RESUMEN
Diabetes mellitus (DM) is a leading cause of preventable cardiovascular disease, but the metabolic changes from prediabetes to diabetes have not been fully clarified. This study implemented a metabolomics profiling platform to investigate the variations of metabolites and to elucidate their global profiling from metabolic syndrome to DM. METHODS: Male Sprague-Dawley rats (n = 44) were divided into four groups. Three groups were separately fed with a normal diet, a high-fructose diet (HF), or a high-fat (HL) diet while one group was treated with streptozotocin. The HF and HL diet were meant to induce insulin resistance, obesity, and dyslipidemia, which known to induce DM. RESULTS: The most significant metabolic variations in the DM group's urine samples were the reduced release of citric acid cycle intermediates, the increase in acylcarnitines, and the decrease in urea excretion, all of which indicated energy metabolism abnormalities and mitochondrial dysfunction. Overall, the metabolic analysis revealed tryptophan metabolic pathway variations in the prediabetic phase, even though the mitochondrial function remains unaffected. CONCLUSION: This study show that widespread methylations and impaired tryptophan metabolism occur in metabolic syndrome and are then followed by a decline in citric acid cycle intermediates, indicating mitochondrial dysfunction in diabetes.
RESUMEN
Steatosis can sensitise the liver to various challenges and favour the development of non-alcoholic fatty liver disease (NAFLD). In this context, fructose feeding promotes endotoxin translocation from the gut, contributing to disease progression via an inflammatory process. Citrulline is protective against fructose-induced NAFLD; we hypothesised that this property might be related to its anti-inflammatory and antioxidative action against endotoxin-induced hepatic injuries. This hypothesis was evaluated in a model of perfused liver isolated from NAFLD rats. Male Sprague-Dawley rats (n 30) were fed either a standard rodent chow or a 60 % fructose diet alone, or supplemented with citrulline (1 g/kg per d) for 4 weeks. After an evaluation of their metabolic status, fasted rats received an intraperitoneal injection of lipopolysaccharide (LPS) (2·5 mg/kg). After 1 h, the livers were isolated and perfused for 1 h to study liver function and metabolism, inflammation and oxidative status. In vivo, citrulline significantly decreased dyslipidaemia induced by a high-fructose diet and insulin resistance. In the isolated perfused rat livers, endotoxaemia resulted in higher cytolysis (alanine aminotransferase release) and higher inflammation (Toll-like receptor 4) in livers of fructose-fed rats, and it was prevented by citrulline supplementation. Oxidative stress and antioxidative defences were similar in all three groups. Amino acid exchanges and metabolism (ammonia and urea release) were only slightly different between the three groups. In this context of mild steatosis, our results suggest that fructose-induced NAFLD leads to an increased hepatic sensitivity to LPS-induced inflammation. Citrulline-induced restriction of the inflammatory process may thus contribute to the prevention of NAFLD.