Tirozin izomerek szerepe eritropoetin- és inzulin-rezisztenciában

Abstract

Background: Hydroxyl radical converts Phe to para-, meta- and ortho-Tyr (p-Tyr, m-Tyr, o-Tyr), while Phe is converted enzymatically to p-Tyr in the kidney and could serve as substrate for gluconeogenesis. The pathological isoforms m- and o-Tyr are supposed to be involved in development of hormone resistances. Patients with end-stage renal failure (ESRF) treated with erythropoiesis-stimulating agents (ESAs) are often ESA-hyporesponsive, this is associated with free radical production. Production of p-Tyr is decreased in ESRF and it can be replaced by o-Tyr in proteins. Levels of pathological Tyr isoforms are elevated in septic patients. Renal glucose output contributes significantly to whole body glucose production during fasting. Glucose produced in kidney is derived from gluconeogenesis, and amino acids may be substrates for this process. Aims: In our first study, we aimed to examine the role of Tyr-isoforms in ESA-responsiveness. In our second study, we aimed to investigate the role of different Tyr-isoforms and Phe in carbohydrate metabolism of non-diabetic septic patients. Methods: Four groups of volunteers were involved in our first cross-sectional study: healthy volunteers (CONTR; n=16), patients on hemodialysis without ESA-treatment (nonESA-HD; n=8), hemodialyzed patients with ESA-treatment (ESA-HD; n=40) and patients on continuous peritoneal dialysis (CAPD; n=21). ESA-demand was expressed by ESA-dose, ESA-dose/body weight and erythropoietin resistance index1 (ERI1, weekly ESA-dose/body weight/hemoglobin). In our second study, correlations of Phe and three Tyr-isoforms with carbohydrate metabolism was examined in 25 non-diabetic septic patients. Daily insulin dose (DID) and insulin-glucose product (IGP) were calculated and their connection with Phe and Tyr parameters was assessed. Blood glucose variability was characterized using mean absolute glucose change (MAG). Serum and plasma levels of Phe and Tyr-isoforms were detected using a reverse-phase high performance liquid chromatography (rpHPLC)-method with a fluorescence detection. Results: We found significantly lower p-Tyr levels in all groups of dialyzed patients when compared to control subjects, while o-Tyr levels and o-Tyr/p-Tyr ratios were significantly higher in dialyzed patients. Among groups of dialyzed patients, the o-Tyr level and o-Tyr/p-Tyr ratio were significantly higher in ESA-HD than in the nonESA-HD and CAPD groups. There was a correlation between weekly ESA-dose/body weight, ERI1 and the o-Tyr/p-Tyr ratio (r=0.441, p=0.001; r=0.434, p=0.001, respectively). o-Tyr/p-Tyr ratio proved to be an independent predictor of ERI1 (β=0.330, p=0.016). In these multivariate regression models most of the known predictors of ESA-hyporesponsiveness were included. Upon investigation of non-diabetic septic patients, urinary m-Tyr/p-Tyr ratio was higher in patients with DID and IGP over median compared to those with DID and IGP below median (p=0.005 and p=0.01, respectively). Urinary level of m-Tyr and m-Tyr/p-Tyr ratio showed a positive correlation with DID (r=0.310; p=0.009 and r=0.271; p=0.023, respectively) and with IGP (r=0.343; p=0.004 and r=0.315; p=0.008, respectively). Serum Phe was negative predictor of both DID and IGP, while serum p-Tyr/Phe ratio was a stronger, positive predictor of these parameters. Urinary level of m-Tyr and ratios of urinary m-Tyr/p-Tyr, o-Tyr/p-Tyr and (m-Tyr+o-Tyr)/p-Tyr were positive predictors of both DID and IGP. The MAG value was found to be higher in patients who died at the intensive care unit compared with survivors. Discussion: Our findings may suggest that elevation of the ratio of o-Tyr/p-Tyr could be responsible for decreased ESA-responsiveness in dialyzed patients. Phe and isoforms of Tyr have a predictive role in carbohydrate metabolism of non-diabetic septic patients. Phe may serve as substrate for renal gluconeogenesis via enzymatically produced p-Tyr, while hydroxyl radical derived Phe products may interfere with insulin action, in loco in the kidney.