Acute Liver Failure Induces Glial Reactivity, Oxidative Stress and Impairs Brain Energy Metabolism in Rats.

Acute liver failure (ALF) implies a severe and rapid liver dysfunction that leads to impaired liver metabolism and hepatic encephalopathy (HE). Recent studies have suggested that several brain alterations such as astrocytic dysfunction and energy metabolism impairment may synergistically interact, playing a role in the development of HE. The purpose of the present study is to investigate early alterations in redox status, energy metabolism and astrocytic reactivity of rats submitted to ALF. Adult male Wistar rats were submitted either to subtotal hepatectomy (92% of liver mass) or sham operation to induce ALF. Twenty-four hours after the surgery, animals with ALF presented higher plasmatic levels of ammonia, lactate, ALT and AST and lower levels of glucose than the animals in the sham group. Animals with ALF presented several astrocytic morphological alterations indicating astrocytic reactivity. The ALF group also presented higher mitochondrial oxygen consumption, higher enzymatic activity and higher ATP levels in the brain (frontoparietal cortex). Moreover, ALF induced an increase in glutamate oxidation concomitant with a decrease in glucose and lactate oxidation. The increase in brain energy metabolism caused by astrocytic reactivity resulted in augmented levels of reactive oxygen species (ROS) and Poly [ADP-ribose] polymerase 1 (PARP1) and a decreased activity of the enzymes superoxide dismutase and glutathione peroxidase (GSH-Px). These findings suggest that in the early stages of ALF the brain presents a hypermetabolic state, oxidative stress and astrocytic reactivity, which could be in part sustained by an increase in mitochondrial oxidation of glutamate.

Distinct metabolic profile according to the shape of the oral glucose tolerance test curve is related to whole glucose excursion: a cross-sectional study.

BACKGROUND: The shapes of the plasma glucose concentration curve during the oral glucose tolerance test are related to different metabolic risk profiles and future risk of type 2 DM. We sought to further analyze the relationship between the specific shapes and hyperglycemic states, the metabolic syndrome and hormones involved in carbohydrate and lipid metabolism, and to isolate the effect of the shape by adjusting for the area under the glucose curve. METHODS: One hundred twenty one adult participants underwent a 2-h oral glucose tolerance test and were assigned to either the monophasic (n = 97) or the biphasic (n = 24) group based upon the rise and fall of their plasma glucose concentration. We evaluated anthropometric measures, blood pressure, lipid profile, high-sensitivity C-reactive protein, glycated hemoglobin, insulin sensitivity, beta-cell function, C-peptide, glucagon, adiponectin and pancreatic polypeptide. RESULTS: Subjects with monophasic curves had higher fasting and 2-h plasma glucose levels, while presenting lower insulin sensitivity, beta-cell function, HDL cholesterol, adiponectin and pancreatic polypeptide levels. Prediabetes and metabolic syndrome had a higher prevalence in this group. Glycated hemoglobin, total cholesterol, triglycerides, high-sensitivity C-reactive protein and glucagon were not significantly different between groups. After adjusting for the area under the glucose curve, only the differences in the 1-h and 2-h plasma glucose concentrations and HDL cholesterol levels between the monophasic and biphasic groups remained statistically significant. CONCLUSIONS: Rates and intensity of metabolic dysfunction are higher in subjects with monophasic curves, who have lower insulin sensitivity and beta-cell function and a higher prevalence of prediabetes and metabolic syndrome. These differences, however, seem to be dependent on the area under the glucose curve.