Scientists at Washington University School of Medicine have made a surprising discovery about the origin of diabetes. Their research suggests that problems controlling blood sugar -- the hallmark of diabetes -- may begin in the intestines. The new study, in mice, may upend long-held theories about the causes of the disease. Because insulin is produced in the pancreas and sugar is stored in the liver, many scientists have looked to those organs for the underlying causes of diabetes. In the new research, scientists studied mice that are unable to make fatty acid synthase (FAS) in the intestine. FAS, an enzyme crucial for the production of lipids, is regulated by insulin, and people with diabetes have defects in FAS. Mice without the enzyme in the intestines develop chronic inflammation in the gut, a powerful predictor of diabetes. "Diabetes may indeed start in your gut," says principal investigator Clay F. Semenkovich, MD. "When people become resistant to insulin, as happens when they gain weight, FAS doesn''t work properly, which causes inflammation that, in turn, can lead to diabetes." First author Xiaochao Wei, PhD, and Semenkovich, the Herbert S. Gasser Professor of Medicine, professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, collaborated with specialists in gastroenterology and genome sciences to determine what happens in mice that can''t make FAS in their intestines. The first striking thing we saw was that the mice began losing weight," says Wei, a research instructor in medicine. "They had diarrhea and other gastrointestinal symptoms, and when we looked closely at the tissue in the gut, we found a lot of inflammation." Initially, the researchers thought that the mice became sick because of changes to the mix of microbes that naturally live in the gut, where they help digest food and synthesize vitamins. "The mice had substantial changes in their gut microbiome," Semenkovich says. "But it wasn''t the composition of microbes in the gut that caused the problems."