A report from the 8th Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology, Chicago, Ill, April 19-21, 2007

Cardiology Review® Online, June 2007, Volume 24, Issue 6

The American Heart Association's (AHA) annual conference on Arteriosclerosis, Thrombosis, and Vascular Biology offered a number of insights into the early identification and treatment of patients at risk for heart disease and diabetes, and contained important take-home lessons for primary care practitioners.

Although much of the conference related to bench research in molecular biology, significant presentations for primary care physicians focused on 2 poorly understood conditions, insulin resistance and metabolic syndrome. Overall, the sessions pointed out that primary care physicians often have a tough time because the current treatments and diagnostic tools are inadequate. As a result, practitioners have to expend greater effort to earlier identify patients with these conditions.

A hidden precursor to diabetes

"Insulin resistance is a condition in which insulin is not having the expected effects in a patient that it would have in a normal person," said Marc Hellerstein, MD, PhD, professor of human nutrition at the University of California-Berkeley who co-moderated a session on obesity, diabetes, and nutrition at the conference. "Normally, insulin drives glucose into muscle or fat cells, and slows down the production of glucose by the liver. In someone with insulin resistance, their body has to produce more and more insulin to keep up with the resistance. The result is hyperinsulinemia," he said.

Hellerstein said that insulin resistance is both difficult to diagnose and dangerous. "The problem is 2-fold: resistance may predispose people to heart disease, and when the pancreas is forced to make more insulin for years, it may sometimes become exhausted and fail." Insulin resistance is often a gateway to diabetes, according to Hellerstein. "Almost all adult diabetics have insulin resistance, but only 25% to 30% of those with insulin resistance go on to have diabetes," he said.

"We need to be able to measure insulin resistance, but so far, there really hasn't been a good way," Hellerstein said. "It's really difficult if you just use blood insulin, because when the pancreas starts to fail, the insulin will fall even though the patient is still insulin resistant."

Diabetes Care

Hellerstein and colleagues published an article in (2007;30(5):1143-1149.) describing a study of 35 patients that compared an experimental method of measuring insulin resistance that he helped develop, with the traditional method, called the glucose CLAMP, which had been around for about 30 years.The CLAMP method takes 4 hours, a nurse, a doctor, and several technicians, and costs $2000 to $3000, Hellerstein explained. By contrast, the method developed by Hellerstein and colleagues measures all body glycolysis using an isotope ratio mass spectrometer. "The patient drinks some glucose, and we can measure it very rapidly, sensitively, and accurately," he said.

Unraveling the sticky problem of metabolic syndrome

Primary care physicians are already looking at diabetes and heart disease as part of a larger cluster of health conditions called metabolic syndrome. "We are trying to help primary care practitioners and specialists understand the molecular basis of metabolic syndrome," said C. Ronald Kahn, MD, professor at the Jocelyn Diabetes Center at Harvard Medical School, who presented on molecular insights into links among insulin resistance, obesity, and cardiovascular disease.

Because of the difficulties in treating metabolic syndrome, early identification is even more important, Kahn said. The condition "is very difficult to treat, and we have many medications that improve the situation, but in the end they don't actually fix it permanently," he said. "Most [patients] are not going to be treated with a single medication, but will require combination therapy."

"Physicians have to look at benchmarks such as lipid and glucose metabolism and the treatments available. We're trying to understand which ones improve insulin sensitivity, because that underlies many of the problems you see here," he said.

Kahn explained that even though present-day therapies are inadequate, doctors can take measures to improve insulin sensitivity, especially in select patients. "How much we can improve it varies a lot; the people who can benefit most are obese individuals and people with type II diabetes, because they have the greatest levels of insulin resistance." These individuals can benefit most from insulin resensitizing therapy such as metformin and the thiazolidinediones, Kahn said.

"Metabolic syndrome is almost synonymous with insulin resistance," according to Berkeley's Hellerstein, who noted that the syndrome includes obesity, high blood pressure, high triglycerides or low high density lipoprotein (HDL), and often disorders of blood clotting.

