Short Summary: The science of diabetes with Dr. Scott Soleimanpour, blending personal insights and cutting-edge research that gets into mitochondrial biology and more.
About the guest: Scott Soleimanpour, MD, is a physician-scientist at the University of Michigan’s Caswell Diabetes Institute, where he runs a lab studying pancreatic beta cell biology and mitochondrial quality control in diabetes.
Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Full transcript and other information on Substack.
Episode Summary: Nick Jikomes interviews Dr. Scott Soleimanpour about the biology of diabetes, exploring the pancreas’s dual role in digestion and blood sugar regulation via beta cells, which produce insulin. They discuss type 1 diabetes as an autoimmune condition with rising incidence and complex beta cell issues, and type 2 as a progressive disease tied to beta cell failure, not just obesity. The conversation covers mitochondrial function in beta cells, lifestyle factors like diet, and the limits of current treatments, offering practical advice for prevention and management.
Key Takeaways:
The pancreas has two parts: the exocrine (98%) makes digestive enzymes, while the endocrine (1-2%) regulates blood sugar with hormones like insulin from beta cells.
Type 1 diabetes involves autoimmunity and intrinsic beta cell defects, with rates increasing due to environmental factors, not just genetics.
Type 2 diabetes hinges on beta cell dysfunction, not obesity alone—only 1 in 5 overweight people develop it, showing other factors matter.
Beta cells are energy-intensive and long-lived, relying on mitochondria; stress from overwork (e.g., excess insulin demand) can lead to failure.
Current diabetes drugs don’t rejuvenate beta cells; only TZDs (rarely used) preserve function, highlighting a gap in treatment.
Related episode:
M&M #140: Obesogens, Oxidative Stress, Dietary Sugars & Fats, Statins, Diabetes & the True Causes of Metabolic Dysfunction & Chronic Disease | Robert Lustig
*Not medical advice.
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Episode transcript below.
Episode Chapters:
00:00:00 Intro
00:05:37 Pancreas and Beta Cell Basics
00:11:42 Scott’s Personal Journey with Type 1 Diabetes
00:16:24 Pathogenesis of Type 1 Diabetes
00:21:47 Rising Rates of Type 1 Diabetes
00:27:06 Type 1 Treatment and Beta Cell Regeneration
00:33:21 Type 2 Diabetes & Beta Cell Failure
00:39:47 Insulin Resistance vs. Secretion in Type 2
00:47:03 Diet, Lifestyle, and Type 2 Diabetes
00:55:50 Mitochondrial Biology in Beta Cells
01:01:20 Pre-Diabetes to Diabetes Transition
01:07:35 Reversibility of Type 2 Diabetes
01:14:39 Intrinsic Beta Cell Problems in Type 2
01:26:44 Final Thoughts and Treatment Gaps
Full AI-generated transcript below. Beware of typos & mistranslations!
Scott Soleimanpour 1:32
yeah. So, yeah, I run a pancreatic beta cell biology laboratory at the University of Michigan. I've been here for a little over 11 years. We're really interested in the regulation of mitochondrial quality control in beta cells and how that relates to the pathogenesis of both type one and type two diabetes. And then we try to use our basic laboratory to try to bridge questions that are relevant for understanding the pathogenesis of diabetes and and to hopefully learn insights that can be valuable for translation to the clinic
Nick Jikomes 2:19
and these pancreatic beta cells are obviously key for understanding diabetes. So let's just give everyone a very, very quick, very basic crash course in the pancreas and the beta cells in particular. What is the pancreas basically doing as an organ, and how are beta cells working at a very basic level in a normal, healthy individual? Yes, great question.
Scott Soleimanpour 2:41
So I like to think of the pancreas is actually two organs together. So you have 98% of the pancreas. That is what we call the exocrine pancreas. That's the parts of the pancreas that are responsible for making digestive enzymes that will be fed into the gut to help you digest food, like fats, especially in your food. And then there's a whole, you know, inner interconnected series of ducks that collect that those digestive enzymes and then get them into the intestine. And then one to 2% of the pancreas are called the endocrine pancreas. That's what we study in my lab. And the endocrine pancreas is primarily organized into these structures called islets of longer Hans. And they're essentially micro organs that are made up of many different cell types that are kind of sprinkled throughout the pancreas, and the different cell types in the islet release hormones that have a lot to do with the regulation of glucose levels in the body. You mentioned the beta cells, the beta cells in a human comprise maybe 40 to 50% of the cells in the islet, and they make insulin, which is the hormone that is really important for helping us metabolize glucose, getting glucose into our cells so it can be metabolized. And then another, you know, there are, you know, five to six different endocrine cell types in the in the islet, but the other one that people think about a lot and hear about a lot are the alpha cells, and those cells make a hormone called glucagon. That's also about 40% of the cells in the eyelid. And glucagon does a lot of things. But, you know, most of the time, people think of glucagon as a hormone that helps you respond to, you know, low blood sugar, starvation and the like. So we have about one, you know, this is again, approximate. We have about a million islets in the pan. Creus of an adult human, and in a normal person, when you're eating a meal and you have nutrients come into your body, especially carbohydrate, but also amino acids and fat, the those those fuel stimuli raise your blood sugar, especially the carbohydrates as they're metabolized and they that elevation in the blood sugar stimulates those beta cells to release insulin, to go into the bloodstream so you can metabolize that sugar.
Nick Jikomes 5:37
So so we can think of the pancreas as having two main parts. The bulk of the mass is actually devoted to making digestive enzymes. So those enzymes are manufactured there, and there's some kind of distribution or piping system that then gets all those enzymes shipped out to our gut, where they actually do the work of chewing up our food. And then a smaller portion of the pancreas, but a very important portion is this endocrine portion, and this is where we start talking about hormones and insulin, and we get into the diabetes biology and all that stuff.
Scott Soleimanpour 6:10
Exactly, yeah. And you know, insulin is, you know, not released into a duct network, right? So there's these islets are really vascular. They have a really, really, you know, substantial blood supply, you know, one to 2% of the cells, but they have, like, an outsized vascular flow relative to the rest of the pancreas. So the islet cells, the beta cells, alpha cells, they just release their hormones right into the circulation, and then they go and do the job of metabolizing
Nick Jikomes 6:44
nutrients. And do they have outsized vasculature? Because the very nature of what's going on here with insulin is to sense and respond and help regulate blood glucose levels. So I'd imagine it's got to be a very quick and sensitive mechanism there.
Scott Soleimanpour 6:59
Absolutely, yeah. I mean, I think, you know, these are cells that need a lot of nutrients, but then there are also cells that need to be rapid responders to what's going on in the body. So, you know, I think those are two prominent reasons why they're really vascularized cells. And
Nick Jikomes 7:16
then we usually talk about two types of diabetes, type one and type two. I know that you also have a personal connection here. So do you want to talk about that a little bit, how you got into this, and how that connects the type one diabetes and what that is, and maybe we'll talk about that for a bit before probably spending the book for time on type two.
Scott Soleimanpour 7:36
Yeah, absolutely. And thanks for giving me the opportunity to talk about that. Yeah, so I was diagnosed with type one diabetes when I was five. So, you know, not to give away my age, but like we're, we're approaching 40 years that I've had diabetes. And you know, you know, I was born and raised outside of Cleveland, Ohio, small town called Youngstown, Ohio, and that kind of, you know, changed everything for me. So, you know, I was a, you know, just normal kid like to eat snack, maybe a little too much, and then all of a sudden, I had two weeks of like this, increasing kind of just not feeling well. The story that I prominently remember, I don't remember much from that age, was we were at a wedding, a family wedding, and I kept going to the bartender to ask for Coke or Pepsi or whatever. And because I was thirsty, so I would have a Coke or Pepsi, I would drink it, and then I'd run to the bathroom, and then I'd come back, and then my dad would see me going back for like, more. He was like, stop drinking. Why are you drinking so much coke? And I was like, I'm thirsty. I don't know what to tell
Nick Jikomes 8:55
were you thirsty for like, a water, or were you thirsty for something sugary?
