World-renowned beta cell researcher, John L. Leahy, MD, answers frequently asked questions regarding new insights into the role of the beta cell in the pathophysiology of T2DM. These FAQs have been excerpted from a recorded conversation between Dr. Leahy and leading primary care doctor, Doron Schneider, MD. To listen to the full conversation go to New Concepts, Research and Therapies: A Conversation.
Dr. Leahy’s research interests have included pancreatic beta cell dysfunction and insulin resistance in diabetes, and he is currently the principal investigator in studies examining the mechanisms of beta cell compensation. He also serves as a reviewer for the Metabolism Study Section of the National Institutes of Health.
Dr. Schneider practices internal medicine at Abington Memorial Hospital in Abington, PA. There he serves as Director of the Center for Patient Safety and Healthcare Quality, Deputy Program Director for the Internal Medicine Residency and is a clinic preceptor, hospitalist and teacher.
Click on any question to listen to Dr. Leahy's response:
The average provider ten years ago 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 ten years ago was a simple understanding of a lot of beta cell researchers that for people who get Type II diabetes 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 tolerant 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.
2. What is happening to pancreatic beta cells in people with pre-diabetes?
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 II diabetes has been right up there with these types of 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 II 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.
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 where even in a normal environment it just can’t keep up anymore. Or alternatively, it may be that 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. There is some feeling out there, there may be toxins in the environment or some other environmental issues that are actually detrimental for beta cell function.
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.
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 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 really 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 in 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.
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 II 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. 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 not 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.
One of the things that we cannot do in the diabetes biology world is try and separate tissues as if they work in isolation. The glucose homeostasis system is this incredibly interactive system where the brain regulates the liver and it regulates beta cells and the beta cell carefully controls the hepatic glucose production and peripheral tissues are impacted by adipose sites and vice versa. It goes on and on. And the reason this is important is if you actually look at thiazolidinedione, the TZDs, the drugs that I think the average provider would say is a pure insulin sensitizer. It’s the drugs we have to promote insulin sensitivity and they don’t have any impact on beta cells. Well, that’s not so clear for two reasons.
5. Do any of the traditional drugs used to treat type 2 diabetes directly affect the beta cells?
One of the things that we cannot do in the diabetes biology world is try and separate tissues as if they work in isolation. The glucose homeostasis system is this incredibly interactive system where the brain regulates the liver and it regulates beta cells and the beta cell carefully controls the hepatic glucose production and peripheral tissues are impacted by adipose sites and vice versa. It goes on and on. And the reason this is important is if you actually look at thiazolidinedione, the TZDs, the drugs that I think the average provider would say is a pure insulin sensitizer. It’s the drugs we have to promote insulin sensitivity and they don’t have any impact on beta cells. Well, that’s not so clear for two reasons.
The first is there are lots of studies using TZDs in either pre-diabetes or early diabetes and you get an improvement in insulin sensitivity, of course. But, in fact, the bottom line is they’re stabilizing beta cell function. And the concept is that if the beta cell is being driven by this metabolic stress -- maybe some hyperglycemia, other metabolic factors, it over secretes and you get beta cell failure from over secretions. So now I come in with an insulin sensitizer -- I rest, quote, unquote, I rest the beta cell. That actually allows the beta cell to remain healthy and so you stabilize beta cell function. So many scientists actually look at these TZD intervention studies in early diabetes or pre-diabetes and conclude this insulin sensitizer stabilizes beta cell function. So, is that a direct or indirect affect? Well, clearly indirect affects occur. There’s beta cell rest -- no one’s going to deny that.
The other issue is, however, there may be direct effects. I am a big believer, in part because it’s what I study in my laboratory -- that the signaling pathway which TZDs act on which is called PPAR-gamma that is expressed in beta cells, that’s active in beta cells -- I believe it controls important genes -- so maybe we’ll figure out with time there’s a direct affect. But at least TZDs clearly do have either indirect or direct affects on beta cells as well as promoting insulin sensitivity. So that’s that class of drugs.
