Fructose metabolism is associated with anesthesia/surgery induced lactate production

Abstract

Background: Elderly individuals display excessive lactate levels that may contribute to development of cognitive impairment following surgery, including delayed neurocognitive recovery (dNCR). Since the origin of this increased lactate is unknown, here we assessed associations between metabolic pathways and postoperative dNCR. Methods: This study included 43 patients (≥65 years old) who had surgery under general anaesthesia. We also used a mouse model in which 20-month-old mice were exposed under sevoflurane to induce postoperative dNCR. Metabolomics were used to measure metabolites in the serum of patients and brains of mice following anaesthesia/surgery. Isotope labelling and metabolic flux were used to analyse flow and distribution of specific metabolites in metabolic pathways. Results: Among 43 patients, 17 developed dNCR. Metabolomics showed significantly decreased postoperative serum fructose 1-phosphate levels in dNCR compared to non-dNCR patients. Similar results were found in the mouse model. Isotope labelling and metabolic flux experiments in mice showed fructose but not glucose entered glycolysis, increasing lactate levels after anaesthesia/surgery. Administration of intraperitoneal fructose inhibitors to mice effectively inhibited the increased lactate levels and cognitive dysfunction following anaesthesia/surgery. We also found anaesthesia/surgery increased IL-6 levels in mice, and that IL-6 may function upstream in fructose activation. Conclusions: These results suggest that anaesthesia/surgery activates fructose metabolism, producing excessive lactate and ultimately contributing to postoperative cognitive impairment. Fructose metabolism is thus a potential therapeutic target for dNCR.