Dr. Schneider: Good morning. 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, you know, in the paradigm of the past we used to think that Type II diabetes was one that really was related to insulin resistance and the beta cell itself was view very much as a secondary player in the pathophysiology. My understanding is that 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 II 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 II 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 cleaver 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 II diabetes has been right up there at the beginning of 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 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.  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 where 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 endoplasmic reticulum stress.  It could other kinds of environmental factors we haven’t even identified.  I mean, I think 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.  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 what we, in primary care are already 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 gage the sensitivity of the beta cell or 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 the 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 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.  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 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 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 -- 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 where 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:  I think that what you’re really talking about is translating knowledge of basic pathophysiology into the hands of clinicians at the bedsides so that they can really take into account that understanding in choosing drugs and interventions that will, in fact, work with the best side affect profile, the best efficacy profile and the best safety profile and so with that, let’s then transition a little bit from pathophysiology to treatment and some of the decisions that we make. I think about this very much in the context of how we’ve evolved with chemotherapy, for example, for cancer and how with some of the newer approaches we’ve gone from, you know, a very blunt instrument with some of the chemotherapeutics to very specific monoclonal antibodies that target cancer cells specifically so there’s less and less collateral damage, if you will, to normal tissue.  I think about how we’ve evolved with insulin therapy and how we’ve moved to analogs and how by understanding pathophysiology and trying to mimic the insulin secretion from the pancreas, some of the newer analogs have profiles that very much are more in line with how our normal pancreas works.  And as we then think about really what is at the root of the diabetes discussion here -- understanding sensitivity and understanding beta cell pathophysiology -- we can then take that same leap in the choices that we’re making for patients.  Because at the end of the day we want, again, for patients to have an effective treatment, a treatment that has low rates of hypoglycemia and has rates of weight gain or affect on weight that are pretty much neutral or beneficial.  Because that’s what my patients care about as a primary care doc is for me to treat them effectively, safely, one that doesn’t have many side affects.  And the more we understand basic pathophysiology and choose to mimic that, mimic nature, I think we’ll be able to achieve those outcomes.  So having said all that, I’m wondering if we could transition a little bit into really how some of the newer agents and some of the newer classes of medications really are more pathophysiologic and, hence, maybe are choices that our patients may benefit from.  So I guess I’m kind of opening it up for you to kind of talk about incretins, incretin therapy in the context of what we just went through with a better understanding of pathophysiology.  What do you think?

Dr. Leahy: Okay, so, that’s a great question and I think I would start with that by really taking the theme you just had which is starting to 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 as I said 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 -- which I’ll mention in a few minutes -- 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 then 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 super 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 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.  The second issue of the incretin system was of interest some years ago and continues to be of interest is because these hormones that are released from the GI tract when we eat and promote these islet affects that I told you, the system is wounded in Type II diabetes -- it’s reasonably defective.  There is clearly defective incretin regulation that occurs somewhere during the process of the disease and we believe that is part of the impaired islet function -- the beta cell dysfunction -- and the failure to turn off glucagon at a meal promoting post-meal hyperglycemia in patients with this disease and so if that’s true, getting agents which actually work on that system predictably would be a positive and they are a positive.  Again, if you look at the drug classes we have, they help to control post-meal blood sugars just in the way it would have been predicted.  And then just the third issue that’s important, and it actually ties in with your introductory comments, so we’ve had drugs that promote better insulin secretion for more than 50 years, which are sulfonylureas.  And so you might say, “Well, they’re pretty good.  You know, why would I want another drug.”  Well, 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.  The problem is that sulfonylurea kind of loses that.  And so you can give this drug and promote more insulin secretion than you would want when blood sugars are pretty normal, or frankly, low. And so that’s been one of the downsides of those drugs for years -- a risk of hypoglycemia.  And with the incretin system the concept was well this is an important intracellular system, which is also glucose responsive and maybe these drugs will preserve glucose responsiveness and they do.  And so one of the benefits that is superior to sulfonylureas is a considerably lower risk of hypoglycemia.  So that’s the reason I think we move in to try to use biology to create new drugs and the newest ones we have are incretins that brings some interesting benefits.

