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

Recently, the gut microbiome has been recognized as an environmental factor in the pathogenesis of type 1 diabetes (T1D). Reduced enrichment of short-chain fatty acid (SCFA)-producing pathways in the gut microbiome and SCFA levels are correlated with an increased T1D risk. We have previously shown that free fatty acid receptor 2 (FFA2), one of the main SCFA receptors, is expressed on pancreatic β cells and mediates the crosstalk between the gut microbiome and β cells in type 2 diabetes (T2D). However, the role of β cell FFA2 in T1D has not been explored. To examine this, we used our novel mouse model, a tamoxifen (TMX)-induced adult onset β cell FFA2 knockout (FFA2 βKO) and its controls (cre control and floxed control), treated with multiple low-dose streptozotocin (MLDS) to model T1D. Surprisingly, 57% of FFA2 βKO mice were protected from MLDS-induced T1D for 43 days and exhibited normal glycemic control owing to a trending higher β cell mass, whereas 100% of the control group mice developed diabetes. As transcriptome data showed marked upregulation of negative regulator of type 1 interferon (T1-IFN) signaling genes, suppressor of cytokine signaling 1/3 (Socs1/3), in FFA2 global knockout islets, we hypothesized that at the early stage of MLDS-induced T1D, when abundant IFN⍺ is presented, adulthood deletion of FFA2 in β cells attenuates T1-IFN signaling via further increase of Socs1/3, resulting protection from MLDS-induced T1D. In fact, both ex vivo and in vivo experiments showed reduced T1-IFN signaling in FFA2 βKO islets and mice. Early in the MLDS insult (7th day) FFA2 βKO mice showed higher β cell mass due to less apoptosis. Collectively, adulthood deletion of FFA2 in β cells attenuates T1-IFN signaling, leading to less apoptosis and higher β cell mass, conferring protection against MLDS-induced T1D in the early stage.