Scott Soleimanpour 8:58
Probably a little bit of both. I will say that I can't give you, like, the greatest play by play of the inner workings of the five year old mind. But like, for some reason in my head, it was Coke or Pepsi that I really wanted. Could also just be that I was a kid at a wedding and was like, Oh, I can have Pepsi,
Nick Jikomes 9:16
but you were, you were unusually thirsty. Oh
Scott Soleimanpour 9:19
yeah, yeah, absolutely. And you know, then my folks were like, Wait, there's something not right here. And you know, that evening, you know, I was still using the bathroom a lot, you know, we you know, and my parents were kind of putting their heads together what was wrong. And then, you know, shortly thereafter, they took me to the hospital, check me out. My blood sugars were through the roof. I got admitted to the hospital and and then, you know, that kind of just, that was a world changing event for me. So you know, some of this is recollections that are shared with my. Folks. But they just said, you know, I was really, really interested in what was going on as much as a five year old could be. I really was, back then, when you get, got diagnosed with diabetes. Now, so I should also say I'm a physician who takes care of people with diabetes too, when you when you diagnose folks with diabetes Now, oftentimes they're in and out of the hospital very quickly, sometimes, you know, hours. But back then, there was this belief in the mid 80s that, you know, you admitted the patient to the hospital and you had, like, intensive education and training and all these things. So I spent two weeks in a children's hospital in my hometown. Oh, wow. And yeah. And so, you know, I was in the ICU for a couple of days because my sugars were really bad. But most of the time I was just in a pediatric floor. And so I started expressing an interest in, like, helping out with the staff, figuring out what else was going on. I just kind of that lit that fire of interest in, you know, diabetes and medicine and the like, so, so that that kind of changed everything and and I became very interested in knowing more about this disease. And I don't know it's probably the way I was raised, or whatever, but, like, maybe being a Midwestern kid, like, if you have a problem, you have to fix it yourself. But I very much kind of drilled into this, you know, and I don't think it came from externally. I think this was just me. Diabetes was my disease. I wanted to figure out why I had it and see if I could fix it and and that's kind of just been the fabric of my entire life.
Nick Jikomes 11:42
Wow. And is five so, so for type one diabetes, what people often call, we used to call child childhood diabetes, because you diagnose it at a relatively young age, is five, is, is five years of age, a normal age? What's sort of that distribution look like?
Scott Soleimanpour 11:58
Yeah. I mean, I think that, you know, typically it's somewhere between the five to 12 window. So I was probably on the youngish end, but like, that's, that's prototypically in the old days, like juvenile onset diabetes, like I was, I was on the earlier kind of window of that, but still, like, kind of in this typical place for for type
Nick Jikomes 12:21
so it's truly a childhood onset. It's not an adolescent thing. Normally, yeah, I would say, if
Scott Soleimanpour 12:27
you, like, looked at the numbers in detail and said, What is the biggest population? But the thing that we know now about type one is that you can get diagnosed with type one throughout your lifespan. So, you know, I take care of people with type one, we have folks come into the clinic that get diagnosed with type one in their 20s, 30s, 40s.
Nick Jikomes 12:46
Is that because? Is that because they had it all along and it was a failure of the diagnosis, or, you know, to pick it up? Or are people getting it at later ages as well? Yeah,
Scott Soleimanpour 12:56
so that's also a great question. I think that the more we learn about type one there, there are a few things. So I think historically, there were people that were get diagnosed with diabetes as an adult, and then the assumption is, oh, it's got to be type two diabetes as you're an adult. But when you rigorously study some of these folks, it doesn't change the fact that their blood sugars are high, but it just changes the assumption you made when you met them. But when you when you measure production of your own insulin, when you measure auto antibodies to see if there's an immune attack, then it starts to change the picture, and then make you think, oh, you know, there could be type one here. Now we know you can diagnose. There's clearly type two that gets diagnosed in childhood as well. So I think the age barriers have kind of slowly disintegrated away. Yeah. And while you get more type one in childhood and more type two in adulthood, the you know, the age barriers, I think are kind of starting to change, and we just look at like, what's the clinical picture? What does the data tell us about what, what the patient might have? And I see, and then we have to kind of do our best to try to fit people into a box, which is also sometimes challenging,
Nick Jikomes 14:17
yeah, I would imagine. So, so, I mean, clearly, there's, there's always been a kind of bimodal distribution here, right? There's a cluster of people who get it relatively young, often in childhood, those are almost always type one. The people who get it closer to adulthood are usually type two. So that probably gave rise to the presumption, most of the time, that if you were an adult, it had to be type two, even though not necessarily, and vice versa. Then over time, I think there probably was some true blurring here, because I suspect just as type two has become more common at younger and younger ages due to diet and lifestyle issues that happen earlier in life, I would imagine that maybe the autoimmune side of this or type one can happen later and later in life as history has progressed, because there's probably things in our environment that can. And instigate that at later times than they used to. Yeah,
Scott Soleimanpour 15:02
I think that's that's a very fair way to put it. And some of it is also changed based on our the evolution of our understanding of the diseases. So as you said, you know, in the mid 80s it there was no type one or type two. It was juvenile onset and adult onset. And then we learned, oh, wait, you can get, you can get this picture in adulthood. Okay, we need to change the names. And then in the late 80s and early 90s, they started to call it insulin dependent, because there were adults on insulin that didn't look like a prototypical type one. And there's non insulin dependent diabetes, well. And then some folks thought, well, that doesn't work either, because, like, everyone on insulin doesn't have the same type of diabetes, yeah. And so then later it evolved into type one diabetes, which, again, most people think maybe some degree of autoimmunity, and type two diabetes, maybe some metabolic problems, but I can tell you too, like, personally, I have problems with those names too, because they're we're learning more about these diseases, and so, you know, maybe it's a lot of you know, discussion about nomenclature, but I think as we learn more about these diseases, it changes the way We We view them, and what causes them and and what goes into it.
Nick Jikomes 16:24
Can you give us a brief overview of what we know the pathogenesis of type one diabetes today, my understanding someone who pays attention to stuff, but it's not in the field, and not, you know, I'm not up to date on the literature in this particular domain. I think historically, the my understanding has been that type one is an autoimmune thing. Your immune cells attack your own pancreatic beta cells and destroy them, and then they're destroyed, and then you can't make your own insulin. Is that the full picture, or is that incomplete? So
Scott Soleimanpour 16:54
that is the perfect general distillation, and that's what I was taught in med school, and that's what our medical students learn here, and that is the view. But I give a lecture to our med students, and then I kind of shake things up, because it's, it's not the full view. So what we're what we're learning from the genetics, the pathology, the histologic study of type one, the natural history is that, yes, there's an immune component, but that's not it. There's also an intrinsic beta cell problem that occurs in type one. I see there's also some evolving work that the exocrine pancreas at the beginning, which I was like, Oh, that doesn't do anything. Forget that. There also seems to be some evidence that there's problems in the exocrine pancreas and type one that might agitate the eyelid immune interface and also contribute to to the disease. So I think of type one, really, if you want to be fair, as a multi organ disease, it's an org It's a disease of sick beta cells and then sick immune cells and potentially a sick pancreas writ large, that then have these conversations that lead to Overall beta cell loss. The other interesting thing is, the beta cells themselves seem to not always fully disappear in type one, if you look under, you know, a microscope, and we've had, you know, the field has had the fortune to study autopsy specimens or pancreas sections of folks that had type one and passed away and donated their organs for research. And a lot of these folks, sometimes people up to 50 years with type one still have detectable beta cells and the immune attack of these especially nuance at type ones. The immune attack, relatively speaking, is kind of underwhelming. And you have like, this patchy pattern where you'll have, like, some islets and some beta cells surrounded with, like, a small number of immune cells, and then other islets. There's no immune cells at all. So, you know, it started to kind of change our view that it's not just all about the immune system. There's probably more to it. And I'm happy to go into detail on what are all those things too. But I think it's, it's fair to say at this point that you know, if you're talking to someone that isn't in the field, that doesn't know much about diabetes, and it's like, give me like two words, autoimmune disease, yeah, it's not wrong. But I think if you say, Yeah, well, it's autoimmune disease, it's autoimmunity plus these other things. So
Nick Jikomes 19:54
there's probably some intrinsic component here. Basically, some people are just born with beta. Cells that aren't quite functioning in the fully normal way. Maybe the other part of the pancreas is sort of leaking enzymes over there, and that's aggravating something too. And then somehow, someway, the immune system gets triggered inappropriately to attack these cells. What do we know about do we know what those immune cells are recognizing? Are the beta cells in type one people, type one diabetes? Are they producing some kind of molecule that the immune system is mistaking as a pathogen, or something like this?
Scott Soleimanpour 20:28
Yeah, they're so so I will give the caveat that I'm not an immunologist, but I do know my immunology colleagues, I mean, this has been a focus for a long time, is really identifying those antigens that the beta the immune cells respond to. Certainly there are hybrid peptides and abnormal forms of insulin that seem to be immunogenic, but the discovery of the diversity of these probable abnormal peptides likely coming from a beta cell source that kind of MIS educate the immune system, or are educating just fine, but then you have abnormal cells in the thymus that normally would, you know, we call them auto reactive T cells. They normally would be cleared, and you wouldn't kill your beta cells, but for some reason, these auto reactive T cells are hanging around, and then they go and attack the beta cell. So, yeah, you know, I think insulin, it's, it's pretty safe to say that, like hybrid forms of insulin, insulin peptides are a part of it, but there's probably more to the story. And and, you know, the challenge is kind of, how you identify all of those very unique peptide antigens, but really phenomenal immunologists trying to figure all that
Nick Jikomes 21:47
out, have the rates of type one diabetes changed over time? Has it gotten better or worse? That
Scott Soleimanpour 21:55
is a again, I almost, I'm so glad you asked these questions. So, yeah. So there's this assumption, right, that diabetes is on the rise and it is worldwide, and then the next thing that people say is, oh, well, we're all gaining more weight, and it's all type two,
Unknown Speaker 22:11
right, right, but
Scott Soleimanpour 22:14
Right, and that's not wrong, that type two diabetes is on the rise and obesity rates worldwide are on the rise, and those things are not wrong. Oh, boy. What are you about to say? Type one diabetes incidence is also on the rise. It's not, maybe the steepness of the
Nick Jikomes 22:28
ground, right? But I, you know. But that would say, you know, if, hopefully, I'm not caricaturing too much, if, sort of, one of the old views was, this was like a fully intrinsic you're born with it, type of thing you would not expect to see this. So that implies that something in the external world is probably causing this rise Absolutely.
