Practically everyone gets fatter as they get older, however, according to a new study from researchers at Duke University some people can blame their genes for the extra padding. The new findings show that two different mutations in a gene called ankyrin-B causes cells to suck up glucose faster than normal, fattening them up and eventually triggering the type of diabetes linked to obesity. The team state that the results, which were generated 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. The opensource study is published in the Journal of Clinical Investigation.
Previous studies show that the more severe of the two mutations, called R1788W, is carried by nearly one million Americans. The milder mutation, known as L1622I, is shared by seven percent of the African American population and is about as common as the trait for sickle cell anemia.
The researchers discovered ankyrin-B more than thirty years ago. Earlier studies from the team found that ankyrin-B acts as a kind of protein anchor, tethering important proteins to the inside of the cell’s plasma membrane. Since this initial discovery the lab have implicated defects in ankyrin-B in a wide variety of human afflictions, including irregular heartbeat, autism, muscular dystrophy, aging, and, more recently, diabetes.
Diabetes is quickly becoming one of the greatest threats to public health, according to previous studies, as waistlines expand around the world. If the current trends continue, one in three Americans will have diabetes by 2050. Patients with type 1 diabetes do not make enough insulin, the hormone that helps process the glucose that builds up in the bloodstream after a meal. Patients with type 2 diabetes, the form linked to obesity, make insulin but become resistant to its effects.
The team state that this is one of the first examples of a susceptibility gene that would only be manifested through a modern lifestyle. They go on to explain that as the obesity epidemic really took off in the 1980’s, when sugary sodas and French fries became popular. They stress that it’s not like humans suddenly changed genetically in 1980, however rather people have carried susceptibility genes that were exacerbated by this new diet. The researchers hypothesize that the findings are just the beginning, and that there are going to be many genes like this.
Several years ago the team 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. However, it was still unclear how these changes in the genetic code could set a course for diabetes.
To get at that answer the current study used mouse models which carried these same human genetic variants. The data findings showed that animals with two copies of the R1788W mutation made less insulin than normal mice. The results also showed that despite this shortcoming, their blood glucose levels were normal. The researchers then performed the rodent equivalent of a glucose tolerance test, commonly used to screen for type 2 diabetes in people, to determine how quickly glucose was cleared from the bloodstream in the mutant mice. To their surprise, the mutant mice metabolized glucose more quickly than normal mice.
The lab explain that glucose doesn’t enter cells and tissues all on its own, and instead has to rely on a second molecule, called GLUT4 transporter to gain access. They go on to add that normally GLUT4 hangs out in the cell and when insulin is present it alerts GLUT4 to spring into action to transport glucose into the cell. When insulin goes away the GLUT4 transporters close the channels and return into the middle of the cell.
However,the current study found that this wasn’t the case with the mutant mice. The results showed 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. The team state that this was an advantage when they were young, because it protected the animals from low insulin levels. However, 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. They hypothesize that 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.
The team surmise that if people with these mutations are detected early enough, they become prime candidates for intervention with precision medicine therapies. They 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.
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