title: Abnormal proinsulin congeners as autoantigens that initiate the pathogenesis of Type 1 diabetes.
abstract: Exposure of concentrated and purified monomeric insulin solutions to inorganic oxidants as iodine and chlorine lead to the appearance of a minor peak on gel chromatography that was disulfide cross-linked. It exhibited a 20-fold reduction in bioactivity, a markedly decreased immunoreactivity and a different electrophoretic pattern as compared to the starting material. The covalent dimer was formed by way of aggregation. These findings were reproduced by incubating monomeric insulin in normal blood spiked to hyperglycemic levels. In contrast, normoglycemic blood used as incubating medium failed to induce dimerization. Since the conformation of proinsulin is similar to that of insulin, involving the exposure of the anterior A7-B7 disulfide bridge, the authors hypothesize that proinsulin dimers rather than insulin dimers might be formed in Type 1 diabetes (TD1), leading to the autoimmune destruction of pancreatic B-cells. Proinsulin is present in a soluble aggregate state in the coated granule and may further accumulate allowing disulfide exchange due to abnormalities of the processing enzymes. This might be caused by inborn errors in genetically susceptible children or perhaps secondary to viral infection, whereas crystallization of insulin in mature granules is unlikely to be conducive to dimerization. Dimeric proinsulin would then migrate to pancreatic B-cell membranes to be taken up by surface immunoglobulins on B-lymphocytes that would in turn present it to cytotoxic T lymphocytes. The abnormal configuration of this congener would not be recognized as self by the immune system, triggering a selective destruction of pancreatic B-cells in the early pre-clinical development of TD1, resulting eventually in clinical disease. Since proinsulin is continuously converted to insulin in the coated granules of Type 2 diabetics, dimerization is unlikely in this condition. As pointed out by earlier investigators, TD1 is not a homogeneous disease, since several of its clinical features are different in children up to 6 years of age as compared to older patients. It is thus conceivable that there are subsets of TD1 triggered by dissimilar autoantigens and we propose in the present hypothesis that a conformationally altered congener of native proinsulin might play such a role.
authors.affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Calgary, Foothills Medical Centre, 1403 - 29th Street N.W., Calgary, Alta., Canada T2N 2T9. csorba@ucalgary.ca
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Csorba
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Lyon
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000737:chemistry* / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D019281:Dimerization; D006801:Humans; D011384:Proinsulin / Q000737:chemistry* / Q000276:immunology*; D013329:Structure-Activity Relationship
chemical_list: D001324:Autoantigens; D011384:Proinsulin