Scott Soleimanpour 22:49
And then if you look at these, you know, historic, but I think, very powerful, monozygotic twin studies. And you know, they give you this idea that there is an environmental component to type one and a genetic one. So you know, the old studies suggest that if you have one twin that gets type one, the other identical twin has a rate of getting to type one at about 50% there are some people that think that we might have underestimated those, because maybe we didn't study those the other twin long enough, and it could be even as high as 70% but if it was fully genetic, then it would be 100% the other twin, type one, it's not so
Nick Jikomes 23:32
it's still way more. It's still largely genetic, because there's huge genetic component, because way more in the background, right? But it's definitely not 100%
Scott Soleimanpour 23:40
right, right? And is the environmental component part of the reason why the incidence is rising. It's very possible. And that's also, you know, there are lovely studies like, you know, the Teddy study and Daisy said, these studies that are trying to figure out, like, Okay, well, we kind of know, we at least know the genetics. We don't know what the genetics are doing. We know that genetics have been profiled, right? What are the genetics mean as a whole other kettle of fish, but the environmental triggers are still, you know, really intensely being studied. And we there's a lot that we really don't know, yeah,
Nick Jikomes 24:19
and I mean, we don't necessarily need to get into it. It sounds like it's still fairly mysterious, but immediately that makes me think of just the general rise in autoimmunity that we've seen for some number of decades now. This would seemingly be related to that. It's just a piece of that puzzle. Why? Why are our immune systems developing and being trained differently over time?
Scott Soleimanpour 24:39
Yeah, I and if I had the answer for that question, then I probably would be living on some fancy private island or something like that, right? But, like, you know, we don't, we don't know, you know that there is some, you know, I think good evidence that certain, you know. Viral proteins are found in islets of folks of that have type one. There are certain, you know, you know, sophisticated immunologic studies that show viral proteins in the islet, or in these immune cells that are attacking islets, that make you think that you know, certain viral types might give you give rise to it as an as an environmental trigger, I think that most people would say that's not unreasonable to think that. But like, if you ask somebody, well, tell me the specific virus type or which viruses, then it gets a little murky. So like some folks think there's good information on aroviruses, Coxsackie virus has been like, linked to type one, going back 3040, years. No one has disproven Coxsackie virus involvement. I think people still believe that that's a possibility. And then, you know, there are other environmental things that people have discussed, but like, you know how strong the evidence is. I don't really know, you know, like, cows milk antigen was one of them for a while, and it's like, Oh, when did you feed your young one milk when? You know, I don't know how strong that that data, those data are, but I know the folks that are doing Teddy and the like, they're trying to find strong links in the environment too, because they realize it's not, it's more than the genetics, even if the genetics are a big part of it, yeah,
Nick Jikomes 26:32
yeah. So the bottom line is, type one diabetes is on the rise. To some extent. It's not as common as type two. It might not be rising as fast as type two, but it's not a purely genetic phenomenon, right? Okay, so, and just to put an end to this section, so the sort of end problem with type one is that the beta cells get destroyed to some extent, and so the body's capacity to actually make and secrete insulin is what is compromised. Yeah, absolutely.
Scott Soleimanpour 27:06
And, you know, so our patients with type one, you know, require lifelong insulin replacement therapy. And, you know, we live in an era now where you can get insulin, you know, from pumps and but you can take in, you know, the old school way is you take a shot, you know, under the skin and different forms of insulin and checking your blood sugar. And that's still the backbone of therapies, ever since insulin was discovered over 100 years ago. But you know, we're moving towards an era, hopefully in the next few years of maybe more automated insulin pump technologies, and then even into the science fiction, hopefully science fact of maybe stem cell replacement, of insulin producing beta cells.
Nick Jikomes 27:53
Do those beta cells for type one? Are the beta cells constantly trying to regenerate themselves? Are they dividing and then the immune system just keeps attacking them? Keeps attacking them? Or do they just sort of permanently go away and
Scott Soleimanpour 28:05
they don't reject? Another really good question that it's hard to answer, because when we get the tissue from a deceased donor, it's hard to know, right? Was this like a new beta cell, or was this an old one that managed to like, hide and evade all these years? Yeah, there's been a lot of speculation about, like, what is those origin story of those beta cells that are still there? Yeah, there, there. There are some folks that believe both that they were, you know, they might be lost their identity so that, so that the immune system couldn't pick them up like a pseudo camouflage of sorts. There's some good evidence to support that. You know, there's also some evidence that maybe there is some regenerative signals. But again, is it one or is it both? Is it a little bit of everything? It's hard to know, but it does give some ideas in terms of like, maybe things that you could do, Is there potential for endogenous regeneration? Would that be sufficient? Who knows, if you were to try to stimulate endogenous regeneration? Do you need to camouflage those cells? Because the immune system is still around, right? You know these? These are things that we're we're actively trying to figure out, and I don't think people quite know, mostly because you know you can't, and you rightly shouldn't be able to, you can't do that like from someone with diabetes, right? That's a, this is an organ that you can't really study in real time.
Nick Jikomes 29:38
So, so turning to type two diabetes, I'll kind of let you steer us in the beginning here. You know, what is type two diabetes? Are there multiple subtypes? How do you start to think about this today in terms of what type two is and what the sort of core dysfunction leading to it is.
Scott Soleimanpour 29:57
So, you know, I always give. Everyone the preface that, yes, I'm a beta cell biologist, and so, you know, lot of people are always like, Well, the thing that you study is center to your universe. That means must be why you study it. But as a kid with diabetes, I got to beta cells because I thought they were core to the disease, and not necessarily because, like, I happen to work in someone's lab, and I'm carrying the flag, right? So I'm, I'm trying to make sure that people don't think I'm. I'm biased. But, you know, everyone will make their own decisions. I will say this whenever people ask me about the origin of type two diabetes, like, obviously, metabolic overload. You know, obesity is definitely part of the equation. Like, you know, no one will dispute that, but there are some interesting peculiarities when you look in the clinical space that make you wonder, like, Why do you get type two? So here's a couple of them. One of them is, if you look in the US, one in approximately one in two people are considered overweight. Okay, if you look in the US, one in 10 people have type two diabetes or have diabetes, and vast majority of them have type two diabetes. So here's the here's the interesting thing, the majority of people that are overweight or that have type two diabetes are also overweight. So I'll do a quick distillation of the math and say, All right, if 50% of the population is overweight, 10% have type two then, in a reductionist way, one out of every five overweight people have type two diabetes, right?
Unknown Speaker 31:44
Yep.
Scott Soleimanpour 31:46
But turn that number on its head. That also means four out of every five
Nick Jikomes 31:51
people only. You could say only one in five. Why isn't it five Exactly? So
Scott Soleimanpour 31:56
four out of five people that are overweight don't have diabetes. And then you could say, oh, well, you haven't studied them long enough. But like, these are, like, long longitudinal like, looks at our population, it's it's not these, and the these things are pretty constant. So then what is up with those four people that don't get diabetes versus the one person that does? And this is where I say the beta cells matter. If you're overweight, you have obesity in both, in all the cases, the folks with type two diabetes have a beta cell problem. Yeah, they have beta cell failure, burnout, loss of function, you know, however you want to term it. And so you know this, you know. And then really elegant work that was done in Seattle, you know, in the late 90s, early 2000s kind of really solidified this study, this effect in in human, in the humans, in studies in humans, that the folks that get type two diabetes develop an intrinsic beta cell problem, that their beta cells can't compensate appropriately for their relative degree of insulin resistance that's driven by their relative degree of obesity. So this is a beta cell disease, another
Nick Jikomes 33:11
way of saying all of that is obesity in itself cannot possibly be the driver of type two diabetes, right?
