The Diabetic Heart

J.L. WEBB

The Diabetic Heart

Scientists Meld Metabolic and Cardiovascular Research


The negative effects of diabetes on heart diseases have been known for years, thanks primarily to comprehensive studies funded by the National Institutes of Health, which provided the evidence physicians and researchers needed to develop better treatments and medications. But most of the questions about why that link exists remain unanswered.

The latest effort to ascertain the underlying causes of so-called "diabetic heart" is fusing the talents of metabolic and cardiovascular researchers who mostly have worked independently of each others' disciplines. It probably will be years before their findings reach clinical significance for front-line physicians, but in the meantime the collective work of these discovery scientists is a promising step in the realm of shared research.

Daniel Kelly, MD, is scientific director of the Burnham Institute at Lake Nona. Last spring, that facility, southeast of Orlando, launched a joint venture with Florida Hospital to combat what Kelly calls "the pandemic of obesity" as it relates to the diagnosis and treatment of type 2 diabetes.

It is a "worldwide problem driven primarily by changes in lifestyle," Kelly said. "But it probably also has genetic components." Kelly laid out the problem as a preface to his strategy for addressing it.

"The leading killer in type 2 diabetes is cardiovascular disease, the actual vascular disease that leads to heart attacks and coronary and peripheral vascular disease," Kelly said. The other factor is that after a diabetic patient has a heart attack, "they seem more likely to have more problems with heart failure … compared to non-diabetics. We don't understand why the heart, after a heart attack, is more susceptible in diabetics. That's why we're interested in developing this new discipline," he said.

Anthony Morrison, MD, was directly involved in the research that preceded the "new discipline" to which Kelly refers. Morrison is a professor of endocrinology and co-director of the University of South Florida Diabetes Center in Tampa. He, in concert with co-director John Malone, MD, was very involved in one of the most significant multi-centered clinical research trials. It was funded by the NIH. From 1983-93, the Diabetes Control and Complications Trial (DCCT) studied the long-term incidences of cardiovascular disease in type 1 diabetics. USF was one of 29 trial centers in the U.S. where that study proved "high blood sugar is a significant contributor to eye, kidney and nerve complications (for diabetics), but it was not statistically significant (regarding) large blood vessels," Morrison explained.

That interventional study was followed by an observational trial, the Epidemiology of Diabetes Interventions and Complications (EDIC). "All the participants (in the DCCT) were asked to continue in an observational trial," Morrison said. The patients were seen by their primary care physicians and had annual follow-up evaluations. In December 2005, the New England Journal of Medicine published a conclusion based on the EDIC that said "intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes."

The upshot, Morrison explained, is that after more than a decade of follow-up, "those people who had intensive controls early on in lowering blood sugar were now at less risk for a large major blood vessel event, compared to those who had poor control" over their blood sugar. "The term 'metabolic memory' came out of that study," Morrison said, which means the "blood vessels appear to remember what the blood sugar control was years before and continue to respond to that at least 8 to 10 years later."

Enter Kelly and his research assignment at Burnham.

"The fundamental premise of what we do is that we won't understand why diabetics' hearts begin to become dysfunctional until we understand the metabolic abnormalities that underlie that (occurrence)," Kelly said. "For many years, cardiologists and cardiovascular scientists have kind of looked at the heart in a vacuum … because considerations haven't been given to metabolic problems, which are now known to occur in obesity and diabetes," he said. It has been difficult to make breakthroughs in this area because the people who are interested in the metabolic disease are working in their own little spheres on diabetes, obesity and genetic abnormalities. And the people who have been working on cardiovascular disease have been looking at hardening of the arteries, hypertension and things like that," Kelly said.

"We are interested in the way the diabetic heart handles fat, not so much sugar, although that is important, too," Kelly said. "As it turns out, diabetics, because they can't use the glucose for energy because their insulin is not working, they have to use fats all the time. We believe that it is the piling up of fats in the heart that lead to the unique and very severe forms of heart disease in the diabetic," he said. "So, we are developing animal models to mimic this to prove that this hypothesis is correct."

The team that is being assembled at Burnham to study the diabetic heart is formidable. Kelly said he will recruit 25 to 30 principal investigators, along with their staff, which should total between 300 and 350 people. Over the next five years, Kelly said, "we want to bring in scientists who are interested in metabolism in one program, and we want to bring in scientists who are interested in all aspects of cardiovascular disease. And we want to bring them together in a very novel, unique disciplinary way. We sometimes call it an interdigitation between the two programs," he said.

In doing so, Kelly said he is hopeful "we can move much more rapidly than if either group was doing the research alone. …We're breaking down all those barriers and trying to do something unique."

The enigmatic results of Burnham's scientists are being regularly published, Kelly said, and one of his priorities is "moving these discoveries as rapidly as we can to clinical significance. The way that we have done that in the past, when we were at universities, is that the medical school and the clinical researchers would collaborate with us. In this case, we are very interested in developing partnerships with the local (healthcare) systems so we might begin to see one of the discoveries we make in the laboratory have relevance for patients," he said.