hope to learn with doing that type of research and how is it going to benefit the patient with type 1 diabetes?

Mark Huising: So, I think there is great value in knowing. There is intrinsic value of basic research that is not be underestimated. We did not know how delta cells work until we and some of our colleagues started to put these things on the table and we now know that this break down of crosstalk locally within islets is part and parcel of the early pathophysiology of diabetes and I think that’s important to know as well. How this would benefit somebody with type 1 diabetes is it’s known that in type 1 an aggravating problem is not the lack of insulin which is obvious for the lack of beta cells but also beta cells normally somehow are able to curve excess glucagon secretion and we think that is these local feedback mechanisms urocortin 3 coming from beta cells activating delta cells, that somatostatin doesn’t only feedback on beta cells but may well feedback on alpha cells as well and will help keep the alpha cells under control, prevent hyperglycinemia and if your beta cells are gone when you have type 1 diabetes, there will not be a feedback control on alpha cells and alpha cells proceed to secrete too much glucagon, which is as we all know not particularly helpful. So, I think there is a real potential here to not only learn basic mechanisms but also start to learn more about mechanisms that could potentially be targeted therapeutically.

Steve Freed: So if you were teaching in med school, teaching a bunch of PCP’s, number one what is the benefit for them to understand this? And can they use that knowledge to help type 1 and type 2 patients?

Mark Huising: I teach a large physiology course. That’s one of the things I teach and it’s actually a lot of fun and what it does is it gives me an opportunity to not even go into too much detail on this per se, I use it usually as an example. This is the most recent findings, this is not what you would find in your textbook but we are still finding new things. What you’re learning from textbooks is what people did 5 or 10 years ago and hopefully this kind of stuff will be properly added in the next generation of textbooks. What it allows me to do is instill some understanding into that it’s not just beta cells or not just insulin but that there is this really complex interaction going on that is important to at least appreciate. And many of the kids coming through my classrooms, they don’t know the difference between type 1 and type 2 or they might of heard a thing or two about it, but they don’t really know how to distinguish the two, that they are really quite different diseases and that there is also a wide spectrum of disease and what we lump together as type 2. So just an opportunity to be able to talk about those things with them and to impress upon them that this is a very serious healthcare problem that is not going to go away anytime soon. 10 years from now, these are going to be the folks who are at the frontlines having to deal with this in their clinics and in their hospitals and being able to talk to them early on hopefully I’m able to make some kind of an impression that this is important not just to know how it works but also that if we don’t learn how to manage this better, we’re going to have as a society and as a country I think, a major problem on our hands and that’s a whole different side of what I get to do, which I really also appreciate.

Steve Freed: You know it’s interesting talking to you because your type of research doesn’t make the 5 o’clock news most of the time so what you do is kind of unique for what you do but the information, really a lot of it doesn’t get out there into the medical communities.

Mark Huising: Well, this is why I appreciate you talking to me so hopefully I can at least share some of the things that we do and that we are learning really new things at a pretty good clip and some of these might ultimately progress to the point that your audience might learn about them as a mechanism but that some new drugs can help their patients manage their disease better.

Steve Freed: How long have you been involved in research?

Mark Huising: In research? Oh, I think about 20 years if you count my undergraduate education where I also did research.

Steve Freed: So including your undergraduate, what is probably the most important thing that you’ve discovered besides the self-driving cars?

Mark Huising: No I won’t take credit for those nor will I take credit for the Internet. (laughter) I think this feedback control. It really its important. It makes perfect sense for those of us who study physiology. Our whole body is driven by negative feedback. To me it was surprising that this hadn’t been figured out yet. It sets the homeostatic set point for glucose. Healthy individuals, folks with no diabetes, they set their glucose based on the feedback that I just described to you. And if that feedback breaks down…I saw a talk today in the same session that I presented in, with a mutation of glucokinase and that mutation of glucokinase had an immediate and dramatic effect on the patients with an activating mutation causing hypoglycemia. I mean it illustrates that a single mutation just in a delta cell affecting this feedback control can have profound effects on somebody’s glucose levels so I think that’s really important and I think it behooves us to know about these things so that we can take advantage of it when trying to design better ways to manage disease.

Steve Freed: So, have you learned anything here, and it’s not over yet, but that can possibly help your research?

Mark Huising: Oh, I’ve learned a ton. I always learn from listening to colleagues. I always learn not just from the science but also from the techniques, the creativity that they put on display and tackling the problems that they study and it’s always wonderful to come to a meeting like this and learn from them and then talk to them and find ways to collaborate so that we can help each other do the best that we can and finding out the most that we can and I am big believer in understanding how things work. If you don’t understand how things work it becomes difficult to fix it. I know sometimes we don’t understand how drugs work but I am a big proponent to understanding things and then using that information hopefully to our benefit and if it were just one individual, there is only so much you can do so we need this scientific community to help all of us improve the work that we are able to do.

Steve Freed: Well I thank you for what you do because without the research, we wouldn’t be here.

Mark Huising: Thank you very much for that. Thank you for taking the time.