Causes of Diabetes: Insulin, Mitochondria, Genetics, Metabolism | Scott Soleimanpour | 213

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