The Mosaic of Diabetes

Steven R. Smith, MD; Julio E. Ayala, PhD

Disclosures

January 23, 2012

Editorial Collaboration

Medscape &

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Steven R. Smith, MD: Hello. I'm Dr. Steven Smith, Professor at Sanford-Burnham Medical Research Institute. Welcome to this segment of "Developments to Watch," from Sanford-Burnham and Medscape.

Joining me today is my colleague, Dr. Julio Ayala, Assistant Professor in the Metabolic Signaling and Disease Program. Today's program will focus on key research addressing the interplay among multiple organs in the development and progression of diabetes, and of note, how this research will affect clinical practice. Thank you for joining us, Julio.

Julio E. Ayala, PhD: Thank you Steven. Glad to be here.

Dr. Smith: Historically, there has been a lot of focus in diabetes on the pancreas, the beta cell, and insulin production, but some new developments tell us that it's not quite that simple. Tell us where the field is right now.

Dr. Ayala: Traditionally, we think of diabetes as a disease of the pancreas, and obviously the pancreas plays a key role because it is the site of insult that takes us into full-blown diabetes -- whether you're talking about type 1 or type 2. But what we've begun to understand over the past 1 or 2 decades is the involvement of other organ systems, not only in the steps leading up to diabetes, particularly type 2 diabetes, but also in the complications that are associated once a patient has diabetes.

We're talking about deficiencies in liver function, muscle function, and even organs that traditionally would not have been thought of as being involved in diabetes, such as the gut, fat tissue, or brain. It's really taking us into very novel and unchartered territory to explore how multiple organs interact with one another in both normal physiology and also the pathophysiology of diabetes.

Dr. Smith: Let's rewind to about a decade ago. The focus was on muscle and insulin resistance, and we saw some new therapeutics in this area in terms of new drugs.[1] There was a big emphasis on insulin signaling and insulin resistance. Where is that now? Is muscle still important in terms of this discussion?

Dr. Ayala: Absolutely, because muscle is the key site, or one of the key sites, of glucose disposal, and it's still the key player. But now what we're focusing on is how muscle communicates with other organs, such as the liver, where insulin signaling also plays a key role, and then how insulin-signaling pathways that occur in muscle and the liver interplay with one another, both in the context of normal physiology and also when insulin deficiency becomes a reality with diabetes.

Dr. Smith: One example of that would be exercise improving sensitivity in muscle as one of the target organs for physical activity.

Dr. Ayala: Correct. The muscle utilizes fat as a fuel in reducing the fat load in tissues where it is not supposed to be, such as in muscle and the liver; this is obviously beneficial for patients who are insulin-resistant and on their way to becoming diabetic. But the liver also plays an important role in exercise. It is the major site of fuel production for muscle. So, exercise gives us insights not only into muscle function and how we can utilize that to find therapies for diabetes, but also into liver function.[2]

Dr. Smith: Tell us more about the liver -- this issue of fatty liver. We see it a lot in patients with diabetes. What's going on in terms of development of fatty liver in patients who are both obese and have type 2 diabetes?

Dr. Ayala: One of the popular hypotheses that has been developed over the past decade or so is that spillover of fat from where it is supposed to be in our adipose tissue into the liver, and the accumulation of fat in the liver -- the fatty liver -- interfere with the signaling mechanisms that insulin utilizes to exert its actions.[3] We're trying to understand, first, why fat accumulates in the liver in the first place, and then how we can target that with therapeutics to try to reduce the fat load in the liver, return it to its normal function, and restore its ability to respond to insulin.

Dr. Smith: But the liver is not the only organ involved in this discussion, this interplay between these organs. Tell us about the other sites that we need to be thinking about and looking at in terms of understanding diabetes.

Dr. Ayala: As I alluded to earlier, other organs would not have been thought of as being key players in insulin resistance in diabetes. One that is near and dear to me is the gut, because it is the site where many hormones are produced that interact with multiple organs, such as the pancreas, the liver, and even skeletal muscle. So, we're beginning to understand how the gut, the primary site that sees nutrients coming in, plays a key role in insulin resistance in diabetes.[4]

Another organ that's near and dear to me is the brain. There is a lot of communication that comes out of the brain toward peripheral organs, but there's also communication from peripheral organs to the brain. The brain senses when nutrients are coming in. The brain senses when there is dysregulation of nutrient flow and has to react accordingly. If there are defects in the way that the brain reacts, then we can see hints of metabolic disorder.

Dr. Smith: Wait a minute. You're telling me the brain controls glucose levels in the blood?

Dr. Ayala: Absolutely. The brain is sort of the orchestra director, if you will. The research in my own laboratory, for example, has shown that if you activate or deactivate certain receptors in the brain, you can actually improve or interfere with the way insulin works in the liver and skeletal muscle.[5] This is a really unique role for the brain to direct how nutrients are assimilated once they come in and how these peripheral organs react to hormones, such as insulin.

Dr. Smith: So how does that work? How does the brain tell the pancreas, the liver, and muscle what to do? Fascinating idea.

Dr. Ayala: Yes, that is one of the key questions that we're addressing, and others are addressing in several laboratories: How is information about the status of the organism, whether it's mouse models or humans -- how is information about fuel distribution relayed to the brain? And how is that information then relayed back to the organs to dispose of those fuels accordingly? And then where are the steps where that communication is disrupted? We still don't know.

Dr. Smith: Not so long ago, as endocrine fellows, we never would have thought of the gut as being an endocrine organ. Recently, we have been talking about adipose tissue as an endocrine organ as well.[6] How does that fit into this multiorgan concept?

