A major cause of poor wound healing and periodontitis in diabetes is defective immune response to infections. Insulin signaling via the PI3K/Akt pathway is selectively inhibited in the gingival and wound fibroblasts of diabetic rodents and patients. To determine how loss of insulin actions in gingival fibroblasts can affect periodontitis development, myofibroblast insulin receptors (IR) were deleted by crossbreeding IRβ-flox/flox mice with SM22-Cre C57BL/6 (SMIRKO) mice, which were fed with regular diet (RD), while wild type (WT) littermates were fed with high-fat diet (HFD) for 10 weeks. To induce periodontitis, 7-0 silk ligatures were tied around maxillary molars for 4, 7 or 14 days. When mice were sacrificed to assess alveolar bone loss, immune cell populations and inflammatory cytokine expression in the gingiva was assessed. Gingival IRβ expression in SMIRKO and HFD-fed mice was decreased by 70% and 50%, respectively, with comparable reductions in insulin-induced (100nM) phosphorylation of Akt (pAkt). Ligature-induced alveolar bone loss in SMIRKO and HFD-fed mice was greater by 70% and 40%, respectively, as compared to RD-fed WT mice. Post-ligature time course analysis showed that while neutrophil recruitment was delayed significantly, macrophages and lymphocyte numbers were elevated in both SMIRKO and HFD-fed mice. Similarly, neutrophil-recruiting factors CXCL1 and 2 expression were decreased in the gingiva, whereas TNFα and IL-1β expression were elevated. Gingival myofibroblasts from SMIRKO and HFD-fed mice showed dramatic reductions of IRβ expression and insulin-induced pAkt with parallel lowering of E.coli LPS-induced CXCL1 expression via downregulation of TLR2, compared to RD-fed mice. These data provided the first evidence that insulin action is critical for neutrophil recruitment during infection by enabling CXCL1 expression in gingival myofibroblasts, which is inhibited in diabetes.


T. Shinjo: None. Q. Li: None. A. Ishikado: Employee; Self; SunStar Inc. Employee; Spouse/Partner; SunStar Inc. K. Park: None. R. St-Louis: None. H. Yokomizo: None. J. Fu: None. M. Yu: None. H. Wang: None. H. Hasturk: None. T.E. Van Dyke: None. G.L. King: Research Support; Self; Sanofi.


Sunstar Foundation; Iacocca Family Foundation

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