SAT-359 Involvement of Inflammation and Oxidative Stress in the Adrenocortical Dysfunction Displayed by Insulin Resitant Rats: Effect of Hemin Treatment

An increased consumption of sweetened beverages has been linked to changes in the prevalence of obesity and insulin resistance (IR) worldwide. In rats with IR, induced by administration of a sucrose rich diet, we have previously demonstrated a dysregulation of adrenocortical steroid production. As oxidative stress generation and a chronic inflammatory state have been singled out as hallmarks of this disease, in this study we sought to analyze the effects of HO-1 (an antioxidant enzyme) induction on functional parameters in the adrenal cortex. Rats were randomly distributed into Control (C) and SRD- treated groups. After 12 weeks of treatment, animals from both groups were treated with hemin (15 mg/kg i.p every 48 h; H and SRDH groups). An insulin tolerance test (ITT) was performed in week 12 and the rate constant KITT was calculated as 0,693*t1/2. All animals were sacrificed 2 weeks after and blood and adrenal glands were excised. Statistical significance of data was analyzed by ANOVA followed by Tukey’s test. Results showed that fasting glucose levels were increased in SRD (p<0.01 vs. C) and SRDH groups (p<0.001 vs. C) and serum triglycerides levels were higher in SRD (p<0.01 vs. C.) and SRDH (p<0.05 vs. C) animals, but non-esterified fatty acid levels were increased only in the SRD group (p<0.05). Induction of HO-1 was demonstrated in the adrenal cortex of both hemin-treated groups (p<0.01 vs. C). Hemin treatment did not modified insulin response. Analysis of adrenocortical makers of oxidative stress in SRD-treated rats indicates an increase in lipoperoxides (p<0.001) while glutathione (p<0.05) and catalase levels were significantly reduced (p<0.01). These effects were mitigated by hemin treatment. Immunohistochemical studies indicated an increase in the number of Iba1+ (p<0.01) (monocyte derived) cells and higher levels of the inflammasome components ASC and caspase 1 in the SRD-group (p<0.001). Interleukin 1β and iNOS protein levels were also elevated (p<0.05). An increased number of apoptotic cells was also detected in the adrenal cortex of SRD-treated rats (TUNEL+) (p<0.05). These effects were not observed in the DRSH group (p<0.01 vs. DRS). Animals in the SRD group exhibited a lower response in the ACTH stimulation test (p<0.05 vs. C). This effect was not observed in the SRDH group (p<0,001 vs DRS). In summary, induction of HO-1 in the adrenal cortex of SRD-treated rats prevented increases in pro-inflammatory mediators, oxidative stress parameters and in the apoptotic index and restores the functional capacity of the adrenal gland upon ACTH stimulation.