Tackling Diabetes and Obesity From a Different Angle

Evan Y. Snyder, MD, PhD; Steven R. Smith, MD

|Disclosures|October 27, 2011
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Evan Y. Snyder, MD, PhD: Hi. I'm Dr. Evan Snyder, Professor at Sanford-Burnham Medical Research Institute. Welcome to "Developments to Watch" from Sanford-Burnham and Medscape. Joining me today is my colleague, Dr. Steven Smith, Professor at the Diabetes and Obesity Research Center and a practicing endocrinologist.

Today's program will focus on key research addressing the growing public health problems caused by increasing rates of obesity and type 2 diabetes, and how this research will affect clinical practice. Thanks for joining us, Steve.

Steven R. Smith, MD: It's great to be here.

Dr. Snyder: There's no question that you can't be a practicing clinician and not be struck with what is absolutely an epidemic of obesity and type 2 diabetes.[1] Every clinician also knows that there are various ways of trying to address that. There are anti-obesity drugs and there is exercise and diet. How effective, however, are those kind of interventions?

Dr. Smith: It's interesting that you bring up the diet and exercise part because that really is the foundation of all of our obesity therapies. But there is a myth out there about exercise -- that it's good for weight loss -- but it really doesn't seem to do too much. Great health benefits, but you don't get much bang for your reduction-in-body-weight buck when it comes to exercise.

Diets -- everybody has an opinion about diets. The research shows us that most of the diets are equally effective.[2] There's not much difference between them. It's all about calories in, calories out, and eventually that reduction in body weight causes changes in the body's metabolism that fight that reduction in body weight. That's really where some of the interesting science is right now, in understanding these counterregulatory responses to reduced body weight and the hormonal systems that fight the diet and exercise in trying to lose weight.

Dr. Snyder: Of course everybody -- clinicians and patients -- would love to think that they could just take a drug that's going to fix everything and then maybe they don't have to diet and they don't have to exercise. How effective have the drugs been?

Dr. Smith: It's been extremely difficult to develop antiobesity drugs. You may have heard about some of the problems in the past with drugs that have had adverse-event profiles that are not compatible with a disease like obesity.[3] In fact, many companies have been working very hard for at least the last 10-15 years or so to try to identify new targets in drugs that we can use. Right now we have essentially 1 drug on the market for obesity therapy. It's been discouraging in the last couple of years that we don't really have any good medical therapies -- pharmacologic therapy -- for obesity.

Dr. Snyder: Which gets us into what I know has been your clarion call: that we need to focus on fundamental metabolic regulation. That ultimately is what's going to change clinical practice.

Dr. Smith: Exactly.

Dr. Snyder: Could you elaborate a little bit on that?

Dr. Smith: Back in the 1970s we had a war on cancer, and we've worked very hard to understand the fundamentals of HIV and cardiovascular disease. But obesity really wasn't a bona fide scientific area of research until about 15 years ago, when we discovered the hormone leptin and people said that maybe there is a biological basis of body weight regulation.[4] In the last 10 years, we've seen some incredible advances in our understanding of the neuroscience of ingestive behavior and satiety and hunger hormones. We now know that many organs participate. You've got fat cells that secrete hormones -- it's a very complicated system, this body-weight-regulating system involving neuroscience and other disciplines.

Part of the problem in developing drugs is that there are redundant control systems for regulating body weight, so sometimes you have to touch multiple pathways. You're absolutely right: There's a lot we know from this research in the last 10 years, but there's a lot we don't know about how body weight is regulated.

Dr. Snyder: Obviously, everybody who deals with diabetes focuses on insulin. Can a better understanding of metabolic regulation ultimately translate into better regulation of insulin or body weight?

Dr. Smith: It's a great question. We know that reducing body weight will improve many of the comorbid conditions, including type 2 diabetes, hypertension, other metabolic disturbances, and cardiovascular disease risk factors.[5,6] Clearly, insulin resistance is part of that response to the increase in body weight, and reducing body weight will reverse that insulin resistance.[6] I think that's one of the key factors in understanding how obesity leads to the development of diabetes and how reducing body weight can actually improve diabetes as well.

Dr. Snyder: Do you think -- when you have a better handle on metabolic regulation -- that ultimately it will inform the discovery of better drugs? Is that the hope?

