Current immunological view of T1DM and T2DM. (a) Islet inflammation in T1DM. A triggering insult recruits antigen-presenting cells (dendritic cells, macrophages, and B cells). Dendritic cells (DC) pick up self-antigens and immune complexes by pinocytosis and carry them to the pancreatic draining lymph nodes where they present them to autoreactive T cells and activate them. Such T cells migrate back to the islets where they destroy β-cells either by perforin, granzymes, or FasL-dependent interactions (CD8+), or by proinflammatory cytokine release (CD4+). Macrophages and B cells can also act as antigen-presenting cells. The cross-talk between B and T cells promotes the development of plasma cells, the release of autoantibodies, and the formation of immune complexes, which all together create a vicious cycle of inflammation and death. (b) TRAIL effects on islet inflammation. Experimental studies have shown that TRAIL inhibits T cell proliferation/expansion, induces T cell death, promotes Treg expansion, and protects β-cells. (c) Overview on obesity-induced insulin resistance. Obesity increases free fatty acids (FFA) that bind to toll-like receptor 4 (TLR-4) and activate adipose tissue macrophages. At the same time, the expansion of the adipose tissue, which outgrows its vascular supply, induces adipocyte necrosis, which stimulates macrophage recruitment and activation. One recruiting factor is CCL2, which mediates the recruitment of CCR2 monocytes, which differentiate into macrophages. Adipocyte death and innate immune cell activation stimulate the migration of adaptive immune cells. In addition, macrophage migration to the adipose tissue and their activation induce the expression of proinflammatory molecules, such as IL-6, MCP-1, TNF-α, and other adipokines which lead to insulin resistance. Peripheral insulin resistance is featured by impaired glucose uptake, increase of gluconeogenesis, hyperlipidemia, hyperglycemia, β-cell hypertrophy, β-cell inflammation, stress, and death. (d) TRAIL effects on obesity-induced insulin resistance. Experimental studies show that TRAIL reduces fat mass gain, systemic and tissue proinflammatory cytokines, and ameliorates peripheral insulin resistance. This is associated to a reduction of β-cell hypertrophy, inflammation, and loss.