For Release: April 20, 2007
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Key Protein Link in Insulin Signaling Found

HANOVER, NH—Dartmouth Medical School biochemists, working with colleagues at Weill Cornell Medical College, have identified a protein called Rab10 as an important player in the insulin-mediated uptake of glucose by cells, opening the way to potential new drug targets to treat type 2 diabetes.

Gus Lienhard
Dr. Gustav Lienhard

The research, published in the April issue of Cell Metabolism, moves scientists one step closer to understanding how insulin signaling works. It builds on the work of senior study co-author Dr. Gustav Lienhard, professor of biochemistry at Dartmouth Medical School, who discovered a related protein along the multifaceted insulin signaling pathway that sparks a connection for glucose to move into cells.

Glucose found in food is a main source of energy. The body uses complex mechanisms to maintain a constant level of glucose in the blood. After eating, blood glucose rises, triggering release of insulin from the pancreas to lower sugar levels. One way insulin does that is to accelerate the glucose removal from blood into muscle and fat cells.

However, conditions such as obesity strain this system; muscle and fat tissue no longer respond appropriately to insulin. This disruption in the blood glucose regulation, called insulin insensitivity, is a hallmark of type 2 diabetes, which affects nearly 20 million Americans, according to senior co-author Dr. Timothy E. McGraw, professor of biochemistry at Weill Cornell Medical College.

"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," McGraw said.

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, " McGraw continued. "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."

Lienhard had previously discovered another protein called AS160 that, he said, "had the properties expected for a key intermediate insulin signaling to the GLUT4 transporter and was expected to act through a protein known as a rab."

The next step was to determine which rab among the 60 found in animal cells. In their experiments using cell cultures, the team discovered that cells engineered to lack the Rab10 protein suffered an immediate decline in insulin sensitivity.

"Rab10 now appears to be another key middleman in the insulin-GLUT4 relationship. This discovery gives us one more link in the cellular chain of events linking insulin signaling and the regulation of glucose transport," said McGraw.

While more work remains to understand the intricate web of insulin signals, according to the researchers, their results may help expand understanding and possible treatment of insulin resistance and type 2 diabetes.

This study was funded by grants from the U.S. National Institutes of Health.

Co-researchers include co-lead author Dr. Hiroyuki Sano and Jose A. Chavez, of Dartmouth Medical School, co-lead author Dr. Lorena Eguez and Tuan D. Chuang of Weill Cornell; Dr. Mary N. Teruel of Stanford University School of Medicine; and Dr. Mitsunori Fukuda of Tohoku University in Miyagi, Japan.


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