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(Study) https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30742-3
Interview: New Drug Cocktail That Increases Human Beta Cell Proliferation at Rapid Rates
http://www.diabetesincontrol.com/interview-new-drug-cocktail-that-increases-human-beta-cell-proliferation-at-rapid-rates/
Author: Steve Freed, R.PH., CDE
Diabetes in Control is pleased to bring you an exclusive interview with Dr. Andrew Stewart. Dr. Stewart and his fellow researchers at the Icahn School of Medicine at Mount Sinai have discovered a novel combination of two classes of drugs that induces the highest rate of proliferation ever observed in adult human beta cells—the cells in the pancreas that produce insulin. The result is an important step toward a diabetes treatment that restores the body’s ability to produce insulin. The finding involved one drug that inhibits the enzyme dual specificity tyrosine-regulated kinase 1A (DYRK1A) and another that inhibits transforming growth factor beta superfamily members (TGFβSF). Together, they caused the cells to proliferate at a rate of 5 to 8 percent per day.
Steve Freed: This is Steve Freed with Diabetes in Control and we have a very special interview with Dr. Andrew Stewart M.D., scientific director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine at Mount Sinai.
I know you had some breaking news today. For me, it’s really exciting. I’ve been following regeneration of beta cells for probably 15 years. That’s one of the reasons I got involved with diabetes and became a certified diabetes educator. So because of your research, we’ve gone from basically “it’s impossible” three years ago, or maybe five years ago, to “it’s clearly possible for beta cell regeneration.” It is really the holy grail for the treatment, or technically the cure, for diabetes because it’s not about surgery at this point in time. It’s really about bringing the pancreas back to where it was. How long have you been involved with the science of the regeneration of beta cells?
Dr. Stewart: Well, I’ve actually been working on various kinds of regeneration research for about 40 years but mostly in bone for the first 20 years. And about 20 years ago, I got involved in the pancreas business of regeneration.
Steve Freed: And according to your research, you have had a breakthrough and discovered a combination of drugs that can reproduce beta cells from the rate of 5 to 18 percent a day, which technically could be a cure for type 1 and type 2 diabetes.
Dr. Stewart: So, we’re seeing, from my point of view, maybe a whole background. I mean what I say is that up until really the last 10 years everybody thought that type 1 diabetes opened with the immune system destroys all of your beta cells. So if you’ve got type 1 diabetes, you have zero beta cells and therefore you can’t make insulin. It turns out that’s not true. Looking at autopsy studies, it’s now pretty clear that almost everybody with type 1 diabetes — if you can get a pancreas from those people when they pass away — have beta cells left even if they’ve had diabetes for 30, 40, 50, 60, 70 years. If you think about it in terms of gas tank numbers, that the beta cell tank is about 95 percent empty. But there are still residual beta cells in type 1. And then in type 2 diabetes, everybody’s view [is] that it is a disease of insulin resistance and that’s true. It is associated insulin resistance, but it’s clear that there had to be something else because everybody who’s overweight has some resistance. So if obesity or overnutrition were the only cause of type 2 and insulin resistance, then everybody [who is] overweight would get diabetes and that’s clearly not true.
Two thirds of people who were overweight never get diabetes. So that has to be something else. And it turns out that the something else is the reduction numbers of beta cells in type 2. So if you look at the pancreas of people with type 2 diabetes, the beta cells are reduced by about 50 to 60 percent compared to non-diabetics. The weight matched in gender-matched controls. So stepping back — and it turns out that at the moment in the United States, there are 30 million people with some kind of diabetes — all of them are suffering by inadequate numbers of beta cells, but each of them also has residual beta cells who could be subject to regenerative therapies if we had them.
Steve Freed: So with the autoimmune system in type 1 diabetes destroying the beta cells, at what level do we need to be producing beta cells to keep the pancreas running normally. My understanding is we only need 18 percent 20 percent of our beta cells to prevent diabetes?