The same concept in theory could be thought about with metformin. Now, metformin’s major physiological affect is to lower hepatic glucose production. People may know that the drugs been available outside the U.S. for almost 60 years -- this is not a new drug. And amazingly we really didn’t have a signaling pathway or direct mechanism that metformin worked on until a few years ago. There’s still a little bit of debate, but it seems to work on a fuel sensing pathway called AMP kinase which is very active in adipose sites also in peripheral tissues. But again, analogous to the TZD conversation AMP kinase is present in beta cells and is actually fairly active. So, we think about metformin as a liver-specific drug. We give it to try and control fasting blood sugars, which is a reflection of adipose glucose production. Whether it would actually have good effects on beta cells over time, directly or indirectly -- don’t know. Certainly, using metformin in pre-diabetes was clearly legitimized and many primary care doctors are aware of the diabetes prevention program -- the DPP study that used metformin in pre-diabetes and showed a reasonably good affect at prevention of diabetes.
Now, there is a long, long list of other agents that are out there and for the most part they’re not used the same kind of way that the other drugs we’ve talked about are used in the United States. There’s the alpha-glucosidase inhibitor. They essentially slow carbohydrate absorption from the gut. Amazingly, they’re used extensively in Asia and not used much in this country. We have newer drugs that have come out. There’s the cholesterol resin, which is now approved. There’s a drug that we’ve used -- dopamine agonist, which has been used for prolactinomas that’s been recently approved. There is this sort of long list, but I think the classic drugs we tend to think about are the sulfonylureas, metformin, TZDs and the incretin drugs and, of course, insulin.
And just one sort of comment about insulin -- one of the reasons I think it’s so important that the primary doctors have an understanding of the importance of beta cell dysfunction and eventual failure in Type II diabetes is we have to sort of get away from the thinking about insulin therapy in this disease as a last resort and as somewhat a result of a patient’s unwillingness to follow a healthy lifestyle program and understand that some people are programmed for beta cell failure and they’re going to end up with failure requiring insulin no matter what.
Think about using and designing therapies in a disease based on a preferred treatment profile, not just blood glucose lowering, but also from a pathophysiology point of view. And that’s actually so interesting in the diabetes world because we have all these new classes of diabetes drugs and we’ve had these older classes, some of them for 50 years, the reality is we really didn’t get agents to use that were designed from the get-go to do something important based on what we knew about diabetes.
Most of these drugs until about ten years ago were drugs that pharmaceutical companies just almost accidentally discovered lowered blood sugars in some kind of model and then they evolved into treatments for diabetes -- not insulin obviously, but many of our traditional drugs -- even TZDs quite frankly. And then we -- ten years ago pharmaceutical companies got very interested in the incretin system and started to ask, “Gee, I wonder if we have agents that work on the incretin system that would be a useful drug therapy?” And the short answer is ten years later they are useful and we have agents in the clinic, but again they sort of started from a design -- wouldn’t it be interesting to see if X happens if we use a drug in that direction -- and that’s our future. Many of the drugs, or most of the drugs, that will come to us in the future someone decided based on basic science as an important thing to test that ended up being a useful outcome and we’ll get that drug.
So incretins, what are incretins? Incretins are this hugely important physiological system in all of us that helps to control blood sugars after meals. It is the dominant physiological system in that regard. So if anyone goes out and stops and has a spectacular lunch or supper with lots of calories and carbohydrates and enjoys their meal, if they don’t happen to have a problem with glucose tolerance and their blood sugars are pretty normal after that meal, they should thank the incretin system. Because the incretin system is essentially a physiologic connection from the gut and the brain telling islets, “Hey, food is coming, you need to respond appropriately which is to put out more insulin and also turn off glucagon –- two of the key incretin hormones.”
The reason the incretin system is so important is that first of all there are a number of dimensions of that system that have been identified physiologically and are good drug targets. One of them happens to be something called DPP-4 – dipeptidyl peptidase-4 –- which is an enzyme which acts to normally inhibit and to turn off the action of these important incretin hormones. So you can take a drug that’s slows or stops the metabolism so that the incretin system works either better or longer. The second is one of the key incretin hormones called GLP-1 -- glucagon-like peptide-1. It turns out that there are drugs now out there that either look like GLP-1 or bind to GLP-1 receptors and, thus, just essentially replicate this incretin affect.
One of the major flaws of sulfonylureas is they act on a signaling pathway, which is an icon channel right on the beta cell membrane -- right really at the distal stages of insulin secretion and so they bypass all of the important intracellular beta cell biology which makes that cell glucose responsive. So normally that cell is incredibly precise at regulating insulin secretion to the prevailing glucose concentration. Good if your sugar is high, even better if your sugar is low because it turns off insulin secretion.
