Human pancreatic islets are a major focus of diabetes research due to their key role in glucose homeostasis and their potenttal tor transplantation in the treatment ot type 1 diabetes. Currently, no comprehensive analysis of baseline or glucose-stimulated islet gene expression is available. Using oligonucleotide microarrays we analyzed isolated intact human islets incubated at low and high glucose. We identified ∼6000 islet genes, several with clinical implications, as well as a number of glucose-regulated genes. Interestingly, two transforming growth factor β (TGFβ) superfamily members were highly regulated by glucose. One of them, PDF, was found to have a very high expression level compared to other TGFβ superfamily members. Quantitative reverse transcriptase polymerase chain reaction confirmed these results and demonstrated that the highly expressed PDF was ∼10-fold down-regulated by glucose while other TGFβ superfamily members and target genes were up-regulated. These results suggest that a highly regulated TGFβ signaling cascade exists in human islets, and that PDF may play a central role in islet biology. Since TGFβ is involved in differentiation and immune modulation, this novel pathway may link glucose metabolism, immune response and development of human islets. We report here the first gene expression profile of intact human islets. These and similar analyses will provide better understanding of human islet biology and enhance the development of novel diabetes therapies.