Scott Soleimanpour 33:21
Exactly. Now I'm talking garden variety big picture, right? And you can definitely cite examples of extreme obesity syndromes where people will get diabetes. But if you look at garden variety, type two diabetes, you know there is a beta cell problem that is tipping the person over the edge from pre diabetes to diabetes and and there's also a couple other very interesting things. Again, I I distilling large quantities of work done the the vast majority of the genetic loci associated with type two diabetes, and there are a lot. There's probably 400 maybe up to 500 different loci, many of which have very small contributors to the disease, but the vast majority of them encode products that have key beta cell functions I see. So the genetics kind of push us to the beta cell. And to me, I think one of the most fascinating things, and this is I regularly cite, cite this study when I talk to students, or if I go on the road to give a talk to a wider diabetes audience, a study done in the UK by a guy led by a guy named Roy Taylor. They this is done in the pre ozempic, you know, era, but it was published in 2018 and they took early onset type two diabetes patients who were overweight and either with intensive diet or surgery, treated these patients to bring their body weight into the normal body weight range, they were no longer overweight. And here is the fascinating thing. So. The patients split into two groups, about 5050, 50% of the people their blood sugars fell into the non diabetic range. So you could call them responders to the weight loss. Yep, the other 50% they still had diabetes, right? They were non responders. Both groups had identical, you know, liver fat reductions, pancreas fat reductions, weight loss was similar. Amongst the groups, all of these things were the same. The difference between them, the responders and the non responders that stayed with diabetes, the non responders didn't recover. Beta cell function didn't cover the ability to discrete insulin to a glucose channel. So,
Nick Jikomes 35:42
so it comes back to the beta cells again, and you know, just to summarize what we've said so far, it sounds like what you're saying is a so obesity is neither necessary nor sufficient for someone to have diabetes. You can be obese and not have diabetes. You can also be lean or non obese and have diabetes, right? So there might be common drivers, which is why there's a correlation. There's relationship between obesity and diabetes, but it's certainly not one to one,
Scott Soleimanpour 36:09
right, precisely, and, and, and that's not to say that if you're if you have type two and you're overweight, that losing weight and eating right isn't going to help you. I like, you know, that would I'm not. That would be an insane thing to say. And in our clinic, we definitely advise, like, lower weight, you know, exercise, diet, reduce carbon, take all those things that has that is literally the backbone of type two diabetes treatment. But the thing that we always remind our patients is that's a start. And if you're lucky, yes, maybe it'll get you off all your diabetes medications, but there's a good chance it won't. And then when it won't, then we talk about other medical approaches to treat you. So
Nick Jikomes 36:54
let's talk about beta cells and insulin a little bit. So type two diabetes, to what extent this is something that I'm a little confused on? I don't know if, if this is known and I'm just ignorant, or this is still being worked out. So to what extent is type two diabetes an issue of insulin secretion by the beta cells versus insulin resist, insulin resistance elsewhere.
Scott Soleimanpour 37:21
So, you know, there will we talked a little bit about diabetes subtypes too. And I will say there is this evolving look at type two diabetes to break it down into subtypes. Also, I would have to remind myself there are these, like, four letter acronyms for the different subtypes of type two. I'm still trying to get my head around them. They're very helpful. When we talk in the molecular space, I will say I haven't gotten to the point in my clinic where I'm breaking them down into these categories. But there, there are folks with type two that definitely don't have autoimmunity. And you know, they're, they're, you know, definitely like severely insulin deficient. And then there are folks with type two that have severe insulin resistance as well, and they're part of that whole subgroup. And then those, those two are probably like, smaller components of type two. They're not like, tiny, they're they're there. But then probably the bigger ones are kind of the milder obesity related diabetes. And then probably the most prominent one is, like the the milder, like age related diabetes. Those are the two more prominent forms, um, the the so in the in the garden variety, in those two subtypes, you know, you get some insulin resistance. It probably, you know, and there's certainly some correlation with continued weight gain. But most, to most degree, the insulin resistance tends to plateau, and then you get some degree of beta cell dysfunction. But you know, in large part, most of the time, diabetes is a progressive disease. So you know, you see someone with garden variety type two, you start them on, say, a medicine like Metformin, and then you follow the person for 1020, years, and then in 20 years, they're on, like multiple drugs and maybe an injection, or maybe even on insulin, and that that progression is likely related to, like continued beta cell loss with time. So they're both factors. The insulin resistance probably starts first, you know, early on in the disease process, and the beta cell is probably trying to figure out how to deal with it. And then at some level, at some point, it just can't anymore. I see, can't make more insulin. Can't, you can't figure it out anymore. I
Nick Jikomes 39:47
see, so So in some sense, in the abstract, maybe loosely we could, you know, there's insulin resistance to some extent somewhere. The beta cells are trying to keep up with that, so to speak. And they kind of get. Burned out in some way, shape or form,
Scott Soleimanpour 40:01
yep. So I will also say there's also, and I to be fair, because I don't want, I have a few friends in the field, and if they watch this, they'll like, maybe send me a note and get disappointed in me. There is, I will say there is a community of folks as well, and it's not like one or two people. There's like a decent number of folks in our field. Also, I would say this is the commonly held belief. But to be totally fair, there are some people that think that insulin resistance is actually its origin come from the beta cell too. So that some people think that actually, like an intrinsic problem in the beta cell is like over release of insulin that then starts the cascade of peripheral insulin resistance everywhere, and then starts this back and forth feedback that then leads to eventual beta cell loss and diabetes diagnosis. So it may not just be as simple, simple as like, oh, you had too many, too much junk food, and then you just got obese. And then the, you know, the adipocytes and the muscle cells and the liver were wearing your beta cells down. There are some people that think, oh, there was a messed up beta cell hyper secreting early on that set off this insulin resistance as well. So that, I just want to be totally fair to say, there are some folks that think that the origin of insulin resistance actually itself, might be with the beta cell to
Nick Jikomes 41:20
and when we talk about insulin resistance, is there, are there any patterns of So, so many, many tissues are insulin sensitive. They have insulin receptors. My understanding is insulin resistance is often tissue specific. You might have some organ or tissue systems that are insulin resistant, some that are insulin sensitive. These can change over time. Is there, are there any common patterns where certain organs tend to become the most insulin resistant early or, you know, is it, is this? Does this tend to start with the liver or start with the whatever? What do we know there? Yeah, so
Scott Soleimanpour 41:55
now, now I'm a little bit out of my comfort zone, because I'm a beta cell person. I will say that, um, you know, it is believed that the muscle is the one that takes up and processes the vast majority of glucose in our bloodstream and so, so insulin resistance from the muscle probably exerts, like, a very prominent effect On overall, uh, systemic insulin resistance. Yeah, yeah. But, you know, I think that the usual suspects of, like the cell types that we think of that are most prominently reliant on insulin for glucose uptake, are muscle, white adipocytes, white fat, you know, are normal fat cells and the liver. And, you know, and in the case of the liver, you know, it's, it's not insulin, insulin related glucose uptake. It's more insulin related, you know, glucose processing. But in in the adipocytes and in muscle, it's insulin related glucose uptake being, you know, prominent, I'd say, but I'd say muscle does most of the glucose metabolism,
Nick Jikomes 43:01
just a natural, yeah, I mean, you would naturally think that's going to play an outsized role, because it's, I mean, it does play an outsized role. It's, it's
Scott Soleimanpour 43:07
in terms of, like, you know, how does it, you know, do some come and go, and some have differing kind of features during the process? I just, I have to plead my ignorance. It's very possible that that they do. And I just, I just don't know,
Nick Jikomes 43:24
yeah, so I'll, there's a, there's a there's a lot of complexity here. Obviously, I'll let you kind of steer us, but I'm just going to start down a track, and we'll see if this gets back to the beta cells or whatever. But you know, one of the so there's a question in my mind of, obviously, there's a huge lifestyle component that probably has some interplay with some amount of intrinsic factors that different people have that can lead to type two diabetes. People often talk about diet, and obviously that's somehow ties into this. In my mind, I separate, I like to separate dietary food components. So things like we're supposed to consume food, the foods and the things that we're consuming that we're supposed to be consuming, and then things we might be consuming, they're not supposed to be things like endocrine disruptors and chemicals and stuff like that. When we think about type two, well, let me just put it this way, one of the sort of common cartoon caricatures out there for where type two diabetes comes from is, well, you're eating a lot of sugary, starchy foods. You're eating too many carbohydrates, like added sugars. Your cells are overloaded with too much sugar, and the insulin resistance is coming in response to that, and type two diabetes is ultimately sort of coming from eating too much sugar. That would be one caricature that's out there to take us. Where would you take us from that? Yeah,
Scott Soleimanpour 44:43
well, I mean, look, it's, you know, it's, it's easy, you know. I mean, this is the we all try to, like, understand the world in simple ways, right? That's the way that we are kind of wired. Is that an easy way to apply for everybody? No. Of course not. But I mean, certainly like caloric overload, you know, and subs, you know. And if you think about, you know, body weight being a being a balance of caloric intake and weight loss mattering, then certainly there's a component to that. But as you mentioned, you know, there's also an intrinsic component. Like some people have much better resting metabolic rates. There are some people that are more prone to obesity than others, right? There's a genetic component to obesity as well. It's not always as simple as like, oh, you ate 1500 calories a day, and you ate 1500 calories a day, so neither of you should be overweight, right? Like, yeah, there's more to it than that, right? So, yeah, I mean that caricature of, like, Oh, it's just like you were sitting, you know, with, like, what you ate, too much sugar into movement, right? You're eating donuts and Cheetos and whatever, and that's why you have type two diabetes, and you're overweight, and, like, you were eating, you know, grilled chicken salad every day, and you didn't get it right. And like, you know, again, that that's, that's a lot of oversimplification. And so I think you have to give room to the idea of, like, there are intrinsic things that regulate our weight, that regulate our appetite. There are probably certain few foods that are going to be more metabolically problematic in some folks than others, but certainly carbohydrates are, you know, getting attention, which they should because they're making those beta cells work. They're very prominent stimulators of those cells. They're prominent, they're very effectively turned into, you know, lipid and stored in adipocytes and promote weight gain. So like, certainly, carbs getting a bad rap is not necessarily a totally wrong, but I think understanding it as simple as you just ate too much sugar is, is just, it's just too much like it's not as simple as that.
