Abstract
Diabetes mellitus (DM) is associated with a dysfunctional intestinal barrier and an increased risk for systemic infection and inflammation in people, though the pathogenic mechanisms leading to this are poorly understood. Using a canine model of DM, we showed that the peroxisomal proliferator-activated receptor-α agonist fenofibrate modulates plasma lipid profiles and markers of intestinal barrier function. A 3-week course of fenofibrate reduced fasting interstitial glucose and inflammatory cytokine IL-8 and TNF-α concentrations, which correlated with reduced triglyceride levels. The lipidomic profile exhibited significantly lower levels of triacylglycerols, phosphatidylethanolamines, diacylglycerols, and ceramides following fenofibrate administration. On histopathological analysis, we observed an aberrant amount of intraepithelial CD3+ T lymphocytes (IEL) in the small intestine of dogs with spontaneous and induced-DM. Fenofibrate reduced IEL density in the duodenum of dogs with DM and enhanced markers of intestinal barrier function in vivo and in vitro. There were minimal changes in the intestinal microbial composition following fenofibrate administration, suggesting that repair of intestinal barriers can be achieved independently of the resident microbiota. Our findings indicate that lipid metabolism is critical to functionality of the intestinal epithelium, which can be rescued by PPARα activation in dogs with DM.
Highlights
Diabetes mellitus and prediabetes increase the risk for other metabolic complications, such as obesity, cardiac disease, hypertension, and hyperlipidemia, collectively referred to as Metabolic Syndrome
Reduction of fasting glucose levels and serum triglyceride concentrations is associated with decreased immune activation following fenofibrate treatment
Interstitial glucose (IG) concentrations were high in dogs with Diabetes mellitus (DM), reaching a nadir of approximately 146 mg/dL after insulin administration[29] (Fig. 1b)
Summary
Diabetes mellitus and prediabetes increase the risk for other metabolic complications, such as obesity, cardiac disease, hypertension, and hyperlipidemia, collectively referred to as Metabolic Syndrome. We previously reported that peroxisome proliferator-activated receptor-alpha (PPARα) signaling, which regulates mitochondrial fatty acid beta-oxidation, may be key to restoring integrity of the intestinal barrier during chronic intestinal inflammation[6]. In this proof-of-concept study, we investigate the effects of fenofibrate, a PPARα agonist, on lipid profiles, systemic and intestinal inflammation, and intestinal barrier function in a canine DM model. Fenofibrate is used to treat dyslipidemia, DM, and cardiovascular disease associated with metabolic syndrome[12] It is unknown, whether activation of PPARα in vivo by oral dosing of fenofibrate can alleviate intestinal inflammation or reverse barrier disruption in patients with DM. In ethical consideration of reducing the number of animals used in this study, no control group (consisting of dogs that did not receive fenofibrate) were used
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