Curiosity prevails: A conversation with Robert H. Eckel, MD
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For Robert H. Eckel, MD, a desire to learn about the underlying mechanisms driving disease sparked an early interest in what would become groundbreaking research in the fields of lipid metabolism and cardiometabolic health.
“Halfway through my residency training program in internal medicine, I realized there was more to medicine than simply making a diagnosis and making people better,” Eckel, emeritus professor of medicine in the divisions of cardiology and endocrinology, diabetes and metabolism, emeritus professor of physiology and biophysics and Charles A. Boettcher II Chair in Atherosclerosis at the University of Colorado Anschutz Medical Campus, told Healio. “I became incredibly curious about disease mechanisms and why certain drug paradigms did not work. I felt the need to get some answers and research experience.”
Eckel, also past president of the American Heart Association and past president of medicine and science of the American Diabetes Association, would go on to a distinguished career in the fields of lipid and lipoprotein metabolism, nutrition, obesity and cardiovascular risk prevention. He has been one of the world leaders in understanding lipoprotein lipase (LPL) biology and pathophysiology and demonstrated that LPL activity was regulated by insulin in humans. For his lifetime of work, Eckel received the Luminary in Cardiometabolic Medicine award at this year’s Heart in Diabetes CME Conference.
Healio spoke with Eckel about his many mentors, his interest in lipids and cardiometabolic health, and the importance of staying curious.
Healio: What led you to cardiometabolic medicine?
Eckel: In medical school, I worked in a bacteriology lab, so I was exposed to some basic science there. Ultimately, as I tried to decide on a fellowship in both medicine and research, I was deciding between infectious disease or endocrinology and metabolism. At that time during the mid-1970s, lipids were an emerging area of interest, and we were all learning more about the relationship between cholesterol and heart disease. I have also had type 1 diabetes my whole life. I decided if I do not like research, I could go into practice as an endocrinologist.
The late Edwin L. Bierman, MD, the division director at the University of Washington, took a chance on me. I’m thankful to him, endlessly, for taking that chance. My fellowship years were an outstanding, career-changing experience.
I had five high-end job opportunities coming out of my fellowship. I chose the University of Colorado — where I have remained for 40 years — because of Jerrold M. Olefsky, MD, the new division chief at the time. He brought many cutting-edge technologies to the understanding of insulin sensitivity and related aspects of metabolism, diabetes and obesity. With his leadership, I was able to develop some of the first technologies to be applied to lipid and lipoprotein metabolism, including the euglycemic clamp and in adipocyte biology in the laboratory. That began a career that merged lipids and diabetes and CVD very nicely for me going forward.
Healio: How did you first begin your work to learn more about LPL?
Eckel: In the lab, this began with culturing pre-adipocytes. Today, this is a well-developed technology. The late Howard Green, a regenerative medicine pioneer, then at MIT, had recently identified that you could take stromovascular cells from adipose tissue — so-called fibroblasts — and show that you could differentiate these cells into adipocytes in the lab. That paper was 1 or 2 years old when I asked, “Is it possible there is lipoprotein lipase in these fat cells?” That began a career for 40 years in part focused on LPL as a protein that relates to metabolism and not so much atherosclerosis. Once I got to Denver, I was among the first to apply the euglycemic clamp to understanding tissue specific regulation of LPL and fatty acid metabolism and other aspects of lipid and lipoprotein metabolism.
Healio: Your research also turned to the brain. What was that work focused on?
Eckel: Working with Richard J. Robbins, MD, and Daniel H. Bessesen, MD, during the next decade, we identified LPL in the brain and its regionalization. We ultimately identified the presence of LPL in the peripheral nerve and its relationship to diabetic neuropathy and to nerve injury and regeneration.
More recently, in the last 5 to 6 years, with now the lab leadership of Kimberly D. Bruce, PhD, we have been working on how LPL relates to neurodegenerative diseases like multiple sclerosis and Alzheimer’s disease.
Healio: How did this work relate to obesity, metabolic syndrome and diabetes?
Eckel: We used clinical research and animal models to show that LPL in adipose tissue is elevated in obesity but, importantly, rises substantially after weight reduction as a predictor of weight regain. We also did a series of studies showing LPL is regulated in adipose tissue by insulin, and that the regulation is resistant in obesity. However, once people lose weight, they become insulin sensitive.
Later, I wrote a paper with Scott M. Grundy, MD, and Paul Z. Zimmet, MD, in The Lancet in 2005, that helped define the metabolic syndrome, and I was later part of the redefinition of metabolic syndrome. We described the mechanism of metabolic syndrome as being insulin resistant. We ultimately worked with collaborators to develop a model that knocked out LPL in skeletal muscle, and these animals developed metabolic syndrome and were subject to weight gain.
We have also done some work in diabetes on how reductions in LPL activity relates to nerve dysfunction. We also demonstrated how prediabetes can be distinguished from obesity using muscle biopsies.
Healio: How do these conditions converge to drive CV risk, and what can be done to reduce risk?
Eckel: The 1990s was the beginning of a new era for the metabolic syndrome. Ronald M. Krauss, MD, and I published a paper in Circulation in 1998, titled “American Heart Association Call to Action: Obesity as a major risk factor for coronary heart disease.” That paper began in-depth the AHA’s interest in this important issue.
As part of my AHA presidential address in 2005, I outlined a 3-minute lifestyle interview, which has now been incorporated into the AHA Lifestyle guidelines and used as a standard approach for cardiologists and other busy practitioners to assess a patient’s lifestyle in the clinic, as it relates to nutrition and physical activity. As obesity continues to increase, metabolic syndrome follows, along with a higher incidence of type 2 diabetes and CVD.
The idea of a new cardiometabolic medicine subspecialty is something I have been promoting with Michael J. Blaha, MD, and we have published a series of papers about this idea.
Healio: You are the only person to serve as a past president of the AHA, the ADA and The Obesity Society. What perspective has that given you?
Eckel: All my research has been metabolically driven. Anyone who knows me knows I am passionate about these areas. I waved the flag for The Obesity Society to promote obesity as a major comorbidity for many diseases. Leading AHA was a surprise — I was an endocrinologist. But in 2005, they felt the timing was right to bring metabolic disorders front and center. With the ADA, it was always important for me to go beyond glucose. There is so much about diabetes relating to CVD, for example, that is beyond glucose. Of course, that does not mean that glucose is not important.
Curiosity is an incredibly important motivator for me. I am still so curious. But the more you learn, the more you realize what you don’t know. That is what drives you scientifically — to know more and to understand mechanisms more clearly.
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Eckel RH. Luminary in Cardiometabolic Medicine award. Presented at: Heart in Diabetes Annual Meeting; Sept. 10-12, 2021 (hybrid meeting).
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