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.

Background/Aim: The impact of myocardial stressors such as high-fat diet (HFD) and pressure overload has been extensively studied. Toll-like receptor 4 (TLR4) deficiency has been suggested to have a protective role in response to these stressors, although some conflicting data exist. Furthermore, there is limited information about the role of TLR4 on cardiac remodeling in response to long-term exposure to stressors. This study aims to investigate the effects of TLR4 deficiency on cardiac histology and physiology in response to chronic stressors. Methods: TLR4-deficient (TLR4^−/−) and wild-type (WT) mice were subjected to either HFD or a normal diet (ND) for 28 weeks. Another group underwent abdominal aortic constriction (AAC) or a sham procedure and was monitored for 12 weeks. Inflammatory markers, histology, and echocardiography were used to assess the effects of these interventions. Results: TLR4^−/− mice exhibited reduced cardiac hypertrophy and fibrosis after long-term HFD exposure compared to ND without affecting cardiac function. On the other hand, TLR4 deficiency worsened cardiac function in response to AAC, leading to decreased ejection fraction (EF%) and increased end-systolic volume (ESV). Conclusions: TLR4 deficiency provided protection against HFD-induced myocardial inflammation but impaired hemodynamic cardiac function under pressure overload conditions. These findings highlight the crucial role of TLR4 and its downstream signaling pathway in maintaining cardiac output during physiologic cardiac hypertrophy in response to pressure overload.