Pathogenic Mechanism of Autoimmune Diabetes Mellitus in Humans: Potential Role of Streptozotocin-Induced Selective Autoimmunity Against Human Islet -Cells

Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing -cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), a chemically reactive and cytotoxic compound produced by certain gram-positive bacteria, can be preferentially taken up into islet -cells and induce cytotoxicity and autoimmunity. It is hypothesized that humans might be occasionally exposed to STZ through opportunistic infections with the STZ-producing bacteria and/or through ingestion of certain food products that contain STZ. In addition, the potential presence of the STZ-producing bacteria in the gut microbiota of some individuals might be another source of long-term STZ exposure. Because of the high chemical reactivity of STZ and its breakdown products, these chemicals can covalently modify certain cellular macromolecules (e.g., DNA and proteins), and the covalently modified cellular components would serve as new antigens, potentially capable of inducing both humoral and cellular autoimmune responses in the islets of certain individuals. In addition to STZ exposure, the eventual development of autoimmunity against STZ-exposed islet -cells also depends critically on the genetic predisposition of the susceptible individuals plus the opportunistic presence of a conducive, strong environmental trigger, which often is presented as severe febrile viral infections subsequently inducing strong aberrant reactions of the body's immune system. The proposed pathogenic hypothesis is supported by a considerable body of direct and indirect evidence from laboratory animal studies and clinical observations. Certainly, more experimental and clinical studies are needed to carefully further examine each of the key components of the proposed pathogenic hypothesis.