Nick Jikomes 47:03
Yeah. So some of the things you mentioned just to echo some of that and riff for a minute on things other people have told me that I think of when we talk about this. So obviously, there's just, there's intrinsic differences between people in terms of insulin secretion at baseline. You know, you're born a certain way. I'm born a certain way. You might release more. You might release 15% more insulin than I do to the same bowls of food, just because of intrinsic differences between us. Say, there's also obviously what we eat. If either of us, you know, eats more food in general or more of certain types of food, we're going to get more insulin release more of the time. That's going to come into play, especially if you're doing that chronically and at extremes. And there's also the issue of like endocrine disruptors, you know, I've talked with people about microplastics like BPA, and my understanding is they're essentially exaggerating the insulin response. If you get exposed to them at certain critical developmental time periods, this can lead to an exaggerated insulin response that sticks with you, right? So even if you're not, even if you're born with sort of a lower level of insulin secretion response to a bowls of food. If you're then exposed to an endocrine disruptor, it might boost that, and then that will predispose you to things later on. So you got all these things come into play here. Is it fair to say that a common denominator that's always there with type two diabetes? Is that for some reason or another, in some way, shape or form, there was too much insulin release,
Scott Soleimanpour 48:26
so meaning you were making too much that caused the disease,
Nick Jikomes 48:30
making and secreting, I guess. Yeah, well, and that's what
Scott Soleimanpour 48:33
I mentioned. There are folks that think that hyper secreters or hyperactive beta cells might be a cause of insulin resistance and then eventually down the path towards obesity and diabetes. So, you know, does that mean that if you had rested your beta cells this whole time, you would be better off, right? And and so, you know, I think that's where some of those beliefs come from. You know, you mentioned, you know, environmental, you know, things that could maybe impair either make your beta cells work worse and then push you over the edge to diabetes, or maybe, early on, make them hyperactive and maybe set off this insulin resistance cycle. I mean, I think that, you know, the the data on that is very much in real time, and we're in our early days. You know, if you're looking for guests to talk about that, I will plug Jenny Bruin, who's a scientist in Canada at Carleton University, who's doing, like, really, really elegant work understanding kind of, you know, endocrine disruptors and environmental kind of poisons, to oversimplify it, that that affect beta cells. But she's finding some really kind of interesting connections with these things. And I think, you know, is it things like pollutants? Is it? Is it things like in our diet, you know, and, and, you know, there, there obviously could be many different things that we're being exposed to. And it. It's early days, but I think there are people definitely, you know, digging into that. And, you know, it'll be interesting to see what the what the data and the evidence look like, an
Nick Jikomes 50:10
area I really want to dig into here, because I know this gets into sort of the core of some of the stuff that you work on. Before we get to, like, your actual work, we're gonna be talking about mitochondria here, I think. And I, you know, I think mitochondria becoming sort of a hot topic in many different ways across many fields. And I think that's a good thing. People seem to be appreciating them and getting interested, interested in them more and more, mitochondrial biology is fascinating. There's many things we could talk about. One of the, you know, we'll just take it for granted. I've covered this on the podcast before. I think those listening will have some familiarity. Mitochondria used to be separate organisms that kind of got engulfed by bigger cells. So they're, in essence, little, single celled organisms that live obligately Now inside of our cells, but they have their own cell cycle, and they still divide and stuff like that, even within our cells. I think, can you talk to us a little bit about, you know, in the context of beta cells, the mitochondrial biology of the mitochondria in beta cells, how are, how are these things operating under normal conditions when someone is healthy?
Scott Soleimanpour 51:11
Yeah, yeah. Great. Great question, yeah. So it has been a little bit of a kind of revitalization in the mitochondrial biology world, and especially in the beta cell mitochondrial biology world. So you know the the old mitochondria, or the power plant, or the powerhouse of the cell, you know that that kind of has been something you get in high school biology. It sticks with you forever. And then when I talk to people about what I do, they say they parrot it back to me, right? Yeah. But what we're learning now is that these organelles are actually far more interesting than we thought, right? So they're not just client or I call them client organelles that just make energy like they're more than that, right? They do. They signal. They respond to the environment. They, you know, they send signals to other organelles, to, you know, tell the cell what's going on, to maybe change cell fate and processes. And if we talk about our recent work there, then we can get into that. But as you mentioned, you know what, what's kind of the the normal lifespan or function, or, you know, life cycle of a mitochondria. Yeah, this, you know, this is not work that I certainly like only found. You know, this has been pioneered by by many excellent groups, and actually in the beta cell community, probably the most prominent being folks like Nils Larson in Europe, and Orion shear high and now at UCLA and Klaus volheim in Geneva. And so what we know is that mitochondria are not like a kidney bean that just stay the same way all the time. Yeah, they they undergo processes called biogenesis, to kind of increase, you know, kind of the biomass of the mitochondria.
Nick Jikomes 53:09
They literally grow and get bigger. Yeah, they
Scott Soleimanpour 53:11
grow, they expand their biomass, right? You don't like make de novo new mitochondria, but you can expand the biomass of the mitochondria, right? And then these, these mitochondria, live in networks. They're not like isolated, little organelles. They live in networks, and the networks change. And so some, not all, mitochondria are equal. There's a lot of heterogeneity. And so there's a process that's called fission that can separate the sicker, poorly functional ones out of the network so that they can be cleared. And then if you get rid of those ones, then the network can reform through a process called Fusion. And so this life cycle can go constantly. And when you reform a network through fusion, you can share metabolites, you can share nucleotides, you can share DNA. Mitochondria have their own genome. So
Nick Jikomes 54:09
when you when you say network, there is a biochemical connection, in the sense that mitochondria can sort of secrete and absorb things from other mitochondria. Well, they,
Scott Soleimanpour 54:18
they, you know, they fuse, right? So they fizz and fuse, they separate, they aggregate, you know, and they change and evolve, right? And so, you know, that's where it's not like, oh, you know, if you look in a electron microscope, you can see a nucleus, and you're like, oh, that's the nucleus. But when you look at the mitochondria, they're not all the same. They're very different features, very different interactions. Some of them are really, really long and tubular and really big, and then some of them are short and stubby and circular, right? Because this, this is due to a kind of overall network related change in the mitochondria that's happening holistically in the cell and beta cells. Do this too. You know, I think a unique thing about the mitochondria and beta cells are that beta cells are kind of not too dissimilar in terms of their mitochondrial biology. And I want to speak too broadly here, but from a mitochondrial perspective, I think of beta cells, and I think they're under appreciated. They rely on their mitochondria, not too dissimilarly from a cardiomyocyte or from a neuronal cell. And cardiomyocytes and neuronal cells are often thought of as like completely dependent on their mitochondria for their energetics and function. Beta cells are the same way. They don't really use glycolysis for energy generation. They primarily use glycolysis to make the building blocks to get into the mitochondria, to get the to keep the cell going.
Nick Jikomes 55:50
Is that? Does that mean the beta cells are particularly energy intensive? Oh, yeah,
Scott Soleimanpour 55:54
absolutely. Because making insulin and secreting insulin is an energy intensive process, and these cells are, you know, need to be rapid responders to metabolic shifts in the environment. So the mitochondria, the mitometabolism, is really essential for that. I think one of the really strongest pieces of evidence for the importance of mitochondria in beta cells, uniquely, is there are these rare, but, you know, notable heritable forms of mitochondrial diseases that that folks get, and these are oftentimes problems in the mitochondrial genome and and the most there, and, but the patients with heritable mitochondrial disease, they have A lot of different phenotypes. You know, they get muscular, musculoskeletal problems, they can get neuro neuro problems. They can get visual acuity problems. But the most penetrant thing that you see in mitochondrial DNA diseases is diabetes and and it's not because they're obese. These are folks that are born and get, you know, diagnosed with these mitochondrial diseases, you know, extremely early in life, right? So this isn't obesity, it's because their beta cells don't work because of this inherited mitochondrial problem. So it just kind of highlights the real, like, crucial importance of mitos, and so they undergo this life cycle process, because beta cells don't divide and grow very much. Again, not too dissimilar from a neuronal cell. I see what what you have at shortly after birth and within the first six months of life is pretty much what you're going to have for your lifespan.
