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Serotonin Levels in Plasma and Platelets of Adolescents with Type 1 Diabetes

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Serotonin Levels in Plasma and Platelets of Adolescents with Type 1 Diabetes Global Advanced Research Journal of Medicine and Medical Science (ISSN: 2315-5159) Vol. 3(9) pp. 267-274, September 2014 Available online http://garj.org/garjmms/index.htm Copyright © 2014 Global Advanced Research Journals Full Length Research Paper Serotonin levels in plasma and platelets of adolescents with type 1 diabetes Gabriel Manjarrez-Gutiérrez 1,2*, Rocío Herrera-Márquez 3, Teresa Neri-Gómez 1, Jorge Hernández-Rodríguez 4 1Laboratory of Molecular Pathology, Cardiology Hospital, National Medical Center (CMN-SXXI), Mexican Institute of Social Security (IMSS), Mexico City, Mexico 2Medical Research Unit in Neurological Diseases, Specialties Hospital, CMN-SXXI, IMSS, México, DF, México 3Pediatric Hospital, CMN-SXXI, IMSS, Mexico City, Mexico 4Laboratory of Neurontogeny, Department of Physiology, Biophysics and Neurosciences, Center of Research and Advanced Studies (CINVESTAV) IPN, Mexico City, Mexico. Accepted 18 September, 2014 The aim of this study was to determine, in adolescents with type 1 diabetes, 5-hydroxytryptamine (5-HT, serotonin) levels in plasma and platelets, 5-HT transporter (SERT), platelet 5-HT 2A receptor and transglutaminase 2. We performed a cross-sectional studying two groups: 1) adolescents with type 1 diabetes and 2) controls. Three milliliters of blood was obtained from all patients to determine 5-HT levels in plasma and platelets. Furthermore, platelets were obtained to evaluate SERT expression, 5- HT 2A receptor and transglutaminase 2 using Western blot. Dot blot was used for 5-HT. Glucose, glycated hemoglobin, albumin, triglycerides, cholesterol, hemoglobin, mean platelet volume and platelet count were also measured. Results were analyzed using Student t and Mann-Whitney U tests; P < 0.05 was accepted as statistically significant. Adolescents with type 1 diabetes had an elevation of plasma glucose and glycated hemoglobin (P < 0.001) as well as an increase the 5-HT levels in plasma and platelets along with a decreased expression of SERT, 5-HT 2A and increased transglutaminase 2 in platelets compared to controls (P < 0.05). Increased the 5-HT levels in plasma and platelets, together with the decreased expression of SERT and 5-HT 2A receptors and increase in transglutaminase 2 platelets, may have an important role in the prothrombotic state frequently presented by patients with diabetes. Keywords: Serotonin, type 1 diabetes mellitus, platelets, SERT, 5-HT 2A receptor, transglutaminase 2 INTRODUCTION 5-Hydroxytryptamine (5-HT, serotonin) in the body roles as a trophic factor, neuromodulator and regulates multiple biological functions. In the brain, its neurotransmitter have been widely studied (Lauder, 1993; Jacobs and Azmitia,1992; Mercado and Hernandez,1992). At the peripheral level, 5-HT is also synthesized from L-tryptophan (L-Trp) through two *Corresponding Author E-mail: [email protected], biochemical reactions: the first is catalyzed by L- [email protected], Phone: (+52) (55) 56276900, tryptophan-5-monooxygenase (Tph) (Walther and Bader, Ext. 22156. Fax: (+52) (55) 55780240; 2003) to produce 5-hydroxytryptophan (5-HTP). A second 268 Glo. Adv. Res. J. Med. Med. Sci. reaction is catalyzed by a decarboxylase to synthesize 5- as the role of 5-HT in the clotting mechanisms. Therefore, HT(Jacobs and Azmitia, 1992; Boadle-Biber, 1993; the objective of this study was to determine, in Hernandez and Illnerova, 1970). 5-HT at the peripheral adolescents with type 1 diabetes, the concentration of 5- level acts as a hormone, promotes smooth muscle HT levels in plasma and platelets as well as the contraction (Majno and Palade, 1961), modifies the expression of SERT and 5-HT 2A and their potential permeability of blood vessels (Tamir, 1982), regulates the changes in the pathophysiological mechanisms processes of secretion and osmosis (Mössner and regulating the concentration of5-HT levels in plasma Lesch,1998), acts in the inflammatory processes (YuB et al., 2008; Alderman et al., 1996), and actively intervenes in the mechanisms of platelet aggregation and blood MATERIALS AND METHODS coagulation (Lake et al., 2000; McNicol and Israels, 1999). With regard to its participation in the process of The study was approved by the research and ethics platelet aggregation, currently little significance has been committees of the National Commission for Scientific attributed to it because 5-HT has been considered a mild Research in Health of the Instituto Mexicano del Seguro platelet agonist compared to adenosine diphosphate Social (IMSS). All parents of patients provided written (ADP). ADP and 5-HT are highly concentrated in the informed consent after a detailed explanation regarding dense granules