How does cholesterol regulate insulin action in adipocytes?
Professor Gould is looking to understand why fat and muscle cells don’t take in glucose properly in people with Type 2 diabetes, and what role cholesterol plays in that process. If successful, this research could help the development of new treatments to combat insulin resistance in Type 2 diabetes.
Background to research
Insulin is needed to keep blood glucose levels relatively constant, and it does so by stimulating fat and muscle cells to take in glucose from the bloodstream. In order for this to happen, channels (called GLUT4) are sent to the surface so that glucose can move through them, into the cells. In Type 2 diabetes, this doesn’t happen: the cells are resistant to insulin, and don’t send GLUT4 to the surface. In turn, this means that glucose builds up in the bloodstream.
Recent studies have suggested that the levels of cholesterol inside a cell could affect the cell’s ability to take in glucose. A protein called NPC1 controls how much cholesterol builds up in cells, and the NPC1 gene is associated with the development of Type 2 diabetes. Animals that have a faulty NPC1 protein can’t regulate their blood glucose or insulin levels properly, and blocking NPC1 activity in fat cells causes them to respond less well to insulin.
All of this suggests that NPC1 and cholesterol are important in regulating how cells respond to insulin, but we don’t yet know the details of how this works.
Professor Gould aims to understand how cholesterol regulates the movement of the important GLUT4 channels in fat cells, identifying key molecules involved in that process.
To do this, the team will be studying the movement of GLUT4 in yeast cells, as the cellular machinery involved is the same as that in human cells. Using yeast allows the team to run genetic screens, to pinpoint specific genes that look like they’re involved in GLUT4 movement – particularly looking for genes that link cholesterol to how insulin works in fat cells.
In turn, these genes could be targeted by drugs in the future, informing the development of new treatments to combat insulin resistance and Type 2 diabetes.
Potential benefit to people with diabetes
If the team can understand the biology behind why fat and muscle cells don’t take up glucose properly in people with Type 2 diabetes, this information could aid the development of new therapies to help treat this condition.