Scientists use public-database search to identify novel receptor with key role in type-2 diabetes - Office of Communications & Public Affairs - Stanford University School of Medicine

[Use the link above to access the bookmarked article from the news webpage of Stanford University School of Medicine found below. The full text article, published as open access in Proceedings of the National Academy of Sciences (PNAS), is also available. doi:10.1073/pnas.1114513109] “Using computational methods, Stanford University School of Medicine investigators have strongly implicated a novel gene in the triggering of type-2 diabetes. Their experiments in lab mice and in human blood and tissue samples further showed that this gene not only is associated with the disease, as predicted computationally, but is also likely to play a major causal role. In a study published online April 9 inProceedings of the National Academy of Sciences, the researchers combed through freely accessible public databases storing huge troves of results from thousands of earlier experiments. They identified a gene never before linked to type-2 diabetes, a life-shortening disease that affects 4 percent of the world’s population. These findings have both diagnostic and therapeutic implications. The study’s senior author is Atul Butte, MD, PhD, associate professor and chief of systems medicine in pediatrics; its first author is Keiichi Kodama, MD, PhD, a staff research scientist in Butte’s group. Ordinarily, cells throughout the body, alerted to the presence of sugar in the blood by insulin, hungrily slurp it up for use as an energy source. But excessive blood-sugar levels — diabetes’ defining feature — eventually damage blood vessels, nerves and other tissues... Type-2 diabetes ... results from a phenomenon called insulin resistance: the tendency of cells in tissues throughout the body — but especially in fat, liver and muscle — to lose sensitivity and ignore the insulin’s ‘gravy train’ signal. Drugs now used to treat insulin resistance can’t reverse the progression to full-blown type-2 diabetes. ‘We don’t really have a good grasp of the molecular pathology that makes people get it in the first place,’ said Butte, who is also director of the Center for Pediatric Bioinformatics at Lucile Packard Children’s Hospital. In searching for risk-increasing genes over the past 10 years, scientists have used two approaches to hunt them down. One way is to look for variations in genes’ composition — deviations in their chemical sequences that correlate with a higher likelihood of contracting a particular condition... And so a second approach to understanding our genes has been devised. This latter method flags differences in genes’ activity levels, for example in diseased vs. normal tissues, for each of the 20,000 genes in the entire genome. Both types of approaches have generated staggering amounts of data — far more than can fit onto the pages of standard, peer-reviewed journals, whose editors routinely demand (as do federal-government funding agencies) that researchers park their experiments’ results in online, public repositories accessible to others. Now, investigators such as Butte are starting to reach in, drill down and pull out a treasure-trove of potentially valuable information. In this study, the Stanford scientists wanted to know which genes showed especially marked changes in activity, as indicated in earlier comparisons of diabetic vs. healthy tissue samples (notably fat, muscle, liver and beta cells, the only cells in the body that release insulin). Mining public databases, they located 130 independent gene-activity-level experiments — in rats, mice and humans — comprising 1,175 separate individual samples in all. Then, integrating that data, they searched for those genes that showed activity-level differences in the most experiments. They zeroed in on a single gene, called CD44, whose activity changed substantially in diabetic tissues compared with healthy tissues in 78 of the 130 experiments. The chance of this occurring “just due to dumb luck,” Butte said, was vanishingly small: less than one in 10 million-trillion. The uptick in CD44’s activity was especially pronounced in the fat tissue of people with diabetes, he said — intriguing, because obesity is known to be a strong risk factor for type-2 diabetes. The gene was interesting in itself. CD44 codes for a cell-surface receptor not found on fat cells, although those cells do have surface molecules that bind to it. Rather, this receptor sits on the surface of scavenger cells called macrophages (from the Greek words for “big eater”) that can cause inflammation. In obese individuals, macrophages migrate to and take up positions in fat tissue. (Indeed, as many as half the cells in a big potbelly can be macrophages.) Recent medical research has strongly implicated inflammation in initiating type-2 diabetes...”