Dr. Ayala: I think what we're realizing is that organs that we had thought of as perhaps being inert and not key players are really very dynamic and very involved. It's all about the control of fuel distribution. The gut is a site where many hormones are secreted, and we understood that obviously several hormones would be secreted in order to digest nutrients, but now we're beginning to understand that a lot of these hormones play key roles in such things as insulin secretion and food intake regulation, which obviously bears on obesity. Adipose tissue does as well. It's not just inert storage for fat; it is also an organ that secrets factors to which other organs, such as the liver, muscle, and even the brain, react.

Dr. Smith: It's getting a little bit like a spider web here. We've got a lot of lines and connections going on.

Dr. Ayala: Absolutely.

Dr. Smith: How are we going to sort this out? It sounds a little too complicated. Help us out on this one, Julio.

Dr. Ayala: I think we have to take a multistep approach. One of the powers of doing experiments in a test tube is that it allows us to control the individual pathways -- and the sky is the limit in the ways that we can control individual pathways in a test tube. Then, we have to take what we learned in a test tube and apply it to animal models, where we can maybe lose a little bit of the flexibility of how we can manipulate the system, but we can understand how manipulating that particular pathway affects other pathways and affects other organs. So, we really need to take a multistep approach across individual pathways, and then translate that to an organism and see its effects in the context of an entire organism.

Dr. Smith: So we're talking about knockout models, add-back models, and organ-specific manipulation in genes?

Dr. Ayala: Correct. That's one of the great advances in technology in physiology research -- the ability to disrupt the expression of genes or overexpress certain genes, not only in an entire animal but also in specific tissues and even in specific cells within the tissue. That really lets us know how affecting the expression of those genes in one particular organ affects not only the function of that organ but also how that organ communicates or interplays with other organs.

Dr. Smith: You've been studying these animal models for several years now. Which of these organs is most important? I read papers about the liver being the driver. We talked a minute ago about the brain, muscle, and adipose tissue, and we have the beta cell -- who is in charge here? This is a little confusing for us clinicians.

Dr. Ayala: I think no one organ is in charge. I think when you start tinkering with one, obviously it affects the others, but that doesn't mean that there is one that is above the others. Like you said, it is a spider web. If you take one piece of the spider web off, it might affect the entire web. But if you take another piece of the spider web off, it can also affect the entire web. That doesn't mean that one is more important than the other. They are all important. The entire network is important. That's the way I view it.

Dr. Smith: What does this tell us about the potential for new targets to treat common chronic diseases, such as obesity, type 2 diabetes, and even metabolic aspects of cardiovascular disease? What have we learned, and what do you think that means for us in the future in terms of the clinical practice?

Dr. Ayala: I think what we've learned is that we have a great challenge in front of us, that there's not one single approach, because even though diabetes is one name, it's not a single disease. It's a constellation of complications. I think what the research has taught us is that there isn't going to be a single treatment or a single cure. We're going to have to take a multistep approach to answer these questions, and to address these diseases.

The concept of personalized medicine is really gaining favor -- to be able to identify the specific signatures of a given patient's version of diabetes, if you will, and then finding the right combination of therapies to address that version.

Dr. Smith: Let me make sure I understand that right. What you're suggesting is that some patients may have a liver disease-dominant type of diabetes, some people more muscle, fat, or brain. Is that what I'm hearing?

Dr. Ayala: That's correct. One system may perhaps dominate over the others. It still affects the others, but one flavor of diabetes may be more liver-centric than muscle-centric or fat-centric.

Dr. Smith: How are we going to sort this out? You talked about animal models and our ability to use those. How does this translate into the clinic? What do the next steps need to be in some of our clinical research to help us understand the variety of different flavors, as it were, of diabetes?

Dr. Ayala: I think the power of mouse models is that it really gives us a direction that we can then follow in humans. It gives us a better understanding of where we should be looking. The next step is to apply other technologies to really begin this fingerprinting process, if you will, so that we can then translate and take what we've learned from the animal models and apply it to humans as best we can.

Dr. Smith: In other words, you think that we might be able to match a person and an animal model? Is this where we're going? Is that possible?

Dr. Ayala: That would be an ideal. Obviously, the mouse models that we use are not a perfect correlate to a human. There are many differences between mice and humans. But it gives us a direction to, as best we can, match a particular disease model in a mouse to a human. Then, we can use that information to treat that specific version of diabetes in a human. We may not be able to find the answers to all versions of diabetes in humans by looking at mouse models, but at least it gives us a handle on some of them.

Dr. Smith: This is exciting preclinical research. For our clinical colleagues, what can they look forward to in the future? What do you see when you look over the horizon in terms of how this research is informing our clinical practice in the therapeutics that they are looking for to treat these patients?

Dr. Ayala: When I look over the horizon, what I see is this concept of personalized medicine -- that we're going to have to address each individual's version of diabetes by first identifying what version they have on the basis of the pre-clinical data that we can generate, and then identifying the proper treatments for that particular version. So, the concept of personalized medicine is where I see clinical therapeutics going forward.

Dr. Smith: We have multiple organs here. Does that mean when we treat diabetes, we need to be thinking of multiple therapies as well, maybe targeting the brain, the liver, muscle, but in a personalized fashion?

Dr. Ayala: Absolutely. It's really a nice merger of how the complexity of the problem yields a complex solution to the problem.

Dr. Smith: That was a very interesting topic. Thanks, Julio, for participating in this program.

Dr. Ayala: Thank you, Steven.

Dr. Smith: And we would both like to thank you for joining us today. I hope you will join us for additional programs in the "Developments to Watch" series on Medscape.

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