Dr. Smith: Sure. We've been focusing -- and the industry has as well -- on central targets, regulating appetite as a means of reducing body weight and improving diabetes control. There's been a shift over the last couple of years such that the pendulum is swinging toward approaches to turn on fat-burning, approaches to increase metabolism to raise metabolic rate.[7] This pendulum is swinging away from the brain in many ways, even though there's still a lot for us to learn about the satiety signals in the brain.

Dr. Snyder: The brain -- that's my favorite organ. As you know, I'm a neurologist and a neuroscientist, so it's always good to hear that even other organs, like the pancreas and metabolic regulation, ultimately come back to regulation by the brain.

Of course, even when we understand these signals, it doesn't mean that people are off the hook. They can't now not worry about exercise and not worry about their diet. That's not what you're saying. Is that correct?

Dr. Smith: Yes. Remember, I said in the beginning that diet and exercise are the fundamentals. They're the foundation of all other therapies. Even people who have bariatric surgery to control their body weight and reduce their diabetes problems also need to pay attention to what they're doing.[8] I like to think of diet and exercise as being a way to allow medications to work and to allow bariatric surgery to do its work as well. It's really fundamental to everything that we talk about in obesity medicine.

Dr. Snyder: One thing that I think has become very salient to pediatricians like myself is an epidemic of obesity and type 2 diabetes in kids. When I was in training, in fact, it was called type 1 diabetes -- child-onset; type 2 was adult-onset. But now, here we are as pediatricians, dealing with kids with what used to be called adult-onset diabetes. How do you interpret that and how do we address that?

Dr. Smith: That's just the tip of the iceberg. We're seeing adolescents in particular showing up with type 2 diabetes.[9] It's not the classic type 1 juvenile diabetes. The other part of the iceberg is the next generation, those in their 20s and 30s, who are developing diabetes, whereas historically diabetes was a disease of 40, 50, and beyond. I think what we're seeing really is a shift because of the obesity epidemic toward this earlier development of type 2. Adolescents are a big problem, but these 20- and 30-year-olds that are developing diabetes are going to be a really big problem as well.[10]

Dr. Snyder: Are you confident that this is also a reversible trend?

Dr. Smith: If you catch people before they actually develop diabetes, you can prevent or delay the onset of diabetes. We know that from the US DPP (Diabetes Prevention Program) study.[11] We know that from a wide variety of studies. I think the key really is diabetes prevention, particularly in these younger years. Weight loss is key to that. You really cannot prevent diabetes without reduction in body weight. Exercise alone just doesn't seem to do it.

Dr. Snyder: That does get us into what the next steps are and what the future holds in store, which is the area of research that the [Sanford-Burnham] Orlando campus is really at the cutting edge of investigating. Tell us a little bit about the calorimetry research center in Orlando.

Dr. Smith: We're developing clinical research infrastructure to be able to bring people into these calorimetry rooms. They allow us to measure -- in what really is a little dorm room -- how many calories somebody burns and whether they're burning fat, carbohydrate, or protein. That gives us a glimpse into their metabolism and helps us understand whether we can turn on fat-burning, whether we can turn off appetite. The energy-balance equation really hinges on this kind of technology.

Dr. Snyder: It sounds like we should each have one of these rooms in our kitchens, right? At home.

Dr. Smith: It would be great. And a lock on the refrigerator would be a good thing, too.

Dr. Snyder: Obviously this involves participation. A lot of the research you do is with human subjects and involves patients' participation in research. Is that true? How do you recruit your patients? How can actual patients help you advance our understanding of this problem?

Dr. Smith: I think it's important to understand that many of the fundamental basic discoveries were in animal models and only some of those apply to the human condition. I tell people all the time that it's essential for us to do our research in the clinic to be able to understand whether the fundamental pathobiology is the same in humans and mice, for example, and participating in clinical research is a key part of that. People understand that intuitively, that participating is important. We have some great volunteers who do give us their time in support of our research programs.

Dr. Snyder: I would imagine that clinicians in private practice can help to advance this research by referring patients to you or to other centers like yours throughout the country. Is that true?

Dr. Smith: Exactly. There's a dual component. We have physicians who refer patients to our research protocols. We also go straight to patients. In fields like obesity and diabetes, people are very motivated to participate, with the idea that they will maybe help themselves but also help that next generation; I think everybody understands that diabetes is transgenerational. They see it in their parents and grandparents and they don't want it to happen to their children.

