Oxidative stress mediates metabolic and endocrine dysfunctions induced by fructose.

SCHINELLA G; CASTRO MC; FRANCINI F; MASSA ML; GONZÁLEZ ARBELÁEZ LF; GAGLIARDINO JJ

México

Congreso; XXIII Congreso de la Asociación Latinoamericana para el Estudio del Hígado; 2014

The prevalence of Type 2 Diabetes Mellitus is increasing worldwide, normally associated to other risk factors: hypertension, obesity, unhealthy diets and sedentary lifestyle. Recent publications suggested that the increase in fructose consume registered in the last decades has contributed to the current obesity and diabetes epidemics. Administration of a fructose rich diet (FRD) to normal rats mimics this situation. Objective: to evaluate in a model of pre-diabetes the possible preventive effect of the antioxidant lipoic acid (LA) on the insulin-resistance (IR), liver steatosis, metabolic dysfunctions, oxidative stress (OS) and inflammation triggered by a FRD. Material & Methods: Wistar rats were fed during 21 days a commercial diet and tap water (control [C]) or fructose in the drinking water 10% (F) and C and F plus LA (35 mg/kg body weight/day, i.p. during the last 5 days of the treatment) (CL and FL). After that, animals were sacrificed and measured glycemia (GOD-PAP), triglyceridemia (TG) (colorimetric) and insulinemia (RIA). Glucose tolerance test was also performed. In the liver we measured a) OS markers (GSH and carbonyls in proteins) and enzymes of the antioxidant defense system (SOD1, SOD2 and catalase), b) liver steatosis (Oil-Red), c) gene expression of lipogenic enzymes and the related transcription factor (GPAT, FAS, CPT-1, SREBP-1c), d) glucokinase, fructokinase, G-6-Pase and G-6-PDH activities, e) expression of IL-1B, TNFalfa and COX2 and f) insulin signaling pathway mediators (IR, IRS1/2, PI3K). Results: Three weeks of a FRD induced: a) hypertriglyceridemia, hyperinsulinemia and impaired glucose tolerance, b) hepatic OS (increase in OS markers, reduction in the expression of antioxidant enzymes and enhanced p22phox and gp91phox levels ?NADPH oxidase-), c) liver steatosis related to increased FAS and GPAT expression as well as SREBP-1c and decreased in CPT-1 expression, d) enhanced fructokinase, G-6-Pase and G-6-PDH activities and glycogen content, e) increased glucokinase activity related to translocation to the cytosol and enhanced expression of its positive regulator in the same compartment, e) increased in liver inflammatory markers and f) alteration in the insulin signaling pathway. These disturbances were prevented by LA administration. Conclusion: OS could play a pivotal role in the development of the endocrine and metabolic alterations induced by a FRD. The protective effect on the liver glucose sensor (glucokinase) could be partially adscript to a re-localization of the enzyme in the nucleus and the cytosolic regulation by PFK-2. Interestingly LA seems to have also a corrective effect on cytosolic NADPH oxidase expression.