Missing link detected in insulin mechanism

June 19, 2003

HANOVER, NH - Along the multifaceted insulin pathway, Dartmouth Medical School biochemists have found a missing link that may spark the connection for glucose to move into cells. The discovery is another strand in the remarkable web of molecular signals that regulate traffic through cells and helps elucidate crucial aspects of how the hormone insulin regulates a membrane movement process.

The work is being discussed June 21 at the Endocrine Society meeting in Philadelphia by Dr. Gustav Lienhard, professor of biochemistry, who also reported the results in a recent issue of the Journal of Biological Chemistry with colleagues from Dartmouth and Harvard.

Insulin acts to maintain the appropriate level of glucose in the blood. After eating, blood glucose rises, triggering release of insulin from the pancreas to lower the sugar level. One way insulin does that is to accelerate the removal of glucose from blood and into muscle and fat cells. Key aspects of the mechanism for insulin to stimulate this glucose uptake remain to be sorted out.

A conundrum is that muscle and fat cells have proteins known as transporters for ferrying glucose, but these transporters are in the wrong place. Instead of being in the cell's surface membrane where glucose can climb aboard for passage, they are in vesicles within the cell. So insulin, pressing on a muscle or fat cell, prods these vesicles inside the cell to fuse with the surface membrane, putting the transporters where they can ferry the glucose into the cell. Suddenly the surface membrane has many transporters and glucose can enter the cell rapidly.

Lienhard likens the process to a room with too few doors. "You have a lot of people wanting to get into the room that only has two doors so they would all have to go through these two doors. But inside the room is a stack of doors. People are the glucose molecules and the doors are the transporters; in response to insulin, these doors get shoved into the walls of the room and more people can get into the room quickly."

Lienhard leads a team studying how insulin impinging on the outside of the cell spurs these transporter-containing vesicles to move toward and fuse with the cell surface. It involves linking up two specialized areas of cell biology: cell signaling and membrane trafficking.

Insulin binding to its receptor on the outside of the cell membrane initiates a series of actions. That receptor extends through to the inner surface of the membrane and triggers signaling steps, or a signal transduction pathway, that eventually leads to the vesicle movement and fusion.

The Dartmouth researchers have found a protein that seems to bridge the signaling and membrane movement, a span between the signal transduction pathway and the machinery that controls the fusion of the transporter-containing vesicles with the cell surface.

"That was a missing link in this field. If we're right, this looks like a key protein that connects signaling to trafficking. At the end of the signal transduction pathway, we found a protein that's modified by phosphorylation--by putting phosphate groups on it--and this protein also acts on a key protein component in the machinery for vesicle movement and fusion," Lienhard says.

This protein could provide clues for understanding type two diabetes. A hallmark of the illness is insulin resistance: muscle and fat tissues do not respond adequately to insulin. The transporters they need on their cell surface are trapped inside and it takes a higher concentration of insulin to move additional transporters to the cell surface. Lienhard stresses that studies of the protein in diabetic rodent models need to be done.

The findings could also shed light on how hormones regulate movement of membrane proteins in general, Lienhard adds. "The protein has a widespread tissue distribution. It is found in all the major tissues in the body--brain, liver, kidney, so it could function in other systems where a hormone treatment causes the rapid movement of proteins to the cell surface."

The researchers used a cultured fat cell line that originated from mice. Once they found the protein, they were able to identify it by comparing its amino acid sequence to the gene database.
-end-


The Geisel School of Medicine at Dartmouth

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