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<p>Reduced enrichment of short-chain fatty acid (SCFA)-producing pathways in the gut microbiome (GM) and SCFA levels are associated with increased risk of type 1 diabetes (T1D). Free fatty acid receptor 2 (FFA2), an SCFA receptor on pancreatic β-cells, mediates GM and β-cell crosstalk. Here, we examine its T1D-specific role in male mice, using a novel tamoxifen-inducible adult-onset β-cell FFA2 knockout (FFA2 βKO) mouse model and its controls (cre and flox), treated with multiple low-dose streptozotocin (MLDS). FFA2 βKO mice show significantly lower diabetes incidence compared to control mice (57% vs 100%). Early in the MLDS insult (7<sup>th</sup> day), FFA2 βKO mice show significantly lower β-cell apoptosis and higher β-cell mass, persisting up to 43 days. Mechanistically, we observed higher SOCS1/3 expression and reduced T1-IFN signaling in FFA2 βKO islets. Our data suggest that β-cell FFA2 modulates early islet apoptosis, likely via the T1-IFN-SOCS1/3 pathway and may be a pharmacological target for slowing T1D progression.</p>

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Pancreatic β-cell FFA2 deficiency suppresses multiple low dose streptozotocin induced diabetes in male mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Kai Xu,
  • Prabhakaran Kumar,
  • Sophia R. Chang Stauffer,
  • Husena M. Electricwala,
  • Bellur S. Prabhakar,
  • Irene Corona-Avila,
  • Nupur Pandya,
  • Brian T. Layden,
  • Medha Priyadarshini

摘要

Reduced enrichment of short-chain fatty acid (SCFA)-producing pathways in the gut microbiome (GM) and SCFA levels are associated with increased risk of type 1 diabetes (T1D). Free fatty acid receptor 2 (FFA2), an SCFA receptor on pancreatic β-cells, mediates GM and β-cell crosstalk. Here, we examine its T1D-specific role in male mice, using a novel tamoxifen-inducible adult-onset β-cell FFA2 knockout (FFA2 βKO) mouse model and its controls (cre and flox), treated with multiple low-dose streptozotocin (MLDS). FFA2 βKO mice show significantly lower diabetes incidence compared to control mice (57% vs 100%). Early in the MLDS insult (7th day), FFA2 βKO mice show significantly lower β-cell apoptosis and higher β-cell mass, persisting up to 43 days. Mechanistically, we observed higher SOCS1/3 expression and reduced T1-IFN signaling in FFA2 βKO islets. Our data suggest that β-cell FFA2 modulates early islet apoptosis, likely via the T1-IFN-SOCS1/3 pathway and may be a pharmacological target for slowing T1D progression.