title: Type 1 diabetes: can exercise impair the autoimmune event? The L-arginine/glutamine coupling hypothesis.
abstract: Prevention of type 1 diabetes mellitus (T1DM) requires early intervention in the autoimmune process directed against beta-cells of the pancreatic islets of Langerhans, which is believed to result from a disorder of immunoregulation. According to this concept, a T-helper lymphocyte of type 1 (Th1) subset of T-lymphocytes and their cytokine products, the type 1 cytokines [e.g. interleukin 2 (IL-2), interferon gamma (IFN-gamma) and tumour necrosis factor beta (TNF-beta)] prevail over immunoregulatory (anti-inflammatory) Th2 subset and its cytokine products, i.e. type 2 cytokines (e.g. IL-4, IL-6 and IL-10). This allows type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Activation of sympathetic-corticotropin-releasing hormone (CRH) axis by psychological stress induces specifically Th1 cell overactivity that determines enhanced glutamine utilization and consequent poor L-arginine supply for nitric oxide (NO)-assisted insulin secretion. This determines the shift of intraislet glutamate metabolism from the synthesis of glutathione (GSH) to that of L-arginine, leading to a redox imbalance that activates nuclear factor kappaB exacerbating inflammation and NO-mediated cytotoxicity. Physical exercise is capable of inducing changes in the pattern of cytokine production and release towards type 2 class and to normalize the glutamine supply to the circulation, which reduces the need for glutamate, whose metabolic fate may be restored in the direction of GSH synthesis and antioxidant defence. Also, the 70-kDa heat shock protein (hsp70), which is immunoregulatory, may modulate exercise-induced anti-inflammation. In this work, we envisage how exercise can intervene in the mechanisms involved in the autoimmune process against beta-cells and how novel therapeutic approaches may be inferred from these observations.
authors.affiliation: Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, School of Physical Education, Porto Alegre, RS, Brazil.
authors.forename: Maurício da Silva
authors.initials: Mda S
authors.lastname: Krause
authors.forename: Paulo Ivo Homem
authors.initials: PI
authors.lastname: de Bittencourt
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism*; D015444:Exercise; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal
chemical_list: D005973:Glutamine; D001120:Arginine