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Two Gene Mutations Identified in Increased Risk of Obesity and Diabetes

Mutations in the ankyrin-B gene cause fat cells to soak up more glucose, setting the stage for obesity and insulin resistance…

Ankyrin-B was discovered more than 30 years ago by researcher Vann Bennett at Duke University School of Medicine and the Howard Hughes Medical Institute. The gene plays a role in anchoring certain proteins to the plasma membrane of cells. Since its discovery, mutations in this gene have been linked to various conditions, including arrhythmias, muscular dystrophy, autism, and, most recently, diabetes.

Ankyrin-B modulates transporters called GLUT4 on the surface of muscle and fat cells allow glucose to enter the cell. Normally, GLUT4 is active in the presence of insulin, but retreat into the cell when insulin secretion shuts off. Two mutations in ankyrin-B, R1788W, which is carried by nearly one million Americans, and L1622I, which is carried by seven percent of African Americans, have been implicated in type 2 diabetes.

Bennett and his team studied mice carrying two copies of the R1788W mutation to determine how this mutation leads to diabetes. They found the mice with the mutation secreted less insulin than normal mice though they maintained normal blood glucose. When administering a glucose tolerance test, they expected the mice carrying the mutation would be slower in clearing blood glucose. Instead, they found the mice metabolized blood glucose more quickly.

“We thought that the main problem in these mice would be with the beta cells that produced and secreted insulin,” said co-author Jane Healy. “Instead, our most significant finding lay with the target cells, which took up much more glucose than expected.”

Further investigation by postdoctoral fellow Damaris Lorenzo uncovered that the mutated mice had more GLUT4 on the surface of their muscle and fat cells, even when insulin was not present. This allows the cells to take up more glucose in a shorter amount of time, and to continue to take in glucose without the presence of insulin.

The researchers believe that these gene mutations could have at one point held an evolutionary advantage, allowing earlier humans to continue to store energy when food was scarce and insulin secretion waned. “This is one of the first examples of a susceptibility gene that would only be manifested through a modern lifestyle,” said Bennett. Plentiful food allows those with these gene mutations to grow larger fat cells quickly, leading to obesity and eventually insulin resistance and type 2 diabetes.

The researchers would like to further the studies in human subjects, identifying families through genotyping that carry these ankyrin-B mutations, and assessing medical histories and glucose tolerance. Lorenzo envisions in the future, their research could lead to targeted intervention. “If people with these mutations are detected early enough,” he said, “they become prime candidates for intervention with personalized therapies.”

Practice Pearls:

  • Two ankyrin-B mutations have been linked to type 2 diabetes.
  • The mutations cause obesity through increased glucose uptake, even without insulin present.
  • Patients carrying these gene mutations may benefit from personalized therapy. See above lifestyle intervention to avoid weight gain.

American Medical Association (JAMA). Duke University School of Medicine. “Gene fuels age-related obesity and diabetes.” Duke Today. 13 July 2015. Journal of Clinical Investigation.