On the pathogenesis of IDDM

Abstract

A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radicals (O2- and nitric oxide) produced by the beta cells themselves. This entire process is under polygenetic control.

IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis

“…nitric oxide and oxygen-derived radicals) possibly play a role in the destruction of beta cells [3]. Catalase, which protects cells from the toxic effects by hydrolysing hydrogen peroxide, was up-regulated in response to IL-1β exposure, suggesting the presence of hydrogen peroxide in BB-DP rat islets.…”

“…Type I (insulin-dependent) diabetes mellitus is a multifactorial polygenic autoimmune disease characterized by mononuclear cell infiltration in the islets of Langerhans (insulitis) and selective destruction of the insulin producing beta cells [1,2,3]. It is generally accepted that the destruction of the beta cells results from interactions between various environmental factors and immune mechanisms in genetically susceptible people [3].…”

“…It is generally accepted that the destruction of the beta cells results from interactions between various environmental factors and immune mechanisms in genetically susceptible people [3]. The very first events initiating the destructive process have not yet been described in detail.…”

“…During the destructive process IL-1β, TNF-α and IFN-γ are released in the islets resulting in the production of free radicals [e.g. nitric oxide (NO -), super oxide (O 2 -) and hydroxyl (OH -)] in the beta cells [3]. Free radicals are normally scavenged by protective proteins [e.g.…”

“…Many IL-1β effects are mediated by inducing the inducible nitric oxide syntase (iNOS) and its product, nitric oxide [7]; however, NO-independent mechanisms also occur [8,9,10]. We hypothesize that the beta cell, when exposed to IL-1β initiates a protective response in competition with a series of deleterious events, and that in beta cells the deleterious events prevail [3]. In support of this, over-expression in islet cells of scavengers of free radicals, such as catalase and glutathione peroxidase, reduces the deleterious effects of cytokines on beta cells [11].…”