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Type 1 diabetes is autoimmune disease resulting from a progressive decrease in β-cell mass and function (1). The mediators of β-cell dysfunction and destruction include macrophages, T-cells and their inflammatory [...], Pancreatic islet transplantation may successfully restore normoglycemia in type 1 diabetic patients. However, successful grafting requires transplantation of a sufficient number of islets, usually requiring two or more donors. During the isolation process and following clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. Here, we have mapped the major intracellular stress-signaling pathways that may mediate human islet loss during isolation and following cytokine attack. We found that the isolation procedure potently recruits two pathways consisting of [absolute value of mitogen-activated protein kinase kinase (MKK)7 → Jun N[H.sub.2]-terminal kinase (JNK)/p38 → c-fos] and the [absolute value of nuclear factor-κB (NF-κB) → iNOS] module. Cytokines activate the [[absolute value of NF-κB → iNOS] and [absolute value of MKK4/MKK3/6 → JNK/p38] pathways without recruitment of c-fos. Culturing the islets for 48 h after isolation allows for the activated pathways to return to background levels, with expression of MKK7 becoming undetectable. These data indicate that isolation and cytokines recruit different death pathways. Therefore, strategies might be rationally developed to avoid possible synergistic activation of these pathways in mediating islet loss during isolation and following grafting.