Dr. Snyder: This is such a major problem. Is there any way that clinicians -- the actual boots on the ground -- can participate in advancing research just within their own clinical practice?

Dr. Smith: We're actually seeing a trend toward pushing much of the clinical research environment out into the community as well. And this comparative-effectiveness, community-based research is going to be extremely important in developing and testing these research ideas in a real-life setting.[12] Stay tuned for that. There's a big push at the National Institutes of Health for comparative-effectiveness research.

Dr. Snyder: That's really exciting. I imagine that clinicians who are watching this program might be contacting you. Would that be okay?

Dr. Smith: Absolutely. That gives us the ability to have difficult patients referred who may have unusual conditions as well as the garden-variety cases of diabetes, obesity, and other metabolic diseases. It's incredibly important to establish that dialogue.

Dr. Snyder: If they do refer patients, these patients then go back to their real lives, and these clinicians would actually be helping to accumulate data that they then report back to you, so they become part of the research process.

Dr. Smith: Exactly. It used to be siloed and independent. Now it's much more integrated.

Dr. Snyder: That's very exciting. In wrapping up, what do you think clinicians can look forward to in the coming years, on the near horizon and in the next decade?

Dr. Smith: A couple of things. One is the fundamental basic research that you mentioned a few minutes ago. It's really opening our eyes to some new ways of thinking about metabolic diseases and how to regulate metabolism, and diabetes in particular. A couple of hot new things are in the pipeline. You're going to have to watch out for those in the next couple of years, but it is a very rich, basic science world right now that's feeding the clinical development as we move forward. These are really exciting times for us.

Dr. Snyder: Thanks so much for allowing me to participate in a discussion on this really fascinating topic. Thanks again, Steve.

Dr. Smith: It was great to be here. Thank you.

Dr. Snyder: We would both like to thank you for joining us today. I hope you'll join us for additional programs in the "Developments to Watch" series on Medscape.

 
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References

  1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303:235-241.

  2. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009;360:859-873.

  3. Wood S. Diet drug orlistat linked to kidney, pancreas injuries. http://www.medscape.com/viewarticle/740855 Accessed September 1, 2011.

  4. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292-295.

  5. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113:898-918.

  6. Klein S, Sheard NF, Pi-Sunyer X, et al. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care. 2004;27:2067-2073.

  7. Eckel RH, Kahn SE, Ferrannini E, et al. Obesity and type 2 diabetes: what can be unified and what needs to be individualized? Diabetes Care. 2011;34:1424-1430.

  8. Heber D, Greenway FL, Kaplan LM, et al. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95:4823-4843.

  9. Mohamadi A, Cooke DW. Type 2 diabetes mellitus in children and adolescents. Adolesc Med State Art Rev. 2010;21:103-119.

  10. Song SH, Hardisty CA. Early onset type 2 diabetes mellitus: a harbinger for complications in later years--clinical observation from a secondary care cohort. QJM. 2009;102:799-806.

  11. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677-1686.

  12. Kindig D, Mullahy J. Comparative effectiveness--of what?: evaluating strategies to improve population health. JAMA. 2010;304:901-902.

Authors and Disclosures

Interviewer

Evan Y. Snyder, MD, PhD

Program Director, Professor, Stem Cells and Regenerative Biology, Sanford-Burnham Medical Research Institute, La Jolla, California

Disclosure: Evan Y. Snyder, MD, PhD, has disclosed no relevant financial relationships.

Interviewee

Steven R. Smith, MD

Professor, Sanford-Burnham Medical Research Institute; Scientific Director, Translational Research Institute for Metabolism and Diabetes, Orlando, Florida

Disclosure: Steven R. Smith, MD, has disclosed the following relevant financial relationships:
Served as a consultant for: Takeda, GlaxoSmithKline, Bristol-Myers Squibb, Arena Pharmaceuticals, Amylin Pharmaceuticals, Inc., AstraZeneca, Eli Lilly, Orexigen Therapeutics, Inc., BioAdvance
Received a research grant from: Takeda, GlaxoSmithKline, Bristol-Myers Squibb, Arena Pharmaceuticals, Amylin Pharmaceuticals, Inc., Jenrin Discoveries

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