Dr. Schneider:  So, it really does seem like less hypoglycemia is a patient centered outcome that I’d be interested in and these drugs are effective in having insulin secreted in a glucose dependent way.  And can you say just a few more words about the difference in weight and why potentially a sulfonylurea might be a little bit different in its affect on weight gain or weight loss as opposed to an incretin therapy.  Can you say a few words about that?

Dr. Leahy: Yeah, this is, I think, one of the most interesting dimensions of this whole story because if it was ten years ago and one was thinking about let’s go and test in a laboratory agents that work on this system and see what we get hoping we’ll get better regulation of islet function in people with Type II diabetes and hopefully it will be a little bit safer in terms of glucose regulation.  So that would be the concept.  Now we skip ahead ten years and again what has been so interesting is of these two incretin hormones -- one GLP-1 we talked about, a second one called GIP, which its doctor name is glucose-dependant insulin tropic polypeptide (a bit of a mouthful) -- but both of these hormones we’ve learned in the last ten years have a biology that far, far is outside simply regulating islet function.  And, in fact, 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 affect also on actually optimizing glucose regulation and peripheral tissues 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; it’s 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 that 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.  I mean that ‘s real.  But the second issue is 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 affects -- GLP-1 receptor agnes 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.

Dr. Schneider:  Great. So far we’ve talked about hypoglycemia, we’ve talked about weight and I wanted to return back to the basic pathophysiology for one second just so we can highlight the current classes that we haven’t discussed yet.  We’ve talked about sulfonylureas.  We’ve talked about insulin.  We’ve talked about GLP agnes and DPP-4s.  There are other agents on the market and just for us to be clear can you give us a very high level overview about drugs like metformin and the TZDs, acarbose.  Do any of those have any activity directly on the beta cell and how should we be thinking about those in the context of the beta cell pathophysiology?  Just at a high level, can you give us a sense of those other drug classes in the context of the current discussion?

Dr. Leahy:  Yes, so your question was so carefully asked because you used the word directly -- do these other drugs work directly on beta cells and that actually becomes an important part of the question and I’ll tell you why.  So one of the things that we cannot do in the diabetes sort of biology world is try and separate tissues as if they work in isolation.  They clearly don’t.  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 hepatic glucose production and peripheral tissues are impacted by adipose sites and vise 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 scientists try and look so -- these drugs look pretty beneficial at that stage of the disease.  What are they actually doing?  The bottom line is they’re stabilizing beta cell function.  And the concept is that if a beta cell is being driven by this metabolic stress -- maybe some hyperglycemia, other metabolic factors, it over secretes -- we’ve already talked about that -- 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.  We’ve talked about that.  There’s beta cell rest -- no one’s going to deny that.  The other issue is, however, there may be direct affects.  I am a big believer -- in part because it’s what I study in my laboratory -- that the signaling pathway which TZDs act on and 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 with time we’ll find out 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 drug’s 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 is 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 of 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-glycosidase 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 a cholesterol resin, which is now approved.  There’s a drug that we’ve used -- dopamine agnes, 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 the 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 enough failure requiring insulin no matter what.

Dr. Schneider: Great overview as to the different pharmaca therapeutic options that are available for us.  Many of our patients have pre-diabetes or, as you have already nicely alluded to, the genetic predisposition to going on to diabetes and we in primary care have a narrow window to be able to change their course, if you will, or delay at the very least their progression to full-blown diabetes.  What impact does lifestyle modification have with weight loss on beta cell physiology and the progression towards diabetes?

Dr. Leahy: 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 affective.  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 can 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 affects 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 lifestyle.  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 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’re more affective 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.

Dr. Schneider: Right, I think you really phrased the lifestyle modification in the context of beta cell failure extremely well and I would just echo what you have just described as a key cornerstone to primary care and would just make a pitch for primary care doctors to realize that they cannot do this alone and these patients to really achieve the kind of results that you, Dr. Leahy, were just talking about -- they need to be referred out.  They need to be really in a program that is more than just counseling in a primary care office for calorie restriction.  DPP really was a very well-organized trial.  In order to duplicate that most primary care offices are not designed to do that.

Dr. Leahy: If I might -- I want to just echo two parts of that  -- two experiences I’ve had.  The first is 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 in to 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.  The second part to that is 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 who 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 trying to put it into practice for their own life.

