Using a revolutionary technique to turn off chemical signals inside the cell, scientists at Joslin Diabetes Center have discovered that the different metabolic abnormalities present in type 2 diabetes can be caused by knocking out two key signals in liver cells.
Their findings in mice may someday lead to strategies in humans to boost these two different signals, providing a powerful new way to treat the different metabolic components present in the most common form of diabetes.
"By lowering the level of two key insulin signaling proteins in liver cells, we began to uncover just how complex type 2 diabetes and the related metabolic syndrome are," said principal investigator C. Ronald Kahn, M.D., President of Joslin Diabetes Center and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. "Both protein signals needed to be knocked out at the same time to create the full diabetic syndrome, while depleting just one or the other caused only either the glucose or the lipid abnormalities associated with diabetes. Thus, these two pathways complement each other, each controlling a part of the metabolism that is disrupted in type 2 diabetes or the metabolic syndrome."
Others involved in the study were lead author Cullen Taniguchi, M.D., Ph.D., and former Joslin researcher Kohjiro Ueki, M.D., Ph.D., now at the University of Tokyo. Published Feb. 10 in the online edition of the Journal of Clinical Investigation, the study sheds new light on a complex question: How do cells normally process the hormone insulin and what goes wrong in diabetes?
An estimated 18 million Americans have type 2 diabetes, and about one-third do not even know they have the disease. In this disorder, the body does not make enough insulin or resists its effect, a phenomenon called insulin resistance. Without effective insulin, cells throughout the body are unable to convert sugar in the bloodstream to energy, resulting in chronic fatigue, thirst and other symptoms of high blood sugar. People with diabetes also have abnormalities in lipid metabolism and are two to four times more likely to have cardiovascular disease, and they run a higher risk of damage to nerve, eye, kidney and other body tissues.
Previous discoveries by Dr. Kahn's research team provided insight about the pathway that insulin takes to stimulate cells. Insulin docks at a receptor site at the cell membrane. Once this site is activated, chemical signals pass to other proteins inside the cell, including insulin-receptor substrates (IRS). These spark a chain of other reactions. Ultimately the cell's energy machinery is turned on.
The Joslin study focused on two of these early intracellular signaling proteins, IRS-1 and IRS-2, and especially their role in the liver, which is a key organ for both glucose and lipid metabolism. If turned off, how would that affect the onset of type 2 diabetes? And if an effect occurred, was it causative or something that just happens along the way?