Diabetes May Start in the Intestines, Research Suggests
“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.”
Instead, Wei says, the mice got sick because of a defect in fatty acid synthase. The mice without fatty acid synthase had lost the protective lining of mucus in the intestines that separates the microbes from direct exposure to cells. This allowed bacteria to penetrate otherwise healthy cells in the gut, making the mice sick.
Gastrointestinal (GI) disorders are common among all people, including those affected by diabetes. At some point in any patient’s life, the chances that he or she will develop a GI tract problem, be it peptic ulcer disease, gallstones, irritable bowel syndrome, food poisoning, or some other malady, are extremely high.
As many as 75% of patients visiting diabetes clinics will report significant GI symptoms. The entire GI tract can be affected by diabetes from the oral cavity and esophagus to the large bowel and anorectal region. Thus, the symptom complex that may be experienced can vary widely. Common complaints may include dysphagia, early satiety, reflux, constipation, abdominal pain, nausea, vomiting, and diarrhea. Many patients go undiagnosed and under-treated because the GI tract has not been traditionally associated with diabetes and its complications.
Both acute and chronic hyperglycemia can lead to specific GI complications. Diabetes is a systemic disease that may affect many organ systems, and the GI tract is no exception. As with other complications of diabetes, the duration of the disorder and poor glycemic control seem to be associated with more severe GI problems. Patients with a history of retinopathy, nephropathy, or neuropathy should be presumed to have GI abnormalities until proven otherwise, and this is best determined by asking a few simple questions.
###
James D. Wolosin, MD, FACP, and Steven V. Edelman, MD
In a further collaboration with Nicholas O. Davidson, MD, director of the Division of Gastroenterology, the researchers found gastrointestinal effects resembling some features of inflammatory bowel disease. Other investigators studying humans with ulcerative colitis had previously made the unexplained observation that colon biopsies from these patients have low amounts of fatty acid synthase.
“Fatty acid synthase is required to keep that mucosal layer intact,” Wei says. “Without it, bad bacteria invade cells in the colon and the small intestine, creating inflammation, and that, in turn, contributes to insulin resistance and diabetes.”
GI problems in diabetes are common but not commonly recognized in clinical practice. The duration of diabetes and the degree of glycemic control are major determinants in the incidence and severity of GI problems. The entire GI tract can be affected, including the mouth, esophagus, stomach, small intestine, colon, liver, and pancreas, leading to a variable symptom complex.
The workup starts with a thorough patient history and appropriate laboratory, radiographic, and GI testing. In addition to pharmacological therapy, glycemic control and dietary manipulation play an important role in managing GI disorders in people with diabetes.
Inflammation and insulin resistance reinforce each other. Inflammatory substances can cause insulin resistance and inhibit the production of insulin, both of which interfere with the regulation of blood sugar. In turn, insulin resistance is known to promote inflammation.
Further study showed that the ability to build the thin, but important, layer of mucosal cells was hindered by faulty FAS.
That the gut is so important to the development of diabetes makes sense because many people with the condition not only have faulty FAS, but they also frequently develop gastrointestinal difficulties, Semenkovich says.
“Abdominal pain and diarrhea are some of the most common problems we see in people with diabetes,” he says. “We could only connect these ‘dots’ because other experts at the university could help us link what we observed in these mice to what occurs in patients with diabetes and inflammatory bowel disease,” Semenkovich says.
Semenkovich and Wei say much more study is needed, but they say that FAS and a key component of the intestinal mucosa called Muc2 may be potential targets for diabetes therapy. They now plan to study people with diabetes to see whether FAS is altered in a similar way, producing damage to the mucosal layer in the intestines.
Wei X, Yang Z, Rey FE, Ridaura VK, Davidson, NO, Gordon JI, Semenkovich CS, Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin2. Cell Host & Microbe, Feb. 16, 2012.
Funding for this research comes from grants awarded by the National Institute on Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH), by the American Heart Association and by the American Diabetes Association.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
###
Source: Washington University in St. Louis