Direct identification and validation of human β cell-specific biomakers is critical for monitoring the change of human β cell mass at prediabetes and the new-onset diabetes stage and during the therapeutic intervention. Due to technical and ethical constraints, our ability to prospective studies of human β cell biomarkers in response to β cell stress/apoptosis and its correlation with early β cell loss in human is limited. The objective of our study is to develop biomarkers of human β cell stress/apoptosis correlating with β cell loss that can be used to non-invasively monitor the development of diabetes pathogenesis and the outcome of treatments aimed at preserving or restoring functional β cell mass. The goal of this study is to identify potential biomarkers including a panel of noncoding RNAs in human islets that are correlated with β cell stress and apoptosis and to determine whether novel β cell biomarkers in circulation are correlated with early human β cell loss. We hypothesize that β cell ER stress and apoptosis induction increases a panel of noncoding RNAs in human islets in the pancreas of patients with diabetes and dead or dying human β cells can release them into circulation and the levels of these noncoding RNA in circulation are associated with β cell loss. We plan to collect islet cells for miRNA expression profiles by laser capture microdissection (LCM) and determine whether a panel of β-cell specific noncoding RNAs in islets of human pancreas specimens from patients with type 1 and type 2 diabetes are up-regulated by real-time PCR array. We will confirm some up-regulated noncoding RNAs in human islets are β-cell specific by miRNA fluorescence based in situ hybridization (FISH). We will validate this panel of noncoding RNAs, as β cell-specific biomarkers, in plasma of patients with type 1 and type 2 diabetes. Success in our proposed experiments would help us to further develop a panel of β cell biomarkers, which are correlated with early β cell loss, for clinical evaluation of disease stages including pre-diabetes and of therapeutic interventions to promote β cell health and survival.