Nick Jikomes 57:37
I see, so these are long lived cells. Yeah, and
Scott Soleimanpour 57:40
long lived cells really, really become reliant on their mitochondria to survive, but also the mitochondria need really efficient quality control processes to keep that cell alive for years.
Nick Jikomes 57:55
Yeah, right, because the cell isn't going to rejuvenate itself, like, say, a skin cell constantly would. It needs to have a quality control mechanism for mitochondria, because it doesn't have the cell cycle to fall back on
Scott Soleimanpour 58:06
right Precisely, precisely, yeah, and you hit the nail on the head. So, you know, you can make, you know, fibroblast cells that have really messed up mitochondria. And those cells may not grow great, but they can still grow, and it's because they can use glycolysis as an energy producer. A beta cell doesn't do that. It doesn't it can't escape through the cell cycle to keep going. So it's very dependent on the upkeep of these healthy minds.
Nick Jikomes 58:33
So where my mind is going here, based on what you said so far, is these beta cells are long lived. Obviously, a big part of their purpose is to make and secrete insulin according to the demands of the body. And this insulin secreting and making process is intrinsically energy intensive. Therefore this is, this is my thinking here that I'm saying out loud. Therefore anything that sort of stresses those beta cells, that's forcing them to produce more insulin more often. That's that's inherently going to be a very energy intensive process. And I would imagine that doing that too much, or doing that in a defective way is eventually going to break something the same way that you know. I guess just running your car, you know, with your pedal to the metal all the time is going to cause it to break faster than it would if you're following all the speed limits. So if insulin secretion and production are energy intensive, and I am forcing a cell to constantly make more insulin, that's that's going to be highly, highly energy intensive. I could do that through eating more food, especially more of certain foods. I could do that through an endocrine disruptor, getting in there and messing with the beta cells, and I imagine that could also happen just through some intrinsic, inherited issue with the mitochondria of the beta cell. Is that, does that sound reasonable?
Scott Soleimanpour 59:49
It's definitely reasonable. And you know, and then this is where you know the metabolic overload when you try to translate it to diabetes might not just be. Like, you know, you had, you know, ice cream three days in a row, right? But this is like decades of, you know, progressive weight gain, and then these beta cells are working hard to keep up, and then the mitochondria are metabolizing all these nutrients and supporting the metabolism of the cell necessary to make the insulin, to deal with the the excess nutrients and also the potential insulin resistance, right? So it's kind of a little bit of a force multiplier of you're doing an energy intensive process of the insulin production and release. But you're also doing the energy. You're also dealing with the metabolites themselves, right? So then, then you can start to see how, like, you know, sick mitochondria in in diabetes kind of can come into focus here,
Nick Jikomes 1:00:57
when you transition from pre diabetes to full blown diabetes is, is that just, is that a diagnostic line in the sand that we draw by convention, or is there actually some kind of, like biological phase shift that cleanly demarcates a the cells of a diabetic person from a pre diabetic person? Is that, or is it a very much a blurry line there? It's,
Scott Soleimanpour 1:01:20
it's probably more of a blurry line than I would, than we would like. I mean, there are some distinguishing features, but, you know, I always remind everybody like the diagnosis of diabetes is like a construct, right? Like we say this blood sugar is too high, or this hemoglobin, a 1c is too high, and then you have diabetes. Now those diagnostic numbers weren't pulled out of a hat. They were they were associated with, like, risk of microvascular complications and demise due to having sugars that high. So that's why we came up with those numbers. But the there's a line that you draw and then you say, Okay, well, if you didn't go past that line, like what's going on with you, than before, you know the the pathophysiologic features are maybe a little bit more muted, but they're still there, right? And, you know the the there are, again, emerging studies. There's not a ton out there on studying beta cells in the pre diabetic phase, mostly because, when we get islets from a deceased islet donor, first of all, this is a tragedy, right? Somebody's died, we don't get if someone doesn't have diabetes, we just hear that they don't have diabetes. And so then we have to make some assumptions, you know, and all of our deceased donors have this glucose, you know, they have glucose levels measured, and then they also have the hemoglobin, a 1c which is look at your glucose over a 30 day period. And so when we call a islet donor pre diabetic, it's kind of artificially based on that hemoglobin, a 1c value, but we don't know, like, what was going on in the three months before the person died? Like, were they really on their way to get diabetes, or did they have, like, something change? Were they admitted to the hospital for a few months and being pumped full of medications and steroids and stuff that so. So why am I mentioning this? The reason I'm mentioning this is when we get an islet donor with diabetes, you know, the, you know, the the physicians that have prepared the reports, they say, Oh, this patient had diabetes. They took these meds like, you know this, but when we try to do molecular studies of pre diabetes there, it's a little bit of guesswork, because there's no very rarely are we do people walk around with that diagnosis of pre diabetes? We're doing a little better as a clinical field at doing that now, but it's certainly not something like regularly reported. So when we get these islets, and we call them pre diabetes, it's often by stratifying their hemoglobin, A, 1c, and then seeing if they mirror molecular changes that you see in type two. And there are a lot of similarities, but they're often a little bit muted. One thing that we do see is evidence of, you know, transcriptional evidence of mitochondrial problems in these beta cells. Does that mean that, you know, like, had we looked even earlier, would we find them? I don't know, right? And this will be, I think this is the thing that we are really trying to do as a field isle of biology field is like, what is the what are the initiating events? How early Can we go to find things beyond just assessing the genetics in a static way to say, Oh, you have these genetic risks that could give rise to Mito dysfunction or generalized beta to cell dysfunction. But like, what is that patho pathologic? Change that happen right now, we're very reliant on these pre diabetic, you know, islets, based on assumptions from the A, 1c for
Nick Jikomes 1:05:11
someone who has type two diabetes, and let's just imagine the average person with type two diabetes, whatever exactly that means. There's probably right some extended period of progression here. It's not like they wake up one day and they simply have it when they didn't have it the day before. There's a phase of not being diabetic and then being pre diabetic, and then eventually they meet the diagnostic criteria for type two diabetes at key time points along that trajectory. What does reversibility look like? Is it mostly reversible for much of that timeline. Is it partially reversible? Does it at some point become totally irreversible?
Scott Soleimanpour 1:05:46
Um, so, you know, I think that reversibility would probably be dependent on something that is you can kind of measure easily, and then something that's a little bit more difficult to measure. But I think that if you lose your beta cell reserve, your the reversibility becomes much lower, the possibilities go down. Now we don't often do a lot of dynamic testing of beta cell function in the clinics, just mostly because, you know, some of these tests aren't standardized, and then, like, it's hard to often interpret. Like, Oh, does that mean you have like, 80% capacity, 60% 40% you know, we use these in clinical trials, but we don't always use them in clinical practice, because it's hard to translate to the population. But I think if you look at folks that can do again now, we're in this era of ozempic and zepbound and these things, and you can really promote substantial weight loss and dietary modifications. There are going to be people that probably aren't going to ever be cured of their diabetes from those things, because their reserve is just not there or not remediable. And is it either that their secretion just doesn't come back, or the beta cells were just lost, and they're just not around anymore.
Nick Jikomes 1:07:05
It could be either, to some extent, is that what I'm hearing? Yeah,
Scott Soleimanpour 1:07:09
yeah, and it's mostly because we just don't, we don't know a lot. But again, it is possible, right? Because certainly you know that study that I cited a little ways back, if you take you know, there's a especially early onset T, 2d, if you do really, you know, aggressive diet management, they're half of them, you can get their blood sugars into the non diabetic range. So there is some plasticity of the process, right?
Nick Jikomes 1:07:35
And what's sort of the common denominator there? So when you're type two diabetic or pre diabetic, and reversibility as possible. And it's, it's been seen in some studies. What, what is the diet management there is this just focusing on getting insulin as low as possible?
