Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin- activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by high fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared to their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1β and IL-17A exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared to controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes.

This article contains supplementary material online at

This content is only available via PDF.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at

Article PDF first page preview

Article PDF first page preview
You do not currently have access to this content.