Type 1 diabetes (T1D) is caused by autoimmune β cell destruction. The early events triggering T1D and the forces that keep diabetic autoimmunity pancreas specific have been unclear. Our discovery that autoimmune islet destruction is not β-cell-exclusive but includes cytotoxic T cell targeting of peri-islet glia, evoked the possibility that T1D pathogenesis may involve neuronal elements beyond β cell/immune interactions. Recently, we have found that sensory afferent neurons are a critical component in prediabetes initiation, promoting islet inflammation through altered glucose homeostasis and progressive β cell stress. These factors orchestrate a catastrophic cascade culminating in insulin insufficiency mediated by an autoimmune-prone host. This neuro-immuno-endocrinological triad explains diabetic inflammation as a consequence of local neuropeptide deficiency, leading to an innovative concept of disease pathogenesis with novel therapeutic implications.