in the cell, like a hostess waiting for party guests to arrive. 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, postdoctoral fellow Damaris Lorenzo, Ph.D., found that wasn’t the case with the mutant mice. After conducting a number of biochemistry experiments, Lorenzo ddiscovered that the mice had lots of GLUT4 on the surface of their muscle and fat cells even when there wasn’t 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. The researchers believe that long ago, the R1788W mutation -- and the milder L1622I mutation -- may have provided an evolutionary advantage. Aging hunter-gatherer types, who weren’t as effective at chasing down their next meal, needed to gain as much fat as possible to avoid starvation. Now that high-fat, high-calorie foods are plentiful in much of the world, these variants put people at increased risk for modern afflictions like obesity and diabetes.“If people with these mutations are detected early enough, they become prime candidates for intervention with personalized therapies." said Lorenzo, lead author of the study. “That might involve specific strategies to manage their deficits in insulin secretion, as well as adhering to a normal diet and an active lifestyle, with the hope that they can avoid the metabolic diseases that could severely impair their quality of life.”Next, the researchers would like to explore whether the effects they observed in mice hold true in humans. They plan to genotype people in the general population, identify families with ankyrin mutations, and then perform family histories as well as glucose metabolism tests to assess the consequences of these genetic variants at a cellular level. The research was supported by the Howard Hughes Medical Institute and the George Barth Geller Professorship fund.