Type 1 diabetes (T1D) is characterized by cytokine-mediated beta-cell destruction, resulting in life-long insulin dependency for the patient. Glucagon-like peptide-1 (GLP-1) protects pancreatic beta-cells against cytokine-induced dysfunction and destruction, thereby maintaining glucose homeostasis. Incretin-based compounds have emerged as a new class of agents for treatment of T2D, while few reports have also described the effects of incretin-based agents in T1D. However, the mechanisms through which GLP-1 exerts its effects are still poorly understood. We aimed to analyze protein expression profiles of human islets treated with cytokines with/without GLP-1, to unravel the molecular pathways involved in GLP-1-mediated beta-cell protection. Human islets were incubated with IL1β (50U/ml) and IFNg (1000U/ml) with/without GLP-1 (10nM). Beta-cell apoptosis was determined by electron microscopy and beta-cell dysfunction was evaluated by glucose-stimulated insulin secretion. Alterations in protein expression profiles were identified by 2-dimensional difference gel electrophoresis (2D-DIGE) and interactome network analysis. Cytokines induced an almost two-fold decrease in glucose-stimulated insulin secretion (n=6, p<0.05) and increase in apoptosis from 1±0.6 to 18±3.5% (n=3, p<0.05), an effect which was almost completely restored by co-incubation with GLP-1. 2D-DIGE (n=4) and interactome network analysis revealed that GLP-1 alters in an integrated manner protein networks in cytokine-exposed islets. This showed that the cytoprotective effects of GLP-1 are mainly executed through counteracting the effects of cytokines on proteins from different functional classes such as restoration of actin cytoskeleton (e.g. ARP3 and CAPZB), normalization of chaperones (e.g. EIF3I), metabolic proteins (e.g. ALDH) and islet regenerating proteins (e.g.REG1A). In conclusion, GLP-1 alters in an integrated manner protein networks in cytokine-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack and lead to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic patients.