Cambridge, MA - Hepatic insulin resistance appears to mediate the glucose, triglyceride, and HDL-cholesterol abnormalities that contribute to the constellation of heart-disease risk factors called the metabolic syndrome and so may represent a pathophysiologic tie that binds hyperinsulinemia and dyslipidemia as promoters of coronary disease, conclude researchers in the February 2008 issue of Cell Metabolism [1].

The molecular causes of such insulin resistance might make an effective treatment target for patients with the metabolic syndrome, according to Dr Sudha Biddinger (Joslin Diabetes Center, Boston, MA) and associates.

But a leading critic of metabolic syndrome's emerging status as a clinical entity disagrees with what the new findings mean. "The study itself is beautiful," Dr Richard Kahn, chief scientific and medical officer of the Alexandria, VA-based American Diabetes Association (ADA), told heartwire after reading the report from Biddinger et al. "But it's irrelevant to the metabolic syndrome."

Almost every study in humans that has explored root causes of the metabolic syndrome, he said, "showed that there were at least two to four factors, two to four underlying causes, not just insulin resistance."

Yet Biddinger et al say their series of experiments with liver insulin-receptor knockout (LIRKO) mice suggest, among other things, that hepatic insulin resistance alters the lipoprotein profile to make it more atherogenic, such as by lowering HDL cholesterol and raising total cholesterol and apolipoprotein-B (apoB) levels, at the same time that higher insulin concentrations promote hypertriglyceridemia.

One thing I hope will be an outcome of this is that the organizations that have said there is no metabolic syndrome, like the ADA, will at least now admit that a lot of it is tied to a single problem.

Their research further suggests that the proatherogenic derangements caused by insulin resistance can be exacerbated by a poor diet and obesity, which further contribute to the development of atherosclerosis, according to the group. The LIRKO mice rapidly developed vascular disease when given a "Western" high-fat, high-cholesterol diet.

"Together these produce the full complement of lipid abnormalities associated with the metabolic syndrome in humans," write the authors.

At least in the study's experimental model, "insulin resistance is enough to drive these lipid abnormalities in the metabolic syndrome, and when coupled with diet, it's enough to drive the atherosclerosis, too," coauthor and senior investigator Dr C Ronald Kahn (Joslin Diabetes Center) told heartwire.

The group says their research is clinically important "because it suggests that the metabolic syndrome is not merely a collection of abnormalities that should be considered and treated independently, as some experts have advocated. Rather, it appears that the metabolic syndrome is truly a syndrome, in which disturbances in glucose and cholesterol metabolism both stem from a defect in insulin signaling."

Said coauthor Kahn when interviewed, "One thing I hope will be an outcome of this is that the organizations that have said there is no metabolic syndrome, like the ADA, will at least now admit that a lot of it is tied to a single problem and that there is good reason to try to treat it as a commonly linked problem."

The ADA's Kahn is explicitly among the experts Biddinger et al refer to as skeptical of the syndrome's existence. He coauthored a critical review of the evidence basis for what cardiology calls "the metabolic syndrome" and argued, essentially, that there is little real basis for such a distinct entity [3]. The statement was developed by the ADA and the European Association for the Study of Diabetes (EASD) and published in both groups' journals.

The study itself is beautiful, but it's irrelevant to the metabolic syndrome.

As reported by heartwire at the time, the joint ADA/EASD statement said, "There is much fundamental, clinically important, and critically missing information about the metabolic syndrome to warrant a more serious examination of whether medical science is doing any good by drawing attention to and labeling millions of people with a presumed disease that does not stand on firm ground." It went on to recommend management of cardiovascular risk factors individually and to avoid treatments aimed at the constellation making up the alleged syndrome.

The syndrome's definition is a bit fuzzy for a bone fide clinical entity, according to Kahn of the ADA. "There are at least 13 ways to get the 'metabolic syndrome'—five factors taken three at a time." Most studies of the risk-factor constellation, he said, show that "the whole is not greater than the sum of the parts."

He further observed that Biddinger et al's mouse model doesn't account for all of the metabolic syndrome's components, a point that senior coauthor Kahn acknowledged when interviewed.

"They just showed that insulin resistance is related to dyslipidemia, and of course insulin resistance is related to glucose," the ADA's Kahn said. "But it doesn't show that insulin resistance is related to obesity; in fact, we know that it's not. Actually, obesity causes insulin resistance. And it doesn't say anything about blood pressure."