Thiazolidinediones (TZD's) are drugs commonly prescribed to patients with type 2 diabetes, the most common form of diabetes. Current U.S. Food and Drug Administration-approved agents are known as Actos (pioglitazone) and Avandia (rosiglitazone). These oral agents improve blood glucose levels in people with diabetes by improving insulin action in the body. While it is known that these drugs work primarily by binding to a receptor in the nucleus of cells called Peroxisome Proliferator Activated Receptor-gamma (PPARg), all of the molecular signaling events important for the drugs to work are not completely understood.
A new study by researchers at Joslin Diabetes Center in Boston helps to explain how these drugs work. The manuscript appears in the March edition of the American Diabetes Association's journal Diabetes.
In a clinical research study, Joslin researchers Allison B. Goldfine, M.D., Sarah Crunkhorn, Ph.D., and Mary-Elizabeth Patti, M.D., examined muscle and fat tissue from patients with type 2 diabetes before and after they took the drug rosiglitazone. The researchers found that levels of two proteins called Necdin and E2F4, which are important in regulating cell replication, are altered in muscle and fat after patients took the drug for two months. Dr. Goldfine is an Investigator in Joslin's Section on Cellular and Molecular Physiology, Assistant Director of Clinical Research at Joslin and Assistant Professor of Medicine at Harvard Medical School. Dr. Patti is Director of Joslin's Genomics Core Lab and also an Investigator in Cellular and Molecular Physiology and Assistant Professor of Medicine, Harvard Medical School. Dr. Crunkhorn is a postdoctoral fellow in Dr. Patti's laboratory.
"Because the proteins are important in regulating the cell cycle, the findings suggest that the thiazolidinediones may work, in part, by altering the cell differentiation state, or level of cell maturity. Additionally, the two proteins Necdin and E2F4 may represent new drug targets that may be useful in the future for treatment of patients with diabetes," says Dr. Goldfine.
Others who participated in the study include Maura Costello, Hiral Gami, Edwin J. Landaker, and Jose Jimenez-Chillaron, Ph.D., of Joslin; Michio Niinobe, Ph.D., and Kazuaki Yoshikawa, M.D., Ph.D., of Osaka University, Japan; David Lo, M.D., Ph.D., of the La Jolla Institute for Allergy and Immunology, La Jolla, CA; and Amy Warren, Ph.D., of Digital Gene Technologies/Neurome of La Jolla.
Funding for the study was provided by the National Institutes of Health and generous support from the Iacocca Foundation.
About 20.8 million Americans have diabetes. While approximately 14.6 million of these adults and children have been diagnosed with diabetes, 6.2 million of them are estimated to have type 2 diabetes and not know it. An estimated 41 million people in the United States have pre-diabetes, or higher than normal blood glucose levels, but not high enough to be diagnosed as type 2 diabetes. In addition, an estimated 800,000 Americans have type 1 diabetes. Diabetes can lead to many medical complications, including heart attack, stroke, blindness, nerve damage, kidney failure and poor circulation. Diabetes leads to the death of an estimated 224,000 people in the U.S. each year making it the fifth leading cause of death in the United States. Diabetes and its complications cost an estimated $132 billion annually in the nation in terms of healthcare costs and lost productivity.
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