8. Are there any differences between sulfonylureas and incretins in terms of weight effects?
Incretin hormones have a biology that far, far is outside simply regulating islet function. GLP-1 receptors are in most of the tissues of the body and when you give GLP-1 in pharmacological amounts a lot of things happen. Perhaps one of the most interesting and one of the ones which has helped define a favorable clinical profile of the GLP-1 drugs is there are GLP-1 receptors in the feeding centers of the brain and either in animals or humans when you give GLP-1 therapy there is a satiety affect. There’s probably an effect also on actually optimizing glucose regulation and peripheral tissue somewhat, i.e., improving insulin sensitivity and the bottom line is that people lose weight.
Now the fact that sulfonylureas are associated clearly not with weight loss and maybe weight gain is just sort of a different biology because they don’t have an affect on feeding that anybody knows and then this issue of weight gain it’s sort of a generic issue with many diabetes drugs not simply sulfonylureas. Part of it we’ve argued for years is that if people are hyperglycemic enough that they spill glucose in the urine if you now give a therapy, any therapy -- insulin would be another clear prototype -- and drop their blood sugars below a renal threshold then they now hang on to more calories they eat and it’s like they’re eating more even though they’re not. So that’s one issue and that has been legitimized by research for many years.
But the second issue is that there is this feeling that drugs that promote insulin secretion are potentially associated with weight gain maybe because of risks of lows, maybe a patient essentially just eats to try and avoid lows especially during the day when they’re physically active. There is this sort of background behavioral biology people think about with these kinds of drugs that may promote some weight gain.
So the actual mechanism we could argue about it doesn’t really matter. There is a clear sort of defining profile of drug effects -- GLP-1 receptor agonists for the most part are associated with weight loss, certainly many patients. The DPP-4 incretin drugs probably not more associated with weight stability, not drugs we think about with weight gain. And drugs like sulfonylureas and probably insulin in many patients associated with some modest weight gain.
9. How durable are the effects of drugs used to treat type 2 diabetes?
The ADOPT trial was a trial published in The New England Journal maybe three or four years ago and it’s kind of a modern day UK PDS, United Kingdom Prospective Diabetes Study, which was a study to give patients their first diabetes drug -- Type II diabetes -- and then follow them with time and actually see which drug was superior. So, what was learned?
Sulfonylureas can be effective, but they fail pretty fast. They’re not the world’s greatest drugs. Metformin did pretty well though it failed a little bit faster than the TZD and so the TZD was kind of interpreted to be the best and that’s how the trial was interpreted and written, though to be fair the differences between metformin and TZDs was modest enough that there’s an editorial in The New England Journal accompanying it and balanced weight gain, risk of congestive heart failure and cost of the TZD versus metformin and sort of decided maybe metformin was better.
There’s a natural history to the disease and the natural history, we think, is related to beta cell failure. So if beta cells continue to fail, you will no longer respond to this drug. That’s the concept.
So now we move into the question of durability of incretin drugs. And the theory is they might have better durability because we know that they work on the islet cells to promote better beta cell function, i.e., more insulin secretion at a meal, better alpha cell function, i.e., less glucagon secretion at a meal and there’s this background in non-human systems, i.e., cells in animals, that you actually grow more beta cells that are thought to be healthy beta cells from these drugs. That there is a GLP-1 physiology and probably GIP that promotes beta cells expanding in their mass -- a biology that is signaling paths that has been identified to all sorts of things. And so the thought, and I keep saying thought or the speculation or belief -- these very touchy, feelly words -- the thought is that maybe these drugs will have better durability than what we have now.
But if we talk about the ADOPT study, no one’s going to be able to comment on truly durability of effect of any of the incretin drugs until we get out five or more years. And the second thing is you have to do a study that is carefully, carefully designed to compare the ongoing effectiveness of these drugs against other drugs like the ADOPT study. So one of our problems now is the manufacturers of some of these drugs -- they’ve got groups of people who are on their therapy who choose to stay on their therapy, presumably because they work, and they follow them for a long time. People can drop out if it stops working so they just keep reporting on the people who choose to stay in the study and the latest data we have is three years out.
So this is a fundamentally important question and one that I think the average primary care doctor sort of knows in his heart, or her heart, is important, but tends to discount it because it’s so hard to understand what to do with this in a clinical practice and make it effective.
