SAT073 β Cell FFA2 Deficiency Suppresses Multiple Low Dose Streptozotocin (MLDS) Induced Diabetes

Abstract

Abstract Disclosure: K. Xu: None. M. Priyadarshini: None. P. Kumar: None. H.M. Electricwala: None. B.S. Prabhakar: None. B.T. Layden: None. Gut microbiome is recently recognized environmental factor in pathogenesis of type 1 diabetes (T1D). Reduced short chain fatty acid (SCFA) producing gut bacteria and also SCFA levels correlate with T1D risk (TEDDY study). We have previously shown that FFA2 is one of the main SCFA receptors, which is expressed on the β cell and mediates gut microbiome-β cell crosstalk. Based on these data, we hypothesized that β cell FFA2 may play a role in T1D β cell pathology. To examine this, we followed our novel tamoxifen induced β cell FFA2 knockout mice (FFA2 fl/fl; MIP CreERT+, FFA2 BKO) and wildtype littermates (FFA2 fl/fl) after multiple low dose streptozotocin (MLDS) induced T1D. Comparing to wildtype littermates, FFA2 BKO were significantly protected from MLDS insult and exhibited normal glycemic control owing to higher β cell mass. To understand the mechanism of this protective effect, we mined islet transcriptome data from our FFA2 global knockout mice and identified markedly upregulated type 1 interferon pathway in FFA2 global knockout. Accordingly, wildtype islets treated with high dose IFNα (mimicking T1D like conditions) showed significant upregulation of IFNαtargets while FFA2 BKO islets were unresponsive. Using pharmacological inhibition in isolated islets, we identified FFA2 mediated inhibition of NF-κB activation as a critical event in FFA2 mediated regulation of IFNαsignaling. In vivo studies with IFNAR1 antibody showed partial rescue of wildtype mice in the early stages of MLDS induced T1D. Thus, we propose a key role of β cell FFA2 in preserving β cell mass from IFNα signaling mediated damage in T1D. Further studies are needed to test this model. Presentation: Saturday, June 17, 2023