Dr. Stewart: Everybody with diabetes has beta cells left, [so] then the question is what would it take to make them or generate? And so it turns out that people have looked at beta cell proliferation or regeneration at autopsy in every age group, and the only time that there is beta cell proliferation or regeneration in human beings is during the first year of life and a little bit more of residual proliferation when you’re a toddler, and then after that it tapers off to essentially nothing. So the beta cells that people have as adults, they made when they were a baby. They don’t get any more; they don’t proliferate again later in life. And you take the beta cells you’re born with or you got when you were a baby, you take them to the grave with you. And so up until three years ago, or in 2015, there were no ways to make beta cells replicate. So in 2015, we described this molecule called Harmine, also known as telepathine, which turns out to be able to make beta cells regenerate, and then the rate of proliferation that Harmine was able to reduce in human beta cells was about 2 percent per day. And that’s terrific. But at the end of the day, it’s probably if your basal tank is 95 percent empty, you’d like to see more than 2 percent per day. So we sought additional ways to make beta cell regeneration go more quickly and through genomic studies of human insulinomas, which were rare benign tumors of the beta cells that overproduce insulin. We basically analyzed all the genes that were mutated or misregulated in insulinomas and we found that they frequently have abnormalities in genes associated with a family growth factor called TGF-beta and and they’re signaling molecules.
So we thought it would be reasonable to then try using drugs that were smart inhibitors or TGF-beta inhibitors (those are the same thing) and maybe we could use them alone or maybe we could use them in combination with Harmine and get higher rates of proliferation. So what the paper that we just published yesterday shows is that, in fact, was a reasonable guess. If you combine Harmine with the human beta cells, you get about 2 percent proliferation per day. If you read Harmine plus any one of a number of TGF-beta inhibitors basal proliferation increases up to around 5 to 8 percent per day in beta cells derived from organ donors, which is where we get our human islets, and in some of the organ donors, the basis of proliferation rate as high as 15 percent or 18 percent or so. So the one striking feature of this paper that makes it noteworthy is that no one has ever seen this rate of human baby cell replication previously. So that’s pretty exciting.
Steve Freed: So right now you’re able to reproduce beta cells in a petri dish, but not in living organisms. So, what is your next step?
Dr. Stewart: Well, actually that’s a great question. Right now, it’s all in vitro, but we also show in the paper that we can take mice and treat them with Harmine and we can regenerate the beta cells in their pancreas. If we take out 60 percent of the pancreas in a mouse, it will regenerate the whole pancreas, including beta cells, over a period of about three weeks. But if you give them Harmine, it recovers the whole thing in about a week. So we can actually increase in vivo replication in the mouses pancreatic beta cells.
The next big hurdle. Okay, so obviously one of the hurdles is how it affects other organs in our body, like we know that Harmine affects the brain. We know that the other elements can affect other organs, before we can actually go much further. So essentially it is a given that treating a mouse or a human being with one of these drugs alone or a combination is going to have effects on other organs. So it is like a parcel we put in an Amazon delivery truck or a drone, but we don’t have anyone to deliver it, so that’s what we’re working on now. We’re working on ways to target these molecules, specifically the beta cells and to other cells. I say that right now in 2018 there is no perfect targeting molecule known to get things to beta cells, but you know if you look back just three or four years ago, there were no drugs that could make beta cells replicate. So part of the fun of being in science at this phase of scientific development is you know things happen and you can make things happen in biotechnology and violent dramatics allow us to do things that we just couldn’t even think of doing. So I think it’s likely that beta cells targeting drug molecules will be identified in the next few years. And INH and JDRF all putting money into supporting research to identify these targets. And so and we’re certainly puttering our efforts on that.
Steve Freed: Can we break apart the different types of diabetes and how the research will affect them?
Dr. Stewart: In type 2 diabetes, if you think about it, if you make 5 percent new beta cells every day and you just have to go from 50 percent normal to 100 percent, it wouldn’t take you very long to get there. So I don’t think there’s likely to be a major problem in regenerating beta cells in type 2 diabetes, but type 1 is different. You’re starting with a tank that’s much, much closer to empty. And so greater rates of preparation and longer duration of treatment are probably necessary. And as I said, it’s only going to be effective if the immune system can be controlled. If it can’t be controlled, then I don’t think our therapy is going to offer much. Having said that, I think everybody who works on diabetes basic science knows that. And so that is a huge effort. The NIH and the JDRF and FDA are putting literally hundreds of millions of dollars a year into so-called immuno module tree therapies to dial down autoimmunity. And I should say also in Europe and Asia and Australia, et cetera there’s a lot of work being done in that area.