Dr. Schneider: I concur one hundred percent and I think you phrased it perfectly by saying that lifestyle changes will improve insulin sensitivity and by definition improve beta cell responsivity and beta cell function. It will essentially off the beta cell.  I loved that line.  I want to switch gears here very briefly to the adopt trial and thinking about the idea of durability.  The adopt trial several years ago showed us that the agents that we select do fail over time and I’m wondering if you can kind of put into context some of the newer agents that are currently available in the incretin class in the context of the adopt trial and really talk just for a few moments about the durability of some of the newer agents in insuring that the beta cell decline is attenuated or is lessened over time.  Can you say a few words about that?

Dr. Leahy: Yeah, so 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, the attempt is to figure out if I’m going to start a drug which one should I start.  Now, a really important part of this study is to get into the study people had less than three years duration of diabetes, most of them just fairly newly diagnosed or one year or so duration.  Secondly, they’ve never been on a drug.  Thirdly, they had an average hemoglobin A1c of 7.3 percent.  So, through the providers out there when they think about when drugs get started, you know it’s typically higher than that.  And they were given a sulfonylurea glyburide; they were given metformin or they were given a TZD and in that study it was rosiglitazone and then they were followed really for four years, although there were a few people who went for five years and so the data is kind of interpreted out to five years.  So, what was learned?  Remember people starting with short-duration diabetes with an A1C of 7.3 and still a lot of these people failed on therapy.  So, this concept you can put people on a drug and they’ll be on that drug for ten years is just not so true in diabetes especially in today’s world.  And when you now look among the three drugs -- the glyburide sulfonylurea failed fastest, and I think in the diabetes world we’ve sort of decided that sulfonylureas can be affective, but that 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.  So those are the details of the study, but actually how the study gets interpreted because it’s a four or five year study and it’s looking at failure, it’s telling us something about drug durability, i.e., you know, 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, can we do anything to slow or stop this progressive part of the disease, i.e., the English phrase that you that’s used -- the doctors’ speak is, “Is durability a therapy” and that indirectly is meant to be can we maintain or prevent a decline in beta cell function?  So if TZDs failed a little bit slower than metformin, it has been said that TZDs have better durability than maybe metformin and sulfonylurea.  The use of durability is a little indirect there and a little complicated and there weren’t so many differences between metformin and TZDs that we know and it’s a five-year study and, I think, people would like a longer study because then the drugs should really separate more if there really is a durability difference. So now we move into your question which is the incretin drugs and really 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, feely 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, one important finding was -- the study was four years and some people five years and we argue it wasn’t long enough -- so no one’s going to be able to comment on truly durability of affect 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.  One of the GLP-1 receptor agnes drugs, exenatide, still works in a sizable number of people.  Not the five years that we need, or more, and not in a controlled trial with an active comparator so that you can say after five or six or seven years, well the people who were on the incretin drugs failed less than our other existing drugs, i.e., there seemed to be durability.  So I think the term durability is inappropriately used.  It’s thrown around a lot, saying that we know things we don’t know and, I think, for the incretin drugs there is hope that they might actually have a longer duration of effectiveness than what we’ve had before, but no data, no data that confirms that and we have to use them in the now, thinking about are they working for my patient now as opposed to thinking, well let’s put you in this drug and hopefully five years from now it will still be a good drug for you.

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.  Diabetes is not going away.  This is an epidemic that deserves our full attention. The evolving literature is one that you eluded to many times.  We have numerous findings in the last ten years.  I think the next ten years we’re going to understand more and more about genomics and how we’ll be able to predict where our patients are going to wind up and the primary care community needs to pay attention to these kinds of studies as well as the studies that are the clinical trials as well as the genetic trials -- the clinical trials that will help us make the best treatment choices for our patients.  Treatment choices that will help those patients achieve their outcomes in a safe way, in a way with few side affects, in a way that has a neutral affect on weight and really this new understanding of the pathophysiology, and frankly, the limits to our understanding of that.  It was very helpful today.  For me the bottom line is we need to stay tuned and really learn as we go because this is not a done deal.  So, in conclusion, Dr. Leahy, I’d like to thank you for spending time with us today and we appreciate your comments.

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