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Endoplasmic reticulum (ER) dysfunction is a potential contributor to the impaired repair capacity of periodontal tissue in diabetes mellitus (DM) patients. Restoring ER homeostasis is thus critical for successful regenerative therapy of diabetic periodontal tissue. Recent studies have shown that metformin can modulate DM-induced ER dysfunction, yet its mechanism remains unclear. Herein, we show that high glucose elevates the intracellular miR-129-3p level due to exocytosis-mediated release failure and subsequently perturbs ER calcium homeostasis via downregulating transmembrane and coiled-coil domain 1 (TMCO1), an ER Ca 2+ leak channel, in periodontal ligament stem cells (PDLSCs). This results in the degradation of RUNX2 via the ubiquitination-dependent pathway, in turn leading to impaired PDLSCs osteogenesis. Interestingly, metformin could upregulate P2X7R-mediated exosome release and decrease intracellular miR-129-3p accumulation, which restores ER homeostasis and thereby rescues the impaired PDLSCs. To further demonstrate the in vivo effect of metformin, a nanocarrier for sustained local delivery of metformin (Met@HALL) in periodontal tissue is developed. Our results demonstrate that compared to controls, Met@HALL with enhanced cytocompatibility and pro-osteogenic activity could boost the remodeling of diabetic periodontal tissue in rats. Collectively, our findings unravel a mechanism of metformin in restoring cellular ER homeostasis, enabling the development of a nanocarrier-mediated ER targeting strategy for remodeling diabetic periodontal tissue.

Periodontitis is among most common human inflammatory diseases and characterized by destruction of tooth-supporting tissues that will eventually lead to tooth loss. Diabetes mellitus (DM) is a group of metabolic disorders characterized by chronic hyperglycemia which results from defects in insulin secretion and/or insulin resistance. Numerous studies have provided evidence for the inter-relationship between DM and periodontitis that has been considered as the sixth most frequent complication of DM. However, the mechanisms are not fully understood yet. The impact of DM on periodontitis through hyperglycemia and inflammatory pathways is well described, but the effects of DM on oral microbiota remain controversial according to previous studies. Recent studies using next-generation sequencing technology indicate that DM can alter the biodiversity and composition of oral microbiome especially subgingival microbiome. This may be another mechanism by which DM risks or aggravates periodontitis. Thus, to understand the role of oral microbiome in periodontitis of diabetics and the mechanism of shifts of oral microbiome under DM would be valuable for making specific therapeutic regimens for treating periodontitis patients with DM or preventing diabetic patients from periodontitis. This article reviews the role of oral microbiome in periodontal health (symbiosis) and disease (dysbiosis), highlights the oral microbial shifts under DM and summarizes the mechanism of the shifts. [ABSTRACT FROM AUTHOR]