Steve Freed: For type 2 diabetes we’re seeing a lot of people with obesity having type 2 diabetes beta cell failure because of obesity, too much body fat. I can see using your concept to produce more beta cells to get back to 100 percent, but if they continue to eat and gain weight, then we’re just going to be producing more and more insulin and they’re going to gain more and more weight.
Dr. Stewart: I don’t think it’s going to be hard to get the beta cell tank up to 100 percent or even 200 percent. I think that that’s going to happen; that’s doable. But as you point out, it’s the thing that got them into trouble in the first place, overnutrition, and you know being overweight and eating improperly, then they too are going to have problems with extra beta cell work and possibly more cell damage. Having said that, most people with obesity, even most people with extreme obesity, don’t get diabetes. And if you look at the beta cell mass in autopsy studies, it’s much higher than in people who are normal or people who ultimately get type 2 diabetes. So not that I am recommending this, but it is possible to generate to have a number of beta cells as large enough to secrete enough insulin.
Steve Freed: Already on average the long-term efficacy of that isn’t very good. I don’t have any way to promise or any reason to promise that our approach would be better in terms of the weight control. So you know adherence to diet, that’s that’s going to remain a big issue.
So maybe you can just give us a short resume. What is your daily life like?
Dr. Stewart: I’m an endocrinologist. I was at Yale for 20 years and I was at the University of Pittsburgh for 15 years and I have been here [Mount Sinai] for six years. And so I saw patients for about 40 years and I liked it a lot. But I also was doing basic science when I was in Pittsburgh. I was the head of the division. We had a big clinical practice group and I decided, about seven or 10 years ago, that my additional clinical report to the larger group was limited and research was going so well that I wanted to spend my time right into the sunset focusing on on research. It’s exciting. It’s an amazing time in research. You can do things, as I said earlier, that just were unthinkable a decade ago and you can do them quickly and easily. So it’s so much fun, I decided that I would just stop seeing patients and see research and do research. But having said that, I have been doing therapy with diabetes for 40 years. And so I’ve seen the whole thing and I would say to me, it’s very impressive to see how much has happened actually just in the last 10 years. Now we have the artificial pancreas, we have sensors, we’ve got pumps, and we’ve seen amazing things happen and they’re just getting better and better and faster and faster. They’d be great.
Interview: New Drug Cocktail That Increases Human Beta Cell Proliferation at Rapid Rates
http://www.diabetesincontrol.com/interview-new-drug-cocktail-that-increases-human-beta-cell-proliferation-at-rapid-rates/
Author: Steve Freed, R.PH., CDE
Diabetes in Control is pleased to bring you an exclusive interview with Dr. Andrew Stewart. Dr. Stewart and his fellow researchers at the Icahn School of Medicine at Mount Sinai have discovered a novel combination of two classes of drugs that induces the highest rate of proliferation ever observed in adult human beta cells—the cells in the pancreas that produce insulin. The result is an important step toward a diabetes treatment that restores the body’s ability to produce insulin. The finding involved one drug that inhibits the enzyme dual specificity tyrosine-regulated kinase 1A (DYRK1A) and another that inhibits transforming growth factor beta superfamily members (TGFβSF). Together, they caused the cells to proliferate at a rate of 5 to 8 percent per day.
Steve Freed: This is Steve Freed with Diabetes in Control and we have a very special interview with Dr. Andrew Stewart M.D., scientific director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine at Mount Sinai.
I know you had some breaking news today. For me, it’s really exciting. I’ve been following regeneration of beta cells for probably 15 years. That’s one of the reasons I got involved with diabetes and became a certified diabetes educator. So because of your research, we’ve gone from basically “it’s impossible” three years ago, or maybe five years ago, to “it’s clearly possible for beta cell regeneration.” It is really the holy grail for the treatment, or technically the cure, for diabetes because it’s not about surgery at this point in time. It’s really about bringing the pancreas back to where it was. How long have you been involved with the science of the regeneration of beta cells?
Dr. Stewart: Well, I’ve actually been working on various kinds of regeneration research for about 40 years but mostly in bone for the first 20 years. And about 20 years ago, I got involved in the pancreas business of regeneration.
Steve Freed: And according to your research, you have had a breakthrough and discovered a combination of drugs that can reproduce beta cells from the rate of 5 to 18 percent a day, which technically could be a cure for type 1 and type 2 diabetes.