Scott Soleimanpour 1:07:55
Um, so I think that's, uh, you know, I will, I will again, plead my ignorance and to my colleagues in the in the field, who are looking into like the dietary approaches, I I will say, to simplify it, it's certainly about caloric restriction is key, and I think reducing your calorie intake is is important. Now. Are there some diets that may be more advantageous than others, you know, like when I was coming up through my training, you know, and things like Atkins and South Beach diets were, like, really popular, actually, even before that, Mediterranean diets were, were the thing. And then now, you know, I think we have different flavors and permutations that are all kind of around that. But I mean, if you look at largely those diets, they're again, lower calorie, lower carbohydrate, you know, lean protein, vegetables, those types of things. I think those you know, instead of looking, I know a lot of times we always want to look for like the magic bullet, but I often am like, what is the overlap in the Venn diagram, because then, then that's probably the thing most applicable to everybody, right? Whereas, like, maybe one diet will work for one person. Oh, if you do Atkins, you just don't eat a carb the rest of your life, you're going to be fine. But for some people, it might not work. And so i That's why I think that, you know, pretty smart caloric restriction and reduced carbon take seem to be very safe ways to go in terms of lowering insulin levels. You know, I think it's reasonable to think, if you lower insulin, that as an ambient read out of peripheral insulin resistance. It's a good thing. What I'm in practice now and I'm seeing a patient, though it's again, there's not a lot of standardization. So, like, I can't bring them in and say, I can measure their serum insulin levels the day they come in, but it could be variable, and I might not be able to say, Oh, you're at like, the magic number now, right? So we haven't got. There yet we have continuous glucose monitors, I don't know. Maybe we'll eventually have continuous insulin monitors, and then we could get really, really granular on like, your insulin levels need to be this to really see effective weight loss. We're probably not there yet, but it's not, it's not outlandish to kind of think, you know, in in the abstract, in the future, that like lowering food intake and then some way to monitor your insulin resistance could be a way to say, Oh, look, you're unlocking these options that could help you remediate the disease.
Nick Jikomes 1:10:35
What can you tell us about some of the potentially intrinsic beta cell problems that you might see in someone who gets type two diabetes, even though they're not obese and and I mean just something intrinsic that might be born with is there, and to the extent that's there, like, what is it? Does it have to do with the mitochondria? Does it have to do with just an inefficiency and secreting secreting insulin that person has from the get go.
Scott Soleimanpour 1:11:05
Yeah. So there's a lot of discussion on, like, what are the cardinal features of, like, a beta cell that is kind of on its way, yeah, down and, and, you know, I think the the ones that seem to be most commonly seen are, you know, there's definitely a component of mitochondrial dysfunction. And, you know, obviously that's what we study. So it's in my life. So we're pretty we're pretty up to speed on that there. There has been, I think, about 20 years of focus and some nice data on the role of endoplasmic reticulum stress as a component. And again, is it an initiator? Is it responding to something else? You know, there's people that debate those things, but, but thoughts that you know, the ER are, where a lot of the initial insulin processing and folding events, and, you know, occur. And so if you're, if you're a beta cell and your job is to make and release insulin, you could imagine that, like problems in the processing and generation process in the ER could be pretty fundamentally bad. So there's, there's components of that, the two other things, I think, that you see, and by the way, I'll mention two other things, but a lot of these things could also be interrelated, right? There may not be mutually exclusive. Two other things that you sometimes see are problems with a process called autophagy, which is another cellular regulatory process to kind of eliminate, you know, sick or damaged organelles or cellular structures or aged proteins that seems to kind of slow down and be impaired. And then another feature that you know has been reported, and again, some debate on how important is it? But I think you know are regularly seen is the deposition of amyloid in the beta cells of a type two diabetic and and I know you'll say amyloid, you'll think about Alzheimer's disease, but but beta cells make a protein called islet amyloid polypeptide, which which bears some similarity to the amyloid in the brain, but also some distinguishing features and and i, P. P is CO secreted with insulin. It's made, it's processed in beta cells too. And it can be, it can form aggregates, and those amyloid aggregates can also be toxic. So, you know, you put some of those features together, and then you start to see, you know, there's a multi hit approach starting to occur that's damaging your energetic potential of the cell that you need to kind of feed all these processes, eliminating your ability to get rid of kind of sick and old and not functional stuff. Through autophagy, you're depositing aggregates and cells that probably are also nice for things getting bad, by the way, if your autophagy is not working, you can't get rid of those aggregates, those amyloid aggregates, and then, fundamentally, the ER, which are their job, is to make and process insulin. The ER also are not really up to snuff as well. And so you have, like, a lot of these kind of hits occurring that then ultimately, sometimes feed back to the nucleus and then affect, kind of the whole transcriptional nuclear program in the cell too, that may affect cell survival and fate.
Nick Jikomes 1:14:39
Yeah, yeah. You know, I'm struck by by what you told us earlier, that these pancreatic beta cells, so the discrete insulin it's very energy intensive. These are long lived cells. So it sounds like there's a there's an analogy here that I think you mentioned, between these pancreatic beta cells and cells such as heart cells and neurons, long live cells that essentially never divide. Are very rarely divide. And as a consequence of not being able to do a cell division to rejuvenate themselves, they are dependent and also vulnerable to certain bioenergetic disruptions that other cells might not be. And you just mentioned that you can, you can get some of these amyloid beta amyloid like tangles that build up in these pancreatic beta cells. So is there a connection here where, you know, long live cells that are not subject to the same sort of recycling mechanisms that can rejuvenate other cells are are vulnerable to types of cellular cellular degeneration that other cells just aren't.
Scott Soleimanpour 1:15:41
Yeah, I think that, you know, they're, they're just these are cells that, for whatever the reasons, um, seem to have certain kind of proclivities and sensitivities to certain things that other cells may not encounter, may not see, or are far better equipped to deal with, right? So, um, you know we talked about the analogies with, you know, amyloid and the like, and, you know, there are associate you know, there are, like, patients with Alzheimer's or with Parkinson's disease are at a higher risk for developing diabetes, and patients with diabetes are at a higher risk for developing those neurodegenerative disease are they all caused by the same root cause? Like, I'm not going that far. Are there shared pathologies, possibly, is it a, you know, are they genetically the same? I don't again, I wouldn't go that far, but I think it just speaks to, if you if, if these things are related in some way, it may just speak to the fact that there are certain cell types in the body that seem to not be able to particularly well withstand similar types of stressors, and their long lived nature is is likely a very big part of it.
Nick Jikomes 1:16:55
Yeah, yeah. If you so, so if, from a clinical perspective, here you see patients, so let's say you have someone come into the clinic and rather pre diabetic or even they're healthy, but in either case, they're very motivated. They don't want to become diabetic. They want to reverse their pre diabetes, or just stay healthy and not become even pre diabetic. What are some of the key pieces of practical advice that you think apply to most people most of the time. Would one of them be, you know, get a glucose monitor and make sure you're not spiking very high and very low as often as possible. Would you? Would you make any sort of umbrella? Is there any umbrella advice when it comes to specific dietary and lifestyle interventions? Or what would you tell someone who's interested in preventing diabetes?
Scott Soleimanpour 1:17:45
Yeah, that's a great question. So I wish I had more of these patients, unfortunately, because of the, because of the needs in our, you know, in our clinics, like I get, I get the people with diabetes, not the ones that don't want to get it, but sometimes I they come with family members that don't want to get it. So, you know, you know, I don't, I don't regularly advise folks go out and get a continuous glucose monitor, just because it's hard to know what to do with that information. And maybe we will be able to equip that information and learn about how to utilize it effectively in our patient populations that don't have diabetes or might be our at risk patients and in the future. So I would say right now, today, you may not gain a lot of value out of buying one other than you'll see the numbers, and maybe it will like when you have that helping of ice cream, you'll go, Oh, my sugar went up. Look at it went up. Maybe I shouldn't eat that ice cream anymore. But in terms of like, actionable information, of like, we're going to follow this tracing and say this is bad and you're at risk. I don't know if we're there yet with the continuous glucose monitors, but the story will still be told as we apply more technology, and, more importantly, as the technology gets less expensive, right? So I think then, you know, we get into practical things for folks. And you know, look, while I did say that if you were overweight, four out of five overweight folks don't get diabetes, one out of five still do. And 20% risk is still not ideal, right? You wouldn't want to play with a risk for a disease that could really affect your lifespan and and, you know, it's Harry's pretty substantial risk of death due to cardiovascular disease. So, so the number one thing I would say to somebody who comes in is, you know, do everything you can to stay at a healthy body weight. And what does that mean? You know, exercise, eat, right? Stay active. You know, watch your caloric intake and those things, those are, I think you know. And you might say, well, of course, like Captain Obvious, but like you. No those, those things really, I think matter here, because I think you're minimizing the risk to straining your beta cells, and you're minimizing the risk to those kind of, that cascade of things that may lead to to diabetes later, so that that's kind of priority one, as I would put it is, is dietary management, weight management and then, and then staying healthy and fit and exercising. Is it going to prevent you completely from getting diabetes? Of course not. You know there, there are many folks that will still get type two diabetes at a relatively healthy body weight so, but it certainly can lower your risk a lot.
Nick Jikomes 1:20:40
Okay, so let's say you have patients come in. I mean, imagine you have this at some rate, you have patients come in. They take your advice. They say, I've been exercising more, I think I've been eating right. I feel like I've been eating less. I feel hungry more often, but they're struggling to lose weight, and nothing seems to be improving. What's sort of the next layer of advice?
