Owing to strong interactions between pancreatic islets and the surrounding capillary network, we hypothesized that high glucose concentrations might affect key angiogenesis factors from isolated human islets, thus contributing to beta-cell failure in diabetes. Human islets from eight distinct donors were studied following 96 h in culture in the presence of normal (5.5 mmol/l) or high (16.7 mmol/l) glucose concentrations. Similar studies were performed with HUVECs. Human angiogenesis-related genes and corresponding proteins were studied by real-time quantitative PCR (RT-qPCR) and protein arrays respectively. Angiogenesis and proliferation assays were also performed with HUVECs under the same culture conditions. RT-qPCR and proteome analysis of human islets incubated with 16.7 mM/l glucose revealed a significant decrease in pro-angiogenic factors including vascular endothelial growth factor (VEGF) mRNA by 20% and VEGF protein levels by 42% as well as additional proteins such as fibroblast growth factor-4 by 41%, MMP9 by 18%, monocyte chemoattractant protein-1 by 21%, and prolactin by 25%. In contrast, we observed a 17% increase in thrombospondin-1 (TSP-1, listed as THBS1 in the HUGO database) and a 37% increase in angiotensinogen gene expression levels, but neither angiotensin-converting enzyme nor angiotensin II type 1 receptor gene expression was affected. The amounts of anti-angiogenic proteins such as TSP-1 and serpin B5/maspin were also increased by 70 and 98% respectively as well as endostatin by 63%. Angiogenesis assays of HUVECS in the presence of high glucose concentrations revealed a 30% decrease in tree-like tubular network formation. These data suggest that glucose reduces key factors of islet angiogenesis, which might exacerbate beta-cell failure.