Background There are at least two phases of β-cell death during the development of autoimmune diabetes: an initiation event that results in the release of β-cell-specific antigens, and a second, antigen-driven event in which β-cell death is mediated by the actions of T lymphocytes. In this report, the mechanisms by which the macrophage-derived cytokine interleukin (IL)-1 induces β-cell death are examined. IL-1, known to inhibit glucose-induced insulin secretion by stimulating inducible nitric oxide synthase expression and increased production of nitric oxide by β-cells, also induces β-cell death. Methods and Findings To ascertain the mechanisms of cell death, the effects of IL-1 and known activators of apoptosis on β-cell viability were examined. While IL-1 stimulates β-cell DNA damage, this cytokine fails to activate caspase-3 or to induce phosphatidylserine (PS) externalization; however, apoptosis inducers activate caspase-3 and the externalization of PS on β-cells. In contrast, IL-1 stimulates the release of the immunological adjuvant high mobility group box 1 protein (HMGB1; a biochemical maker of necrosis) in a nitric oxide-dependent manner, while apoptosis inducers fail to stimulate HMGB1 release. The release of HMGB1 by β-cells treated with IL-1 is not sensitive to caspase-3 inhibition, while inhibition of this caspase attenuates β-cell death in response to known inducers of apoptosis. Patient Summary Background Type 1 diabetes (also called autoimmune diabetes or juvenile diabetes) is an autoimmune disease. For unknown reasons, at some point in childhood or adolescence, the body's own immune system starts attacking and destroying the insulin-producing islet cells in the pancreas. Once the majority of islet cells are destroyed, patients can no longer produce insulin to regulate their blood sugar and must depend on strict diets and insulin injections. Scientists are trying to understand the early events during the development of the disease. There are two fundamentally different kinds of cell death in cells of higher animals and humans, called apoptosis and necrosis. Apoptosis (also called programmed cell death) is an organized, clean way in which cells die without spilling their contents and without causing an inflammatory immune response. They are simply gobbled up by other cells that serve as the body's garbage collectors. Necrosis, on the other hand, is a more messy process and one that does activate the immune system and cause local inflammation. Why Was This Study Done? The scientists who did this study are interested in the early stages of islet cell death. Specifically, they wanted to know whether islet cells during the early events of autoimmune diabetes die via apoptosis or necrosis. Earlier experiments to address this question had yielded no clear-cut results. What Did the Researchers Do and Find? All the experiments for this study were done in cultured cells in the laboratory. For the most part, the researchers used rodent islet cells, and then they confirmed the crucial finding in human islet cells. They grew the cells under conditions that resembled, to the best of their knowledge, the early stages of diabetes, which caused some of the cells to die. They then did a variety of tests to see whether that cell death was through apoptosis or necrosis, and the results showed that the latter was the case. They also identified some of the key factors involved in promoting and executing the necrosis process. What Does This Mean? One must always be careful to extrapolate from laboratory results like these. With this caveat, the results suggest that early in the development of diabetes cells die by necrosis, and they point to some of the key factors involved. These are important results that will inform future studies toward the goal of understanding autoimmune diabetes well enough to prevent or stop its development. Where Can I Find More Information Online? The following Web sites provide information on autoimmune diabetes. MedlinePlus pages on type 1 diabetes: http://www.nlm.nih.gov/medlineplus/ency/article/000305.htm Web site of the Juvenile Diabetes Research Foundation: http://www.jdrf.org/index.cfm?page_id=101982 Pages on type 1 diabetes from the Canadian Diabetes Association: http://www.diabetes.ca/Section_About/type1.asp Type 1 diabetes pages from the UK National Institute for Health and Clinical Excellence: http://www.nice.org.uk/page.aspx?o=213575 UK National Diabetes Information Clearinghouse: http://diabetes.niddk.nih.gov/index.htm American Diabetes Association Web site: http://www.diabetes.org Conclusions These findings indicate that IL-1 induces β-cell necrosis and support the hypothesis that macrophage-derived cytokines may participate in the initial stages of diabetes development by inducing β-cell death by a mechanism that promotes antigen release (necrosis) and islet inflammation (HMGB1 release).