Researchers Spot Key Molecular Player in Insulin Resistance and Type 2 Diabetes

Scientists at Weill Cornell Medical College have identified a protein called Rab10 as an important partner in the insulin-mediated uptake of glucose by cells, opening the way to potential new drug targets for the prevention and treatment of type 2 diabetes.

Senior study author Dr. Timothy E. McGraw, professor of biochemistry at Weill Cornell Medical College, explains: "Glucose gets into muscle and fat cells assisted by a special transporter called GLUT4. In our study, when Rab10 was eliminated or its activity switched off, insulin was no longer able to properly trigger the recruitment of the GLUT4 glucose transporter to the surface of cells. The recruitment of GLUT4 to the cell surface increases glucose movement from the blood into cells, where the glucose is stored for future use. Thus, Rab10 is involved in the insulin regulation of blood glucose levels. A disruption in the regulation of blood glucose levels, a condition called 'insulin insensitivity', is a hallmark of type 2 diabetes, a disease that affects nearly 20 million Americans."

The finding, published in the April issue of Cell Metabolism, moves scientists one step closer to understanding how insulin signaling works and how insulin insensitivity someday might be prevented.

The glucose found in food is a main source of energy. The body uses complex mechanisms to maintain an ideal level of glucose in the blood. However, conditions such as obesity put such a strain on this system and cells no longer react as they should in the presence of insulin, the hormone that directs glucose uptake.

Because insulin sensitivity is so important, scientists have studied it for decades. "When it's working right, insulin, which is released from the pancreas after a meal, stimulates glucose uptake into fat and muscle cells, thereby lowering the blood glucose level," explains the study's co-lead author, Dr. Lorena Eguez, a postdoctoral fellow in the Department of Biochemistry at Weill Cornell. "That sounds like it should be simple, but researchers quickly learned that this messaging process involves many different molecules inside the cell," she says.

The main "switch" allowing for the influx of glucose into cells is the glucose transporter protein called GLUT4. "When it's not active, GLUT4 is sequestered in vesicles within the cell," according to Dr. McGraw. "In healthy non-diabetics, insulin sets off a chain of biochemical signals that releases GLUT4 to the cell surface. Once there, it forms a kind of 'gate' through which glucose can enter the cell."

Other players have emerged in this process, however. "One co-author on this paper, Dr. Gustav Lienhard, of Dartmouth Medical School, had recently discovered that another protein, called AS160, has a role in insulin signaling to the GLUT4 glucose transporter," Dr. McGraw says. "We knew that AS160 worked on a family of enzymes called rab proteins, so the next logical question was - which rab?"

That question has now been partially answered. In their experiments using cell cultures, Dr. McGraw's team discovered that cells engineered to lack the Rab10 protein suffered an immediate decline in insulin sensitivity.