High glucose concentration in T1D patients modulates apoptotic protein expression: Down regulation of BAX and FAS and up regulation of XIAP Elizabeth Valencia a , Ethel Codner b , Francisca Salas-Pérez a , Carolina Pizarro a , Elena Carrasco P a , Miguel Arredondo c , Francisco Pérez-Bravo a,⇑ a Laboratorio de Genómica Nutricional, Departamento de Nutrición, Facultad de Medicina, Universidad de Chile, Chile b Instituto de Investigaciones Materno Infantil (IDIMI), Facultad de Medicina, Universidad de Chile, Chile c Laboratorio de Micronutrientes, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Chile article info Article history: Received 28 February 2012 Accepted 23 April 2012 Available online 28 May 2012 abstract Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by a progressive destruction of pancreatic b cells. It has been reported that patients with autoimmune diseases exhibit decreased expres- sion of caspase 3 and other pro-apoptotic markers in peripheral blood mononuclear cells (PBMC). Aim: To estimate the expression of apoptosis markers in PBMC from T1D patients cultured with high glucose concentration. Results: At 11 mM of glucose, the pro-apoptotic gene fas showed a 7-fold decreased expression in the T1D group compared to controls, while bax showed a 50-fold decreased expression (medians 0.14 and 0.02, respectively, considering patients as 1). At 44 mM of glucose, there is a decreased expression of the same genes, but less abrupt (medians 0.75 and 0.47). Only the anti-apoptotic gene xiap showed a 2-fold increased expression at 11 mM of glucose (median 2.3). Regarding the clinical history, no relationships were observed with age of diagnosis, ketoacidosis, glucose at debut or GAD-65 and IA-2 titles. Conclusion: We can conclude that the apoptotic mechanisms in PBMC of T1D patients under high glucose conditions are altered, and this is proved by the decreased expression of the pro-apoptotic genes fas and bax and by the increased expression of the anti-apoptotic gene xiap. Ó 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Introduction The incidence of type 1 diabetes (T1D) in Santiago, Chile has in- creased during the last years. These data are concordant with the observation that the incidence of T1D is increasing in Latin Amer- ica and worldwide [1]. T1D is an autoimmune disease whereby antigen-specific T-cells selectively destroy insulin-producing pancreatic ß cells. The acti- vated T cells first invade the islets, leading to ‘‘insulitis’’ phenom- ena. This is followed by destruction of the islets, mediated by a complex interaction between the activated lymphocytes, cytokines and macrophages [2]. Apoptosis is a fundamental process involved in the destruction of ß cells. More recently, ß-cell apoptosis has also been shown to facilitate cross-presentation of islet antigens, an important initial step for the priming or activation of ß-cell-specific T cells required for disease onset. Dysfunction of apoptosis through the fas–fas ligand pathway is related to the onset of autoimmune diseases. Several studies have proposed that the blocking of apoptosis is in- volved in the pathogenesis of these autoimmune diseases [3]. There are two main apoptotic pathways: the extrinsic or cell death receptor pathway, involving the tumor necrosis factor super family of receptors, and the intrinsic or mitochondrial pathway. Mitochondrial proteins BCL-2, BLC-XL, BAX, BAK and cytosolic pro- tein caspase 9 are involved in the intrinsic pathway, whereas FAS, TNFR1 and caspase 8 are extrinsic pathway proteins. Both path- ways converge in the activation of caspases 3, 6 and 7 which finally direct apoptosis through cleavage of actin and other important proteins. Besides these mechanisms, there are inhibitory proteins such as FLIP and XIAP which can act in these two pathways and in- hibit apoptosis. This inhibition is independent of the pathway through which apoptosis was induced [4]. Different studies have reported the existence of impaired apoptosis in peripheral T cells in subjects affected by autoimmune diseases [5,6]. In multiple scle- rosis patients, a resistance to fas-induced apoptosis can occur in peripheral T cells, partially as a consequence of an increased activ- ity of the anti-apoptotic proteins XIAP and FLIP [7,8]. In accordance to this background, the objective of this research is to measure the expression of six apoptosis markers, three of 0198-8859/$36.00 - see front matter Ó 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.humimm.2012.04.020 ⇑ Corresponding author. Address: Laboratorio de Genómica Nutricional, Departa- mento de Nutrición, Facultad de Medicina, Universidad de Chile, Independencia 1027 (3° piso), Santiago, Chile. E-mail address: fperez@med.uchile.cl (F. Pérez-Bravo). Human Immunology 73 (2012) 801–804 Contents lists available at SciVerse ScienceDirect www.ashi-hla.org journal homepage: www.elsevier.com/locate/humimm