Beta Cell Pathophysiology and Its Relevance to Primary Care

A leading primary care physician and a world-renowned beta cell researcher discuss why it is important for primary care doctors to understand the role of beta cells in type 2 diabetes. (13:53)


Dr. Schneider: Dr. Leahy, thanks for joining us this morning.  Today we are going to explore some new concepts and new understanding about diabetes and pathophysiology of diabetes. And really the relevance to the primary care community, and I look forward to understanding where we should be going as a primary care community in thinking about how to best take care of our patients, from a patient-centered approach.  So kind of off the bat, I’m wondering in the paradigm of the past we used to think that Type 2 diabetes was one that really was related to insulin resistance and the beta cell itself was viewed very much as a secondary player in the pathophysiology. My understanding of that is our knowledge of that has actually shifted a little bit.  Can you give us just a little bit of background about the current thinking relative to what’s going on in Type 2 diabetes?

Dr. Leahy: So the question starts with history and that’s actually a wonderful way to do it. The average provider ten years ago when many researchers were focused on the role of insulin resistance in this disease because clearly it was a disease of the older folks, the heavier folks, the ethnic populations where there was more obesity and there was an enormous amount of research that was being done, much of it focused in the United States on defects in insulin signaling and insulin resistance, and as an aside, measuring insulin resistance in patient populations was a little more of a doable prospect ten years ago in clinical research studies.  So everybody knew insulin resistance was important in the disease, and that has not changed.  This is clearly a disease of insulin resistance, and the reason that it’s expanding around the world is because worldwide people are westernizing and getting happier and fatter and moving away from working on farms and working in offices and gaining weight and eating terrible things and all of that’s related to worsening insulin sensitivity.  The change that occurred, I think … and your timeframe is good … ten years ago was a sort of simple understanding of a lot of beta cell researchers who basically said, “Well, sure, but there’s an awful lot of people out there with insulin resistance who never get diabetes. So what’s that all about?”  And for the clinicians who would go see patients in the hospital who were having a gastric bypass obviously were enormously insulin resistant.  No one would debate that.  But they didn’t have diabetes, so how does that work?  And the simple answer is we now skip ahead ten years and there are epidemiological studies, there are basic science studies, there are many intervention studies using different kinds of drugs and there are the newest genetic studies that have all highlighted that for people who get Type 2 diabetes there has to be something wrong with their beta cells.  They can’t compensate to the kind of metabolic stresses that are out there and are worsening and, in fact, these studies when they’re really carefully done and when they’re sort of clever trying to move earlier in time to study people before diabetes, before pre-diabetes and when people are still normally glucose tolerate who will eventually go on to get this disease, there’s already demonstrated defects in beta cell function and probably a reduction in beta cell mass. So I think the way to look at this is researchers these days consider this really kind of a two-hit disease.  You have to have some kind of compromised beta cells at the earliest stages of the disease, and if you don’t face metabolic stresses maybe you’ll be fine your whole life.  But as these metabolic stresses or other issues come along, your beta cells can’t compensate and then the slippery slope starts that gets us to the clinical disease that our primary care doctors deal with.

Dr. Schneider: Well, that’s a wonderful overview and I’m wondering if you can tell us a little bit about actually what’s occurring in the pre-diabetes stage at the beta cell.  I understand a little bit about glucose toxicity, fatty acids, oxidation issues.  Can you give us just a little bit or a primer as to really what is the beta cell experiencing in that phase?

Dr. Leahy:  Yeah, so it’s so interesting because your question is a spectacular question, but it’s also a little bit dated because in some respects we’ve even moved earlier in our thought process trying to define what’s happening at even earlier stages of the disease, before blood sugars even reach the pre-diabetes stage.  And probably one of the most important research accomplishments are genetic studies -- the ability to start to do very, very precise genome-wide genetic studies -- and Type 2 diabetes has been right up there at the beginning with these kinds of studies.  And as it stands right now we have at least 20 genetic mutations that have been identified to raise the risk of Type 2 diabetes.  There’s some debate about a few of these, but most of them appear to be in the beta cell and appear to be related to either impairing beta cell function or beta cell mass.  So that’s probably where we start, and I think a lot of people think that maybe people who carry these mutations either don’t grow enough healthy beta cells early in their life or the beta cells they do have are just not normally functional.  They’re, just, they’re kind of there, they’re okay at that stage of that person’s life, but not later.  And so, something has to happen later.  And what happens later is either an ongoing process of these either genetic or environmental defects so maybe the genetic defect makes beta cells die earlier than they ordinarily would.  So that’s speculation, but someone reaches an age where beta cell mass has slowly been falling and it reaches a stage when even in a normal environment it just can’t keep up anymore.  Or alternatively, it may be that these metabolic stresses you’re talking about -- as one gets heavier and exercises less and eats more of a western diet, then we face all sorts of metabolic issues potentially related to things like increases in free fatty acids or other lipid-related detrimental effects.  It could be related to the beginnings of a rising glucose that is fairly modest, but from a cell point of view is not modest at all in promoting oxidative stress or endoplastic reticulum stress.  It could be other kinds of environmental factors we haven’t even identified.  I mean, I think there is some feeling out there may be toxins in the environment or some other environmental issues that are actually detrimental to beta cell function.  So early in the course of the disease these metabolic changes that we’re all now facing as we westernize put more of a stress on beta cells.  Probably the best legitimized concept is as beta cells compensate and work, in some people that becomes overwork and that actually leads to a beginning of the end which is beta cells compensate, but they can’t do it long enough, they start to fail and that’s the initial part of the slippery slope.  So there’s a lot of concepts out there not still a lot of definitive information how beta cells go from being able to compensate to fail.

