In a long-awaited feat, scientists have created a line of mice with symptoms that mimic adult-onset diabetes. The achievement, reported in today's issue of Cell, could lead to better screening for a disease that afflicts an estimated 5% of adults in Western countries and perhaps help shed light on other genetically complex diseases.
"For years, people have struggled to locate candidate genes [underlying adult-onset diabetes] ... but no major gene has been identified," says report co-author Domenico Accili of the National Institute of Child Health and Human Development. Thinking that the disease may result from a combination of "hits" to several different genes, Accili and his colleagues attempted to recreate diabetes symptoms by breeding mice lacking half their copies of two genes.
People with adult-onset diabetes develop resistance to the action of insulin, which controls blood glucose levels. So Accili and others on the team, led by C. Ronald Kahn of Harvard University's Joslin Diabetes Center, bred two mouse strains, each lacking a copy of a different gene governing insulin metabolism. In one strain, mice lack one of two copies of a gene coding for a protein that binds insulin. In the other strain, mice lack a copy of a gene coding for a protein that helps to regulate the cellular response to insulin. While only a small percentage of mice in each strain showed symptoms, nearly half of their progeny became diabetic. "Just two genes could account for the entire susceptibility to this complex disease," Accili contends.
Other experts are impressed. "I think this is a very exciting development, which shows how these two particular proteins could work together to cause [the disease]," says Graeme Bell, a professor of biochemistry and molecular biology at the University of Chicago. He notes that the reductions in gene function in these diabetic mice may be more extreme than the variations in humans with adult-onset diabetes. Nevertheless, Bell says, the new model points the way toward better understanding of this and perhaps other complex disorders, such as hypertension and some cancers, that may be caused by two or more poorly functioning genes.