NSAID-Induced Enteropathy Affects Regulation of Hepatic Glucose Production by Decreasing GLP-1 Secretion.

BACKGROUND/AIM: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. METHOD: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. RESULTS: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9-a GLP-1 receptor antagonist-worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. CONCLUSIONS: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

Ulcerative ileitis encountered at ileo-colonoscopy: likely role of nonsteroidal agents.

BACKGROUND & AIMS: Ileoscopy is increasingly practiced, but it is unclear what diagnostic and management decisions should ensue if ulcerations are encountered. METHODS: The lead author identified 40 patients with ulcerative ileitis during 1900 consecutive ileoscopies in a community practice. We analyzed the clinical, endoscopic, and histopathologic findings in these patients and related them to drug usage. RESULTS: Although most patients were asymptomatic, ileitis likely contributed to blood loss in 14 and to right lower quadrant pain in one. Endoscopy revealed multiple, discrete, fibrin-covered ulcerations in the prevalvular segment with patches of erythematous stippling, normal intervening mucosa, and occasional mucosal scars or webs. Histologic findings included focal superficial neutrophilic infiltrates, edema, mucosal hemorrhage, lymphatic dilatation, fibromuscular hyperplasia, prominence of the muscularis mucosae, and antral and Paneth cell metaplasia. Granulomas, fissure ulcers, and apoptosis were notably absent. No specific disease process developed in a median follow-up of 3.2 years. Thirty-three patients admitted recently taking nonsteroidal anti-inflammatory drugs (NSAIDs), notably: enteric-coated aspirin at 325 mg/day or less (19), selective cyclooxygenase-2 inhibitors (5), and nonacetylated salicylates (3). Three fourths of nonsteroidal users were taking agents with low or intermediate gastroduodenal toxicity. Lesions disappeared after drug withdrawal, and reappeared on resumption. CONCLUSIONS: Ileoscopy during colonoscopy may identify an ulcerative ileitis. This lesion likely contributes to gastrointestinal blood loss and other clinical manifestations, and likely is caused by NSAID use, including those usually associated with low toxicity or at low doses. Features of NSAID-ileitis overlap with Crohn's ileitis, but differentiation of the 2 entities is critical for appropriate management.