Dr. Schneider: And I think you gave us a really wonderful glimpse into the future and a very important reason why primary care docs need to stay in touch with evolving literature -- genetics is where we’re going to go.  Right now we’re not dealing with genotypes rather we’re dealing more with phenotype and really thinking about patients and how they’re presenting metabolically.  And that was the second half of your answer really and I think why we, in primary care, are really seeing -- patients who are overweight, potentially having the full-blown metabolic syndrome -- and try to best care for that population.  As far as the average primary doctor, is there, or are there, any tests that we should be thinking about to really gauge the sensitivity of the beta cell -- the current function of the beta cell specifically -- or should we be thinking more looking at fasting blood sugars or looking to screen for impaired glucose tolerance.  What really should we be doing, I guess in primary care today to look at beta cell physiology?  Is there anything that is orderable or should be ordering?

Dr. Leahy: So it’s a spectacular question and if you think about it science has sort of moved beyond or faster than what we do in clinical medicine.  So, you know, I can talk to you about the pathogenesis of the disease.  I can talk to you about too much glucose production from the liver, defective beta cell function, insulin resistance of peripheral tissues.  The reality is we measure none of those in a clinical setting.  In fact, there are not specific tests that a doctor can easily order to really quantify any of those.  And, in fact, the surprising and really almost silly answer to your important question is probably the best test we have right now to assess the adequacy of beta cell function is a blood glucose.  Because the reality is if you get someone who’s insulin resistant -- like a pretty big guy who comes into your office --who doesn’t have diabetes, if you measure an insulin level it’s going to be really generous.  It’s going to be high because he’s compensating for insulin resistance.  Alternatively, if you have a little grandmother who comes in who weights 95 pounds who also has normal blood sugars if you measure an insulin level or C-peptide for her it’s going to be really small.  It might even be below the normal range because, again, she’s so insulin sensitive she doesn’t need a lot of insulin.  So you can’t simply measure in absolute terms a measure of insulin secretion or C-peptide and think that’s going to tell us much.  The reality is if a glucose value is above a target range than there’s something wrong with beta cells and that’s probably a fairly gross way to think about this.

Dr. Schneider: It’s a very simple one and very easy to understand.  So why is it then important if we can’t measure beta cell function; if all of these bench top studies really are not necessarily something that can be directly linked to something that primary doctors can be acting on -- why then is the pathophysiology of diabetes and a better understanding of that important and relevant to the primary care doctor and the patient.  I think it is very relevant, but what’s your perspective?  Why should we care as a primary care community about really what’s going on at the beta cell level?

Dr. Leahy: So it’s a multidimensional question that’s going to get several different kinds of answers and I think the most immediate one is I’m just a true believer that our primary care community will be more knowledgeable and be more effective if they better understand at the genesis of such a common disease and start to think about contributing factors that may improve or worsen blood glucose values based on that understanding and also be prepared for effective use of all the drugs we have.  I mean the thing that’s so interesting in our world is that we went from having almost no drugs for treating Type 2 diabetes to an explosion of drugs over the last ten years. In many ways I think the future will be starting to think about using drugs based on presumed pathophysiological benefit as opposed to simple habit – will I do drug A, then I do drug B, then I do drug C.  And I am convinced that there will be a day and I don’t think it’s light years away were we will be using genetic information to define what drug therapy is potentially going to be most effective in that individual, what other kind of interventions.  So that’s sort of the big picture.  I think also from our grooming of the next generation of primary care doctors, their approach to disease, not just diabetes, is very much going to be pathophysiological based and they will have tests available to them that we don’t use today.  So even though we don’t currently test an insulin level, because I don’t think it really tells us a lot, I have no doubt that there will be tests in the future that are legitimized at different stages in the disease that are based on either dynamics of insulin secretion or secretion of other kinds of factors or coordinated looking at different kinds of metabolic testing and putting it together into kind of nomagrams that would make us more effective in thinking about the disease.  And then finally, I think as one just talks to a patient we in some respects have to get away from the concept, “Oh this is a disease of insulin resistance. Oh, you’ve struggled with your diet and exercise your whole life.” “Oh,” don’t say to the patient, but in your mind think, “You’re just fat and the problem is if you took better care of yourself, you know, you wouldn’t be dealing with this disease.”  That’s not always correct.  I mean there is this genetic imprinting that people carry.  There are environmental factors that negatively impact different aspects of glucose control physiology -- one of them beta cells.  The concept: why is there so much diabetes in developing populations?  Well, you know, there’s a real idea out there that maybe malnutrition early in life has negatively imprinted beta cells so they don’t develop properly.  And that could be a huge public health issue for the future.  So, I think the general issue right now is to prepare our doctor population for the future, but also to make them more effective about how they communicate the pathogenesis to the disease, how they start to think about interventions and how they try and balance all these different drugs that are out there as to which might be most effective for the patient who’s sitting in their office.

Dr. Schneider: Well, I very much appreciate that.  I’d like to conclude by, first of all, thanking you.  I think your answers were extremely concise and clear and helpful.  Thank you for spending time with us today and we appreciate your comments.

Dr. Leahy: So it was a pleasure.  Thank you very much.