Scott Soleimanpour 1:21:01
Yeah. So, you know, that's, I mean, this is the challenge, right? So, you know, I think if you're someone who's overweight and you're doing everything you can, from traditional dietary methods and exercise methods, you know, again, you may be someone who's adipocytes, and your and body weight, you're just, you know, it you don't, you have a higher tendency to gain and hold on to body weight. Your body weight set point might be higher, and certainly that's, you know, we're in this era with, you know, GLP one receptor agonists, and you know, you know, tirzepatide and these dual receptor agonists that are coming on the market to try to assist for people that you know, despite really, kind of sticking with it and doing the best they can for weight loss, don't, don't get there, um, and, and certainly, you know, then, then it's a kind of, it's a decision between you and your your physician, but It's understandable. And certainly we have people that you know, and now the FDA has approved these drugs for obesity, independent of diabetes, right for this reason. So medical weight loss is an option. Structured dietary programs are an option. You know, I have a we have an intensive weight management clinic here at U of M that has, it's not just come in and get ozempic and zbound and wagovi, you know, you you know, there's a dietary component to it. And you know, they in for, you know, for the dietary program they're providing, like pre packaged, you know, meals to the patients. So because sometimes it's like, go do this diet, but then it's like, well, then you're left to your own
Nick Jikomes 1:22:45
devices. And did I do just, you know, pre packaged meals, right?
Scott Soleimanpour 1:22:49
So I mean, and I'm not saying that, like people want to eat that way, but sometimes it really helps when you have a challenge. So, you know, these so we have in an intensive weight management program that's that provides that support too, right, so that you're really staying on the caloric restriction to the best of your ability. But, but it's, it's not always like a one size fit all So, right? So I think, you know, I look at it as you need to consider the all of the above, and then let's not forget, although, you know, now in the era of medical weight loss, we're not thinking about it as much, but there are surgical options, right? Bariatric surgery is still available. A lot of people still pursue that. It's very effective. You have newer things like endo barrier and band and these things too. So, you know, there, there's a better and more comprehensive toolkit than, say, there was 30 years ago, 35 years ago, when it was just exercise and diet, and if you just didn't have the right if you weren't dealt the right genetic cards, then you know you weren't going to lose weight, right? So I think that you know, you have to consider that it's nice that we have choices, and then hopefully we'll continue to have more choices in that in that way, so that we can find fits, because certain things are going to work for people better than others.
Nick Jikomes 1:24:14
What about someone with type two diabetes? How are you how do you talk to them about using and looking at the continuous glucose monitor data. Yeah,
Scott Soleimanpour 1:24:24
well, so when you have type two diabetes, then obviously that data is really important to Canvas their glucose control. So that's really given us a lot of powerful information to learn about overall glucose control. You know, in the old days, if you're doing finger sticks, even if you know, and I was a person that was doing between four and eight to nine a day, and somebody would say, Geez, eight, you know, 789, finger sticks. That's so many. But when I did those, that many finger sticks, or even, or even four, which was what we used. Recommend for type ones on insulin as the minimum. That means that during four basically four seconds, the second that your meter reads to you a day, is the only four seconds that you know what your blood sugar is, right. So now think about it. Now you can see what your sugar is like all the time, right? So it's really powerful. It can tell you, you know, when patients have high sugars, what are the irritants to their sugars? Oh, you know, hey, you're you were doing well at breakfast and lunch, and then, you know, your post dinner numbers skyrocket. What was happening then? Oh, you know, you wake up in the morning, super high. Oh, do we have to think about counter regulatory hormones that are at play here, that are, you know, normal hormones that help you wake up, but counteract insulin. So it just gives a picture, so you can structure therapy in a much more logical way, and also allows us to talk to our patients about, you know, rather than once every three months, hemoglobin, a 1c or looking at a glucose log to say you're doing well, you're doing kind of well. You're doing excellent. You're doing poorly, like you can grade things out in a really granular way to try to chip away at, at at problems with blood sugar. So very important to have that CGM for for diabetes. And of course, you know, you need insurance to cover it in the US. So you know, you know, we keep crossing our fingers that, you know, insurance providers and Medicare, Medicaid, you know, support these things because they make such a difference.
Nick Jikomes 1:26:44
We've already covered a lot. Is there anything that you think we haven't covered off on, or anything you want to reiterate about what we did talk about Final thoughts that you want to leave people with?
Scott Soleimanpour 1:26:55
No, you know, I would say this, and I, you know, I kind of leveraged it at the beginning, but like this. This is not like widely held belief. This is a little bit more like me, maybe riffing and giving a little personal opinion. But I really think that diabetes is on a continuum. And I think that the more you know there is this desire to sub classify the forms of diabetes, because it's like, Oh, if we develop more classifications, we'll learn more, and then maybe we can do personalized therapies. Some therapies will work better in some forms of diabetes than others. Have different risks. I'm, I'm, I'm not in any way opposed to some of those things, if they're actionable in the clinic. But I think holistically, the thing that I really believe is that that the continuum of diabetes has something to do with a beta cell problem, and then these irritants, autoimmunity, obesity, metabolic overload, inflammation, that that come at this. And the one thing that we don't have, we have a lot of great treatments for diabetes, and hopefully we're gonna have better we don't have treatments that rejuvenate and and make your beta cells healthy. Mm, so we know that. We know that that is the X frontier, okay,
Nick Jikomes 1:28:19
so, so, yeah, we're not gonna have time to get into like details on the medications, but it sounds like what you're saying is that, you know, beta cell dysfunctions at the core of this, and for better or for worse, the medications and the treatments we have today for diabetes don't actually address that piece. No.
Scott Soleimanpour 1:28:35
I mean, the best that they do is offload work on a tired or sick, especially in type two, a tired and sick beta cell, so that it can kind of limp along or maybe recover, you know, or especially if you lose a lot of weight, maybe recover to the point where your blood sugars are almost well controlled. But there is no medicine that I can give you that will rejuvenate your beta cells. There were some very nice clinical trials that looked at some of the most commonly prescribed diabetes therapies, and the only one that seemed to preserve, preserve, didn't, didn't enhance, preserve beta cell function in the long term was surprisingly drugs in the TZD class, this is drugs like Actos, very rarely prescribed. These are P part gamma agonists, right? We very rarely prescribe those medications now, and they're, they're called insulin sensitizers because they are but actually, that was surprising. That was the only drug class that preserved beta cell function. Um, none of the other drugs do that. So
Nick Jikomes 1:29:49
why aren't those ones more widely used? Is there some other
Scott Soleimanpour 1:29:52
reason? Um, so a little bit of adverse effects and then a little bit of bad press too. I mean, you know, in the, you know, about 15. 20 years ago, there were some, you know, I don't again. I'm not gonna, I don't want to go back and relitigate it. But, like, there were associations drawn between Avandia and and heart disease. You know, was that very strong conclusion? Who knows?
Speaker 1 1:30:14
But the drug companies basically got spooked. Well, there was
Scott Soleimanpour 1:30:19
a lot of spooking, and then prescribers got spooked too. And so then you saw a precipitous decline in the use of a vanity. It's no longer on the market. More recently, there have been some suggestions that, you know, TZDs may have other, you know, off target effects that might not be great, but like most of the time, people don't use them because there can be a little bit of weight gain. It's not, it's not, it's like fluid retention, weight gain
Unknown Speaker 1:30:45
I see, I see, um,
Scott Soleimanpour 1:30:47
and, you know, and so it's it, but it's largely driven by, just like some, you know, just a little bit of the field getting spooked from using them. And it's so they're no longer early. You know, used to be like a very early line agent. Now it's kind of like third line, fourth line agent that you use tcds. And I'm certainly not here going like everyone should be on one. But one of the things that I thought was fascinating about the TCD literature is that it was the only drug that seemed to preserve and sustain beta cell function in type two diabetes, and so it just reiterates this point for me, which is, we don't have anything to preserve beta cells, and if we did, I wonder about our long term ability to to do really, to make really impactful things for people with diabetes. And it's not for lack of trying. You know, we don't have that magic thing, and there are people working on, on on candidates to do that, but it remains a really substantial challenge. Is finding drugs that that rejuvenate or regenerate beta cells or offload the stress of these beta cells so that they can recover.
Nick Jikomes 1:32:11
Alright? Well, definitely learned a lot in this one. Thanks for covering this topic. Thanks for reading with me. Really appreciate it. If there's nothing else you want to leave people with, I think that's a good place to end it. Oh, great,
Scott Soleimanpour 1:32:25
yeah. Thank you so much. And I I'll just want to plug that. You know, I work here at U of M, the Caswell Diabetes Institute. You know, for folks in the Midwest that are seeking diabetes care, for students and trainees that want to work in a really vibrant diabetes environment, you know, this is, this is kind of like, you know, I think it's the Midwestern. I grew up in the Midwest, but I spent 12 years on the East Coast. We're not great at trumpeting what we have available, but this is probably one of the more comprehensive diabetes ecosystems in the country for clinical care and training. And so I would tell folks, if you're interested in learning more about diabetes and training in diabetes, consider coming here. Or if you're someone with diabetes who wants fantastic care, that it's a real passion of not just me, but our colleagues and and we're really proud of what we do in the research and clinical space here.
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