Activation of the innate immune system has been recognized as being associated with T2D patients and those being at increased disease risk. Here we show that inflammation takes place in pancreatic islets both in various T2D animal models and in patients, as reflected by the presence of immune cells and various cytokines and chemokines. Under situations of metabolic stress particularly, islet endocrine cells are a source of cytokine and chemokine production, but other pancreatic islet cells such as immune, endothelial and neuronal cells may also be involved. Notably, in various T2D animal models (and probably in humans too), a process of microangiopathy with subsequent fibrosis takes place that results in islet blood flow alterations and eventually leads to a loss of islet architecture. Taking into account that the microvasculature plays an integral role in islet function and that cytokines are deleterious for β-cells, we suggest that endothelial- islet inflammation might contribute to β-cell impairment in T2D. This hypothesis is supported by the fact that treatments that preserve islet architecture and ameliorate endothelial dysfunction, improve β-cell function. Better understanding of the mechanisms involved in early β-cell failure should lead to the identification of new therapeutic targets for the prevention and treatment of T2D.