Dr. Stewart: So, we’re seeing, from my point of view, maybe a whole background. I mean what I say is that up until really the last 10 years everybody thought that type 1 diabetes opened with the immune system destroys all of your beta cells. So if you’ve got type 1 diabetes, you have zero beta cells and therefore you can’t make insulin. It turns out that’s not true. Looking at autopsy studies, it’s now pretty clear that almost everybody with type 1 diabetes — if you can get a pancreas from those people when they pass away — have beta cells left even if they’ve had diabetes for 30, 40, 50, 60, 70 years. If you think about it in terms of gas tank numbers, that the beta cell tank is about 95 percent empty. But there are still residual beta cells in type 1. And then in type 2 diabetes, everybody’s view [is] that it is a disease of insulin resistance and that’s true. It is associated insulin resistance, but it’s clear that there had to be something else because everybody who’s overweight has some resistance. So if obesity or overnutrition were the only cause of type 2 and insulin resistance, then everybody [who is] overweight would get diabetes and that’s clearly not true.
Two thirds of people who were overweight never get diabetes. So that has to be something else. And it turns out that the something else is the reduction numbers of beta cells in type 2. So if you look at the pancreas of people with type 2 diabetes, the beta cells are reduced by about 50 to 60 percent compared to non-diabetics. The weight matched in gender-matched controls. So stepping back — and it turns out that at the moment in the United States, there are 30 million people with some kind of diabetes — all of them are suffering by inadequate numbers of beta cells, but each of them also has residual beta cells who could be subject to regenerative therapies if we had them.
Steve Freed: So with the autoimmune system in type 1 diabetes destroying the beta cells, at what level do we need to be producing beta cells to keep the pancreas running normally. My understanding is we only need 18 percent 20 percent of our beta cells to prevent diabetes?
Dr. Stewart: Everybody with diabetes has beta cells left, [so] then the question is what would it take to make them or generate? And so it turns out that people have looked at beta cell proliferation or regeneration at autopsy in every age group, and the only time that there is beta cell proliferation or regeneration in human beings is during the first year of life and a little bit more of residual proliferation when you’re a toddler, and then after that it tapers off to essentially nothing. So the beta cells that people have as adults, they made when they were a baby. They don’t get any more; they don’t proliferate again later in life. And you take the beta cells you’re born with or you got when you were a baby, you take them to the grave with you. And so up until three years ago, or in 2015, there were no ways to make beta cells replicate. So in 2015, we described this molecule called Harmine, also known as telepathine, which turns out to be able to make beta cells regenerate, and then the rate of proliferation that Harmine was able to reduce in human beta cells was about 2 percent per day. And that’s terrific. But at the end of the day, it’s probably if your basal tank is 95 percent empty, you’d like to see more than 2 percent per day. So we sought additional ways to make beta cell regeneration go more quickly and through genomic studies of human insulinomas, which were rare benign tumors of the beta cells that overproduce insulin. We basically analyzed all the genes that were mutated or misregulated in insulinomas and we found that they frequently have abnormalities in genes associated with a family growth factor called TGF-beta and and they’re signaling molecules.
So we thought it would be reasonable to then try using drugs that were smart inhibitors or TGF-beta inhibitors (those are the same thing) and maybe we could use them alone or maybe we could use them in combination with Harmine and get higher rates of proliferation. So what the paper that we just published yesterday shows is that, in fact, was a reasonable guess. If you combine Harmine with the human beta cells, you get about 2 percent proliferation per day. If you read Harmine plus any one of a number of TGF-beta inhibitors basal proliferation increases up to around 5 to 8 percent per day in beta cells derived from organ donors, which is where we get our human islets, and in some of the organ donors, the basis of proliferation rate as high as 15 percent or 18 percent or so. So the one striking feature of this paper that makes it noteworthy is that no one has ever seen this rate of human baby cell replication previously. So that’s pretty exciting.
Steve Freed: So right now you’re able to reproduce beta cells in a petri dish, but not in living organisms. So, what is your next step?
Dr. Stewart: Well, actually that’s a great question. Right now, it’s all in vitro, but we also show in the paper that we can take mice and treat them with Harmine and we can regenerate the beta cells in their pancreas. If we take out 60 percent of the pancreas in a mouse, it will regenerate the whole pancreas, including beta cells, over a period of about three weeks. But if you give them Harmine, it recovers the whole thing in about a week. So we can actually increase in vivo replication in the mouses pancreatic beta cells.
