New research has discovered that diabetes in aged, lean mice has a different cellular cause than the type 2 diabetes that results in weight gain. Co-leading researchers Ronald Evans, PhD, and Ye Zheng, PhD, are calling it a new kind of diabetes, type 4, according to a report on the website of the Salk Institute for Biological Studies in LaJolla, Calif. "A lot of diabetes in the elderly goes undiagnosed because they don't have the classical risk factors for type 2 diabetes, such as obesity," Evans, director of Salk's Gene Expression Laboratory and senior author of the paper that was published Nov. 18 in Nature, said in the report. "We hope our discovery not only leads to therapeutics, but to an increased recognition of type 4 diabetes as a distinct disease." The study, published Nov. 18 in Nature, also points toward a possible cure for type 4 diabetes, by blocking immune system cells called T regulatory cells from accumulating in fat. Traditionally, diabetes has been grouped into the rarer type 1 disease, which most often appears in childhood when the pancreas stops producing insulin; and type 2, which is characterized by the body's failure to respond to insulin and most often attributed to being overweight. Both forms of the disease lead to high blood sugar levels. A third type of diabetes results in symptoms mimicking Alzheimer's. But Evans -- after a thin, older family friend developed diabetes -- wondered why some people developed the disease later in life without weight gain.
Mice tell a different story
Evans, along with Zheng, an assistant professor in Salk's Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, and colleagues, set out to compare the immune systems of healthy mice, those with obesity-related diabetes and those with age-related diabetes. The mice with age-related disease, they found, had abnormally high levels of T regulatory cells inside their fat tissue. Mice with obesity-related diabetes had normal levels of Tregs within the tissue, despite having more fat tissue. "We created a census of immune cells in the fat of these mice," Sagar Bapat, a graduate student in the Evans and Zheng labs and first author of the new paper, said in the report. "Simply by counting cell types, we immediately saw there were more Tregs in the older mice with diabetes than any other group." Normally, Bapat explains, Tregs help calm inflammation. But as someone ages, the new research suggests, Tregs gradually accumulate within fat. And if the cells reach a tipping point where they completely block inflammation in fat tissue, they can cause fat deposits to build up inside unseen areas of the body, including the liver, leading to insulin resistance. When the scientists blocked Treg cells from accumulating in the fat by targeting a molecule that the immune cells require, mice no longer developed type 4 diabetes in old age. However, if mice became obese, blocking the Tregs in fat did not prevent type 2 insulin resistance. "It turns out that for this type of diabetes, the treatment is not losing weight," says Evans. "The treatment is actually losing these cells, and we show that it's possible to do that." To comment, email [email protected].
