Anti-Diabetic Drug Found toDramatically Reduce Symptoms ofBowel Disease August 12, 1999Journal of Clinical Investigation/MedscapeWireResearchers at the University of Pennsylvania Medical Centerhave shown that a class of anti-diabetic agents currently on themarket can dramatically decreases the symptoms ofinflammatory bowel disease in mice. Specifically, theydiscovered that these drugs inhibit the activation of a masterregulator of the inflammatory response called NF-kappa B.Their research suggests that these compounds, calledthiazolidinediones (TZDs), may be an effective new therapy fortreating inflammatory bowel disease (IBD) in humans, adebilitating disorder that afflicts millions worldwide. Theinvestigators present their findings in the August 15 issue of theJournal of Clinical Investigation.The Penn team found that when they gave TZDs to mice withIBD, it significantly reduced the symptoms of the disease, asmeasured by a composite index of weight loss, diarrhea, andintestinal bleeding. After about a week of the treatment, therewas an 80 percent improvement in the mice receiving TZDs."We are excited about this because the mouse model in ourstudy has been used for a long time to study treatments forinflammatory bowel disease, and many pharmacologic agentsthat are effective in humans with IBD are also effective in thisanimal model," says senior author Gary D. Wu, MD, anassistant professor of medicine.Inflammatory bowel disease manifests itself in two ways -- oneis limited to the colon, which is called ulcerative colitis. Theother is Crohn's disease, which can involve the entiregastrointestinal tract. The total number of people in the UnitedStates that have either one of those diseases is approximatelyone million.The Penn study focused on ulcerative colitis, which affectsabout 500,000 Americans. "IBD is a chronic disease withwaxing and waning activity and is very debilitating in somepatients," notes Wu. The symptoms in humans includeabdominal pain, diarrhea, intestinal bleeding, nausea, andvomiting. Drugs to treat ulcerative colitis are effective in onlyabout 50 percent of patients. Some of the other drugs used totreat moderate to severe IBD, including steroids and otherimmune modulatory agents, can be toxic to the human system."Because of this, we've been searching for more effective,safer oral treatments for ulcerative colitis," says Wu. Using cellcultures, the researchers are also discovering how TZDs workon a molecular basis. By binding to PPAR-gamma, a nuclearhormone receptor, TZDs ultimately inhibit the action ofNF-kappa B, a master regulatory molecule in the inflammatoryresponse. PPAR-gamma is localized to the nucleus of cellsfound in several tissues of the body, including the cells liningthe inside of the colon. When an activating molecule, such as adrug like TZD, migrates through the cell membrane and into thenucleus, it binds to PPAR-gamma. This complex, hypothesizesWu and colleagues, then activates a gene that makes proteinswhich ultimately inhibit NF-kappa B and the inflammatoryresponse.Because of what is understood from studies in cell culture andnow in animal models about the action of TZDs, the PennInflammatory Bowel Disease Center has just started enrollingpatients in a clinical trial to see if the drugs will be an effectivetreatment for ulcerative colitis. They are using a newgeneration TZD drug called rosiglitazone (Avandia), whichwas released several weeks ago for the treatment of diabetes.