New study may advance treatments to prevent type 2 diabetes and metabolic syndrome

Insulin uses two distinct mechanisms to control glucose and the metabolism of blood fats (lipids) in the liver, a new Joslin Diabetes Center-led study has discovered.

Failures in each of these networks can lead to serious health problems: the breakdown of glucose metabolism that can lead to type 2 diabetes, and the malfunction of lipid metabolism contributing to metabolic syndrome, which is a cluster of conditions that puts people at increased risk of heart disease, vascular disease and type 2 diabetes.

The new study, led by C. Ronald Kahn, M.D., and Cullen Taniguchi, M.D., Ph.D., of Joslin Diabetes Center in Boston and their colleagues, is published in the May edition of Cell Metabolism. The findings open the door to the development of new treatments that one day may target directly the conditions that contribute to type 2 diabetes and the metabolic syndrome.

"Patients with the metabolic syndrome have high levels of both glucose and lipids in the blood. We now understand that insulin that controls the pathways that control glucose levels are different from those that regulate lipid levels. By targeting these specific pathways, we might be able to improve problems with glucose metabolism, lipid metabolism or both," says Dr. Kahn, President of Joslin Diabetes Center and Mary K. Iacocca Professor of Medicine at Harvard Medical School.

Diabetes affects an estimated 20.8 million children and adults in the United States - 7 percent of the population. An estimated 14.6 million Americans have been diagnosed, leaving 6.2 million Americans unaware that they have the disease. In addition, 41 million Americans are thought to have pre-diabetes, or elevated blood glucose levels that put them at risk for developing type 2 diabetes. If untreated or poorly treated, diabetes can lead to blindness, kidney disease, stroke, nerve damage and circulation problems that can result in limb amputations.

Patients generally are diagnosed with metabolic syndrome if they have three or more of the following conditions: abdominal obesity; high cholesterol levels or triglycerides; low levels of good cholesterol; high blood pressure; and high blood glucose. The metabolic syndrome has become increasingly common in the United States, and according to a recent survey, is seen in 24 percent of all adult Americans above age 20 and in about 40 percent of those above age 60.

Exploring the role of the liver The liver is the body's primary chemical factory, and among its key roles is keeping glucose levels in the blood constant between meals. The liver also produces and packages cholesterol and triglycerides to send throughout the body. Insulin's activity in the liver controls both of these processes, but, until now, researchers have not understood how insulin does its job.

"In one of its roles, insulin tells the liver that you have just eaten, that it can stop producing glucose since the food you have just eaten will, for a while, supply an adequate amount," says Dr. Taniguchi, a postdoctoral fellow in Joslin's Section on Cellular and Molecular Physiology and lead author of the paper. "Insulin also is the trigger that tells the liver how to handle lipids. We have been trying for many years to understand how insulin provides these signals, and now we have shown that insulin controls each process differently."