You know, from a scientist point of view diet and exercise should be hugely important especially early in the course of the disease and the simple reason is the following: If you sort of think about what’s happening at that time you’ve got a certain level of insulin demand, i.e., tissue insulin sensitivity or resistance and you’ve got a beta cell that’s able to act at a certain level of function or compensation. And people who are early in the stage of the disease, it’s not normal, but it certainly is some. People can compensate some. And so, if you come in, you can either try and promote better beta cell function and certainly that’s an ongoing issue that we’d like to think about with some of the beta cell specific drugs maybe early in the course of the disease, and I think in the future we’ll have a better idea where they fit, but in today’s world that’s not what we do.
In today’s world we think about trying to lower the demands on the beta cell. And it could be done pharmacologically so there’s metformin is used some -- clearly many providers know of metformin’s use. I have said previously -- I write about that TZDs actually have proven to be incredibly beneficial early in the course of the disease, but they’re complicated because they have side effects and they’re expensive.
So the least expensive, in theory, the most applicable, in theory, and the one which is the safest, in theory, should be promoting healthier lifestyles. And the problem is, I think, for many patients and for many doctors it becomes a complicated conversation that is wrapped up in -- you need to diet, not a terribly attractive word for some patients, and you also need to exercise, i.e., go buy a gym membership and start exercising in a way that is really foreign to many patients. And so trials that have used diet and exercise in a trial design, meaning more than the average patient would do like the DPP, it worked. It was the most beneficial at prevention of diabetes in the agents that were used in the DPP at least against metformin. And it lowered the progression of impaired glucose tolerance to Type II diabetes by almost 60 percent over the three years of the study. At about the same time and in the same journal -- The New England Journal from the same year -- a study was done in Scandinavia that basically showed the same thing -- that diet and exercise can be really effective.
And then if you want to take the most extreme example that probably every doctor has seen -- a patient who has terrible diabetes who’s on every drug known to man, a lot of insulin, gets a gastric bypass. They come back and see you six months or a year later, they’re 50, 100 or more pounds less and their diabetes drugs are gone or almost totally gone. I mean, it’s kind of amazing. So, we have lots of information to say that diet and exercise can work.
We know the physiology and that it improves insulin sensitivity and actually improves cardiovascular risk profiles so it’s quote, unquote unloading the beta cell, which should be good for beta cells, and so all of that tells us it should be a great therapy and I think what’s lacking in our culture and most cultures around the world is finding ways to phrase that and put into practical interventions for patients so they are more effective at it. One of the amazing things is people can actually do fairly modest dietary changes and fairly modest changes in their level of regular activity and really see large improvements in blood sugars. It’s actually sort of amazing at times. But we’re often just not articulate enough to try and help patients to design a program that they actually think they can participate in.
11. How can primary care physicians help patients successfully make lifestyle changes?
I learned some years ago in my clinic that I am not good at predicting who are the patients who will be most successful with diet and exercise. It really comes back to reinforce itself for me almost very frequently.
I’ll see a patient -- they’ll often be there with their spouse -- I’ll talk to them for several minutes and they have lots and lots of questions, specific questions about diet changes and activity and what works and what doesn’t work and we’ll have this really interactive, interesting conversation and then they come back and nothing has changed as opposed to I have someone who’s not all that interested, not all that educated, not seemingly a patient you think is going to be very productive, they come back often with the statement that my spouse is really into this -- they’re ten pounds lighter and over the next year they’re just the absolute poster child of using effective lifestyle modification.
So I don’t think we can use one appointment with a patient and make a decision whether this is a good idea or not and I absolutely agree we need to use the professionals -- the dieticians and educators -- who are much better at speaking in language to patients about practical application of these things than I think the average hurried doctor.
We have available at my institution a cardiac rehab program for patients who obviously have cardiac disease, which is based on effective use of dieticians and also regular exercise and people come actually to the facility and use the gym three times a week under observation. The thing that’s amazing to me is people really get into it. It’s like a club for people. They just really start to adopt healthy lifestyle practices. And we’re now using that facility for our patients without cardiac disease and it’s really turned out to be a very beneficial program because it’s more than just a doctor saying, “Please go exercise. Please watch your diet. Come back and see me in two months we’ll talk about it.” I mean there are true goals and guidelines and true sort of milestones along the way that people get positive and negative feedback on and they work with the staff that’s really into it and with other patients that really like it and it’s a fabulous program.
So I think that’s what we have to think about in our own communities -- sort of find a place where people can work on lifestyle around others who are enthusiastic and really try to put it into practice for their own life.
Listen to the entire conversation between Leading primary care physician, Doron Schneider, MD, and Jack Leahy, MD.