A new study, published in the Journal of Clinical Investigation, has revealed that two different gene mutations, (R1788W and L1622I), of a gene called ankyrin-B are responsible for triggering diabetes. The more severe of the two mutations, (R1788W), occurs in nearly one million Americans; whereas the milder mutation (L1622I), is shared by seven percent of the African American population. Diabetes is a global health threat. Patients with type 1 diabetes do not produce sufficient insulin. Patients with type 2 diabetes make insulin but become resistant to its effects.
“This is one of the first examples of a susceptibility gene that would only be manifested through a modern lifestyle,” said Vann Bennett, M.D., Ph.D., 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. We think our findings are just the beginning, and that there are going to be many genes like this.”
Ankyrin-B acts as a protein anchor, tethering important proteins to the inside of the cell’s plasma membrane and has been implicated in a wide variety of human afflictions, including irregular heartbeat, autism, muscular dystrophy, aging, and, more recently, diabetes.
The research study created mouse models that carried human genetic variants. Animals with two copies of the R1788W mutation made less insulin than normal mice and the mutant mice metabolized glucose more quickly than normal mice. Glucose is carried to cells and tissues through a second molecule called the GLUT4 Transporter. The mutated mice had GLUT4 on the surface of their muscle and fat cells even when there wasn’t any insulin, which meant that glucose could flow into cells and fat tissue causing obesity.
“We thought that the main problem in these mice would be with the beta cells that produced and secreted insulin,” said Healy, co-author of the study. “Instead, our most significant finding lay with the target cells, which took up much more glucose than expected.”
“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.”
“Ankyrin-B Metabolic Syndrome: Age-Dependent Adiposity Combined with Pancreatic Beta-Cell Insufficiency,” Damaris Nadia Lorenzo, Jane A. Healy, Janell Hostettler, Jonathan Davis, Jiayu Yang, Hans Ewald Hohmeier, Chao Wang, Mingjie Zhang, and Vann Bennett. JCI, July 13, 2015.