April - June 2009, Volume 5, Issue 2

Ionescu-Tirgoviste C

Proinsulin as the possible key in the pathogenesis of type 1 diabetes

Acta Endo (Buc) 2009, 5 (2): 233-249
doi: 10.4183/aeb.2009.233

Based on epidemiological, clinic, biochemical and hormonal data (both personal and\r\ninternational), our personal view is that natural history of autoimmune type 1 diabetes could\r\ninclude the following stages: 1) The presence of a complex genetic predisposition towards ?\r\ncell autoimmunity (possibly “latent” until death); 2) The “initiation” of autoimmunity in\r\nsubjects carrying a defect in the post-translational processing of pre-proinsulin/ proinsulin/\r\ninsulin, manifested precociously as increased proinsulin-to-insulin ratio; 3) Stimulation by the\r\nincreased proinsulin of the plasmacytoid dendritic cell clones capable to capture the natural\r\nantigens (proinsulin/insulin, Glutamic Acid Decarboxylase, etc.) from the pancreatic beta\r\ncells; 4) Activation of the process generating reactive T cell clones (Teffs) in the detriment of\r\nprotective immuno-regulatory T cell clones (Tregs), triggering the anti-beta cell attack,\r\nexpressed as autoimmune insulitis and/or the presence of circulating anti beta cell antibodies;\r\n5) The onset of the beta cell apoptosis process mediated by pro-inflammatory cytokines (IFN\r\n?, TNF ?, IL6) or by the direct contact between Teffs and the beta cells; 6) Identification of\r\nthe first secretory beta cell defects (the loss of the first phase insulin response followed by the\r\nprogressive decrease of the area under the insulin curve and the progressive increase of the\r\narea under the blood glucose curve) while fasting glycemia is still normal; 7) The progressive\r\nloss of the beta cell mass. All these processes take place during the pre-hyperglycemic stage\r\nof diabetes, with a higher or lower speed depending on the genetic background. The overt\r\nclinical stage of diabetes, marked by the presence of hyperglycemia, occurs rather late, when\r\nmore than 90% of the beta cell function/mass is irreversibly lost.

Keywords: T1DM, immunogenetics, antigens, proinsulin, T lymphocyte

Correspondence: Constantin Ionescu-T?rgoviste, MD, PhD, “N.C. Paulescu” National Institute\r\nof Diabetes, Nutrition and Metabolic Diseases, 5-7 Ion Movila Street, 020475 Bucharest, Romania,\r\ntel. 0040 21 210 64 60, fax. 0040 21 210 22 95, e-mail: cit@paulescu.ro