"These are all very common abnormalities in their own right, but the combination occurs much more frequently than chance alone would have it, so scientists conclude that there must be a connection between these variables," Hellerstein said. "Often patients have 3 or 4 of these together, and then you have a very high risk for heart disease. Most of the people who get heart disease in our country have metabolic syndrome," he concluded, adding that more than half of patients with the syndrome will get heart disease.

Abnormal adipose tissue metabolism

A phenomenon referred to as abnormal adipose tissue metabolism may also be a key to metabolic disease, especially when it is related to obesity, according to another physician at the conference.

"Obesity may not be a disease of too much fat, but of fat with abnormal functions, which we call adiposopathy" said Samuel Klein, MD, professor of medicine and nutritional science at Washington University in St. Louis. "The question is not just how much fat is present in the patient, but whether the fat is functioning well. You can have a lot of fat if it is functioning well and not get metabolic disease, but if you have even a little fat and it's behaving badly, you can develop metabolic disease," he said.

Klein added that the relevant consideration is the release of fatty acids and adipokines from the fat tissue. Adipokines are proteins made by the fat tissue, which can work as hormones when released into the blood stream, he said.

Klein noted that adiposopathy can contribute to multiple risk factors for heart disease. "Another condition that is part of metabolic syndrome is diabetes. Part of the etiology behind the cascade of insulin and glucose in diabetes is abnormal fat metabolism," he said. "Diabetes is a major risk factor for heart disease, which is also associated with dyslipidemia and high blood pressure," he said.

Although diagnosing adiposopathy is a difficult feat for primary care practitioners, Klein said that diagnosing the metabolic syndrome profile (ie, by testing for increased triglycerides, abnormal blood sugar, and waist circumference) can help identify people with abnormal adipose tissue function.

Reverse cholesterol transport is another important consideration, said Hellerstein, who noted that when new drugs designed to treat metabolic disorders are unsuccessful, the reason is often that the drugs may not increase reverse cholesterol transport, despite increasing HDL

"We need to measure this reverse cholesterol transport, to see if these HDL drugs are really doing their job," said Hellerstein, who also runs the diabetes clinic at the University of California at San Francisco. "Primary care doctors should be aware that HDL levels do not always reflect the functional efficiency of HDL, because HDL concentrations and function are not the same."

a-1 Milano.

As an example, Hellerstein described patients in Italy who have a gene called "These patients have low HDLs, but not heart attacks, and we think it's because their HDLs are very effective," he said.

"The drugs we have right now are not quite good enough, so doctors should always try to treat metabolic syndrome with behavioral methods, such as weight loss and exercise," he concluded.

The dietary pendulum swings

Part of the problem leading to the growth in metabolic syndrome diseases may be an inappropriate emphasis placed on fat reduction over the years, according to Ronald Krauss, MD, senior scientist and director of atherosclerosis research at Children's Hospital and Oakland Research Institute, who also presented at the conference.

"In our hospital, we're starting to see 1 or 2 new cases of adult-onset diabetes a month in kids that are barely in their teens," said Krauss, who moderated a plenary session on diabetes, obesity, and nutrition. "As we start to look more closely at other conditions such as blood lipids, we're finding that even before their teen years, kids are showing abnormal lipid profiles," he added.

American Heart Association dietary guidelines may have been part of the problem, Krauss added. "The nutrition guidelines generally have followed the tradition of advocating for lower fat and substituting carbohydrates for fat as a means of reducing blood cholesterol levels, and maintaining a lower body weight," Krauss said. "But we're finding that for many, those diets don't provide the optimum balance of metabolic factors, and that they lead to excess storage of fat and excess blood levels," he said.

"What we've found is that for many individuals, diets that are high in carbohydrates and lower in fat and protein don't provide the optimum metabolic influence on heart disease risk factors ranging from blood pressure to high blood glucose to elevated lipids," he said.

"We have found that even moderate restriction of carbohydrate intake can benefit those who are at risk. For example, the average American diet has from 50% to 55% carbohydrates, and despite our efforts to encourage the selection of the healthier type of carbohydrates, such as whole grains, most take half or more of their carbohydrates in the form of sugars or starches that can have adverse effects on metabolism. And some people are particularly sensitive to these adverse effects," Krauss concluded.

The next Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology will be held April 16-18 in Atlanta, Ga. Contact

for more information.

scientificconferences@heart.org