Researchers have found that two different mutations in a gene can lead to the type of diabetes linked to obesity.
Researchers found that two different mutations in a gene called ankyrin-B can cause cells to suck up glucose faster than normal, fattening them up and eventually triggering the type of diabetes linked to obesity.
The findings in mice, could help identify at-risk individuals who might be able to tip the scales back in their favour by eating better and exercising more.
"This is one of the first examples of a susceptibility gene that would only be manifested through a modern lifestyle," said Vann Bennett, senior author of the study and George Barth Geller Professor of Biochemistry, Cell Biology, and Neurobiology at Duke University School of Medicine.
"The obesity epidemic really took off in the 1980's, when sugary sodas and French fries became popular. It's not like we suddenly changed genetically in 1980, but rather we have carried susceptibility genes that were exacerbated by this new diet," Bennett said.
Several years ago, the Bennett laboratory found evidence that ankyrin-B mutations might play a role in insulin secretion and metabolism. Since then, several studies have uncovered rare ankyrin-B variants that are associated with type 2 diabetes.
One mutation, called R1788W, was more common in Caucasians and Hispanics. Another, called L1622I, was found exclusively in African-Americans, a group known to be at a particularly high risk of diabetes.
But it was unclear how these changes in the genetic code could set a course for diabetes.
The researchers created mouse models that carried these human genetic variants. They found that animals with two copies of the R1788W mutation made lesser insulin. Despite this shortcoming, their blood glucose levels were normal.
The researchers also found that the mutant mice metabolised glucose more quickly than normal mice.
Glucose does not enter cells and tissues all on its own, but instead has to rely on a second molecule, called GLUT4 transporter, to gain access.
When insulin is present it acts as a kind of doorbell, alerting GLUT4 to spring into action and open the door to let glucose into the cell. When insulin goes away, the GLUT4 transporters close the door, turn around, and go back into the middle of the cell.
However, researchers found that was not the case with the mutant mice. The mice had lots of GLUT4 on the surface of their muscle and fat cells even when there was not any insulin around. That meant that glucose could flow in without necessarily having to bother with the doorbell.
This open door policy was an advantage when they were young, because it protected the animals from low insulin levels. But when the mice got older - or switched to a particularly high-fat diet - it made the mice fatter and, eventually, led them to become insulin resistant.