The next big hurdle. Okay, so obviously one of the hurdles is how it affects other organs in our body, like we know that Harmine affects the brain. We know that the other elements can affect other organs, before we can actually go much further. So essentially it is a given that treating a mouse or a human being with one of these drugs alone or a combination is going to have effects on other organs. So it is like a parcel we put in an Amazon delivery truck or a drone, but we don’t have anyone to deliver it, so that’s what we’re working on now. We’re working on ways to target these molecules, specifically the beta cells and to other cells. I say that right now in 2018 there is no perfect targeting molecule known to get things to beta cells, but you know if you look back just three or four years ago, there were no drugs that could make beta cells replicate. So part of the fun of being in science at this phase of scientific development is you know things happen and you can make things happen in biotechnology and violent dramatics allow us to do things that we just couldn’t even think of doing. So I think it’s likely that beta cells targeting drug molecules will be identified in the next few years. And INH and JDRF all putting money into supporting research to identify these targets. And so and we’re certainly puttering our efforts on that.
Steve Freed: Can we break apart the different types of diabetes and how the research will affect them?
Dr. Stewart: In type 2 diabetes, if you think about it, if you make 5 percent new beta cells every day and you just have to go from 50 percent normal to 100 percent, it wouldn’t take you very long to get there. So I don’t think there’s likely to be a major problem in regenerating beta cells in type 2 diabetes, but type 1 is different. You’re starting with a tank that’s much, much closer to empty. And so greater rates of preparation and longer duration of treatment are probably necessary. And as I said, it’s only going to be effective if the immune system can be controlled. If it can’t be controlled, then I don’t think our therapy is going to offer much. Having said that, I think everybody who works on diabetes basic science knows that. And so that is a huge effort. The NIH and the JDRF and FDA are putting literally hundreds of millions of dollars a year into so-called immuno module tree therapies to dial down autoimmunity. And I should say also in Europe and Asia and Australia, et cetera there’s a lot of work being done in that area.
Steve Freed: For type 2 diabetes we’re seeing a lot of people with obesity having type 2 diabetes beta cell failure because of obesity, too much body fat. I can see using your concept to produce more beta cells to get back to 100 percent, but if they continue to eat and gain weight, then we’re just going to be producing more and more insulin and they’re going to gain more and more weight.
Dr. Stewart: I don’t think it’s going to be hard to get the beta cell tank up to 100 percent or even 200 percent. I think that that’s going to happen; that’s doable. But as you point out, it’s the thing that got them into trouble in the first place, overnutrition, and you know being overweight and eating improperly, then they too are going to have problems with extra beta cell work and possibly more cell damage. Having said that, most people with obesity, even most people with extreme obesity, don’t get diabetes. And if you look at the beta cell mass in autopsy studies, it’s much higher than in people who are normal or people who ultimately get type 2 diabetes. So not that I am recommending this, but it is possible to generate to have a number of beta cells as large enough to secrete enough insulin.
Steve Freed: Already on average the long-term efficacy of that isn’t very good. I don’t have any way to promise or any reason to promise that our approach would be better in terms of the weight control. So you know adherence to diet, that’s that’s going to remain a big issue.
So maybe you can just give us a short resume. What is your daily life like?
Dr. Stewart: I’m an endocrinologist. I was at Yale for 20 years and I was at the University of Pittsburgh for 15 years and I have been here [Mount Sinai] for six years. And so I saw patients for about 40 years and I liked it a lot. But I also was doing basic science when I was in Pittsburgh. I was the head of the division. We had a big clinical practice group and I decided, about seven or 10 years ago, that my additional clinical report to the larger group was limited and research was going so well that I wanted to spend my time right into the sunset focusing on on research. It’s exciting. It’s an amazing time in research. You can do things, as I said earlier, that just were unthinkable a decade ago and you can do them quickly and easily. So it’s so much fun, I decided that I would just stop seeing patients and see research and do research. But having said that, I have been doing therapy with diabetes for 40 years. And so I’ve seen the whole thing and I would say to me, it’s very impressive to see how much has happened actually just in the last 10 years. Now we have the artificial pancreas, we have sensors, we’ve got pumps, and we’ve seen amazing things happen and they’re just getting better and better and faster and faster. They’d be great.