of platelets together with adenosine the procedures to which their children would be triphosphate (ATP) and Ca 2+ (McNicol and Israels, 1999). subjected. A cross-sectional study was planned in 80 5-HT stimulates platelet aggregation and requires the adolescents selected from the Endocrinology Service of concomitant activation of at least one Gi and one Gq the Pediatric Hospital, Centro Medico Nacional Siglo XXI, protein coupled to the 5-HT 2A receptor (Maayani et al., IMSS. Two groups were formed. The first group included 2001; Killam and Cohen,1991; Hoyer et al., 2002) which 40 adolescents of both genders (22 males and 18 through its stimulation the phosphatidyl inositol pathway females) with type 1 diabetes and with a clinical course of is activated, resulting in an increase of cytoplasmic Ca 2+ 4.93 ± 2.9 (SD) years at the time of the study. Study (Offermanns et al., 1997; Schins et al., 2003). Moreover, participants were aged 13.50 ± 0.48 (SD) years and had a high expression of serotonin transporter (SERT) has a body mass index 20.2 ± 1.8 (SD) according to the been demonstrated in platelets (Lesch et al., 1993; national criteria of the Diabetes Group (American Mercado and Kilic, 2010). It has also been observed that Diabetes Association, 2012). The second group was its inhibitors such as sertraline decrease the aggregation comprised of 40 normal adolescents (21 males and 19 and secretion of α-granules in the platelets (Serebruany females, aged 13.31 ± 0.43 (SD) years and with body et al., 2001; Atar et al., 2007). Therefore, stimulation of mass index 20.8 ± 3.5 (SD). This group served as the platelets by 5-HT activates the phosphatidyl inositol control group. There was no observed concurrent pathway, producing an increase in intracellular Ca 2+ . This pathology in either group. Exclusion criteria were the signaling path is mediated by the G αq protein coupled to recent ingestion (<15 days) of medications with the 5-HT 2A receptor (Offermanns et al., 1997). The serotonergic activity (fluoxetine, sertraline, paroxetine, increase of Ca 2+ in platelets also activates the fluvoxamine, citalopram, fenfluramine, buspirone, lithium, transaminases that utilize 5-HT as a substrate for small sumatriptan, or others) or anticholinergics, GTP ases such as α-RhoA and α-granules associated antihistamines, and H1 blockers as well as diabetic with Rab4, there by blocking the activity of GTP (Walther patients with a history of severe hypoglycemia (loss of et al., 2003; Dale et al., 2002; Szasz and Dale, 2002; consciousness or convulsions). Shirakawa et al., 2000). When RhoA and Rab4 bound to All adolescents were fed a normal diet of 55 GTP interact with effector molecules, rearrangement of kcal/kg/day (15% protein, 55% carbohydrates, 30% fats). the cytoskeleton and exocytosis of α-granules to the Patients were under treatment with a combination of fast- bloodstream takes place (e.g., von Willebrand Factor) or acting and intermediate insulin at a rate of 1.0 to 1.5 are exposed to the plasma membrane (e.g., glycoprotein U/kg/day. Three milliliters of blood was collected by IIb/IIIa and P-selectin), thus supporting irreversible venipuncture in borosilicate tubes containing 450 µl platelet aggregation (Mercado and Kilic, 2010; Walther et anticoagulant citrate dextrose (ACD) solution (3.6 mg al., 2003; Dale et al., 2002; Szasz and Dale, 2002; sodium citrate, citric acid 9.9 mg, 11 mg dextrose) Shirakawa et al., 2000; Williams, 2012). between 07:00 and 08:00h and 12h after the last meal. In summary, these data emphasize that the Blood samples were immediately centrifuged at 500 x g concentration of 5-HT levels in plasma depends on the for 3 min in a refrigerated centrifuge (AvantiJ-31, expression of SERT and 5-HT 2A receptor located in the Beckman Instruments, Fullerton, CA) to obtain platelet- platelet membrane. However, at present, neither the rich plasma (PRP). It was then centrifuged for 15 min at contributions of these biological phenomena nor the order 6000 rpm to obtain platelet-poor plasma (PPP) and of appearance in the diabetic clinical state are known. platelet concentrates (PC), where the 5-HT levels in Give in the clinical relevance of the diabetic state, all plasma and platelets were determined by high- mechanisms summarized here are basic and important performance liquid chromatography (HPLC) with Manjarrez-Gutiérrez et al. 269 fluorimetric detection as reported by Peat and Gibb, 12% SDS-polyacrylamide gel. Electrophoretic run was 1983. In the platelet membranes, the SERT expression, carried out at 100 V for 2h. Electrotransference of the 5-HT 2A receptor and transglutaminase 2 by Western blot corresponding proteins was performed on nitrocellulose and Dot blot for 5-HT in platelets were evaluated. In membranes, and the run was carried out at 10 V, 1.30 addition, in the two groups of adolescents, blood glucose mA
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