Abstract

Liraglutide Protects Human Beta-Cell Function From Cytokine- And Immune Cell-Induced Stress In Human In Vitro Models of T1D

Matthias von Herrath, Vice President and Senior Medical Officer, NovoNordisk; Professor La Jolla Institute, NovoNordisk

GLP-1 receptor agonists (GLP-1 RA) are hypothesized to preserve beta-cell  function and enhance insulin secretion in type 1 diabetes (T1D). We evaluated the effects of the GLP-1 RA, liraglutide,  on reaggregated, uniform primary human islets under T1D-relevant stress. We established three high-throughput-compatible islet-immune injury models: a cytokine-induced stress assay, an activated peripheral blood mononuclear cell-islet co-culture, and an islet-HLA-A2-restricted preproinsulin-specific cytotoxic T lymphocyte co-culture. In all models, the decline in beta-cell health manifested as increased basal and decreased glucose-stimulated insulin release and decreased total insulin content. Liraglutide prevented loss of stimulated insulin secretion under cytokine- and immune-mediated stress, most notably by preserving the first-phase insulin response and decreasing immune cell infiltration and cytokine secretion. Our results corroborate the therapeutic potential of liraglutide for the preservation of beta-cell function at the time of T1D onset, provide further evidence of a GLP1-related anti-inflammatory effect, and support the utility of biomimetic islet-immune assays.