Study identifies key factor that links metabolic syndrome

A new study led by researchers at Joslin Diabetes Centre has identified insulin resistance in the liver as a key factor in the cause of metabolic syndrome and its associated atherosclerosis, disorders that put tens of millions of Americans at high risk of cardiovascular disease.

The findings, published in the February issue of Cell Metabolism, provide not only an understanding of how metabolic syndrome occurs, but also pinpoint a target for treatment of the condition. This represents the work of Sudha Biddinger, M.D., Ph.D., and a team led by C. Ronald Kahn, M.D., Head of the Joslin Research Section on Obesity and Hormone Action and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.

'This is one of the first true insights into the role of the liver in the metabolic syndrome and provides guidance for future therapies,'' said senior investigator Dr Kahn, an internationally recognised researcher in diabetes and metabolism. 'Showing this connection between atherosclerosis and insulin resistance is one of the most dramatic findings I've seen in 35 years.''

Metabolic syndrome is a collection of medical problems related to insulin resistance, including obesity, glucose intolerance, hypertension, lowered HDL ('good') cholesterol and elevated triglycerides. Together these are associated with an increased risk of atherosclerosis, the buildup of plaque in the coronary arteries that leads to heart attack and stroke.

The findings indicate that many of the most important features of the metabolic syndrome do have a common cause, thus challenging a joint position statement issued by the American Diabetes Association and the European Association for the Study of Diabetes that questioned the very existence of the metabolic syndrome.

'This study clearly indicates that metabolic syndrome is not merely a collection of abnormalities that should be considered and treated independently, as some experts have advocated,' said Kahn and Biddinger. 'Rather, it appears that metabolic syndrome is truly a group of closely linked disturbances in glucose and cholesterol metabolism that stem from a defect in insulin signalling in the liver.'

Dr Biddinger said the study sought to understand whether insulin resistance - a condition where the pancreas makes insulin but the body doesn't respond to it - could increase the risk of atherosclerosis. 'The fact that one-fourth of American adults have the metabolic syndrome is alarming. The fact that large numbers of children are now being diagnosed with the metabolic syndrome is even more alarming,' said Biddinger. 'These kids are at risk for having heart attacks in their 30s. We really need to understand the connection between the metabolic syndrome and atherosclerosis.'

To try and find out, the researchers engineered mice by 'knocking out' - i.e. genetically eliminating - insulin receptors in the liver. From this one site of insulin resistance alone, these mice developed many of the lipid abnormalities associated with metabolic syndrome. Furthermore, when fed a high-fat diet, the mice developed extremely high cholesterol, more than four times the levels found in normal mice fed the same diet. More importantly, all of the 'knockout' mice developed atherosclerosis, while none of the normal mice did.

These findings 'focus attention on the liver, since resistance in the liver is enough to cause these abnormalities,' said Kahn. 'By pinpointing the liver, it gives researchers a target for developing potential clinical treatments, such as finding a way to overcome insulin resistance in the liver or to change the way the liver responds to insulin resistance.'

The research was funded in part by grants from the National Institutes of Health and The Iacocca Foundation. In addition to Drs. Biddinger and Kahn, other researchers participating in the study included: Antonio Hernandez-Ono, Christian Rask-Madsen, Joel T. Haas, Jose O. Aleman, Ryo Suzuki, Erez F. Scapa, Chhavi Agarwal, Martin C. Carey, Gregory Stephanopoulos, David E. Cohen, George L. King and Henry Ginsberg from the Joslin, Columbia University School of Medicine, Massachusetts Institute of Technology, and the Beth Israel Deaconess Medical Centre.