Missing link detected in insulin mechanism.
Findings could shed light on Type II diabetes
and insulin resistance.
Professor of Biochemistry Gustav Lienhard
June 27, 2003. Dartmouth Medical School biochemists have discovered a protein that appears to be a missing link in understanding how the hormone insulin
regulates the movement of glucose into cells.
Professor of Biochemistry Gustav Lienhard presented the work on June 21 at the 85th Annual
Meeting of The Endocrine Society in Philadelphia and in a recent issue of the Journal of Biological Chemistry. The findings
by Lienhard and his fellow researchers at Dartmouth and Harvard could provide clues for understanding Type II diabetes, which
is often characterized by insulin resistance. The findings could also shed light on how hormones regulate movement of membrane
proteins in general, Lienhard said. "The protein 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," Lienhard
Insulin acts to maintain the appropriate level of glucose in the blood. One way insulin does
that is to accelerate the removal of glucose from blood and into muscle and fat cells. These muscle and fat cells have proteins
known as "transporters" that can ferry glucose into the cells. However, the transporters are located deep within the cell
in vesicles, and so are not immediately available for glucose movement. Insulin presses on the outside of the muscle or fat
cell, prodding the vesicles within the cell to fuse with the surface membrane. This makes the transporters available to carry
glucose into the cell more rapidly.
Lienhard likens the process to a room with too few doors. "You have a lot of people wanting
to get into a room that only has 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.
"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 said.
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 protein 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.
by Hali Wickner