Lipotoxicity: The missing link between diabetes and periodontitis?

Lipotoxicity refers to the accumulation of lipids in tissues other than adipose tissue (body fat). It is one of the major pathophysiological mechanisms responsible for the progression of diabetes complications such as non-alcoholic fatty liver disease and diabetic nephropathy. Accumulating evidence indicates that lipotoxicity also contributes significantly to the toxic effects of diabetes on periodontitis. Therefore, we reviewed the current in vivo, in vitro, and clinical evidence of the detrimental effects of lipotoxicity on periodontitis, focusing on its molecular mechanisms, especially oxidative and endoplasmic reticulum stress, inflammation, ceramides, adipokines, and programmed cell death pathways. By elucidating potential therapeutic strategies targeting lipotoxicity and describing their associated mechanisms and clinical outcomes, including metformin, statins, liraglutide, adiponectin, and omega-3 PUFA, this review seeks to provide a more comprehensive and effective treatment framework against diabetes-associated periodontitis. Furthermore, the challenges and future research directions are proposed, aiming to contribute to a more profound understanding of the impact of lipotoxicity on periodontitis.

Validation of a physiological type 2 diabetes model in human periodontal ligament stem cells.

OBJECTIVES: Type 2 diabetes (T2DM), a recognized risk factor for periodontitis, is characterized by insulin resistance. However, the molecular mechanisms concerning the role of insulin resistance in linking T2DM and periodontitis remain poorly elucidated due to the absence of an appropriate T2DM cell model. We aimed to explore an appropriate model of T2DM in human periodontal ligament stem cells (hPDLSCs) and uncover the involved mechanisms. MATERIALS AND METHODS: hPDLSCs were incubated with common reagents for recapitulating insulin resistance state including high glucose (HG) (15, 25, 35, 45 mM), glucosamine (0.8, 8, 18, 28, 38 mM), or palmitic acid (PA; 100, 200, 400, 800 µM), combined with LPS for 48 h. The insulin signaling pathway, inflammation, and pyroptosis were detected by western blots and quantitative real-time polymerase chain reaction (RT-qPCR). The effects on osteogenesis were evaluated by alkaline phosphatase staining, alizarin red S staining, RT-qPCR, and western blots. RESULTS: HG failed to recapitulate insulin resistance. Glucosamine was sufficient to induce insulin resistance but failed to trigger inflammation. In total, 100 and 200 µM PA exhibited the most proinflammatory, insulin resistance, and pyroptosis induced role, and inhibited the osteogenic differentiation of hPDLSCs. CONCLUSION: Palmitic acid is a promising candidate for developing T2DM model in hPDLSCs.

Serum Concentrations of Cartilage Intermediate Layer Protein 2 Were Higher in Overweight and Obese Subjects.

Background: Cartilage intermediate layer protein 2 (CILP2) is associated with a variety of plasma lipoproteins and lipid traits. However, the correlation between CILP2 and obesity remains unknown. The aim of this study was to investigate the relationship between circulating CILP2 levels and obesity based on body mass index (BMI). Methods: A total of 252 subjects were divided into three groups: normal weight (n = 124), overweight (n = 94), and obese (n = 34). Metabolic parameters were measured in a fasting state. Serum CILP2 concentration was tested by enzyme-linked immunosorbent assay. Multivariate linear regression analysis was used to explore the relationship between CILP2 and obesity. We also conducted bioinformatics analysis to further explore the genes and signaling pathways related to CILP2. Results: The concentrations of serum CILP2 in the overweight and obese groups were significantly higher than that in the normal weight group. In multiple linear regression analysis, BMI was positively correlated with CILP2 concentration after controlling gender and age. Being overweight and obese were independently correlated with CILP2 concentration after adjusting for gender, age, SBP, DBP, FBG, 2-hour OGTT blood glucose (2h-BG), fasting blood insulin (FIns), TG, TC, HDL-C, LDL-C, and FFA. Bioinformatics analysis showed that the genes related to CILP2 are primarily associated with lipid metabolism and insulin resistance. Conclusion: We speculate that CILP2 may attribute to metabolic disorders in obesity.

Pyroptosis in periodontitis: From the intricate interaction with apoptosis, NETosis, and necroptosis to the therapeutic prospects.

Periodontitis is highly prevalent worldwide. It is characterized by periodontal attachment and alveolar bone destruction, which not only leads to tooth loss but also results in the exacerbation of systematic diseases. As such, periodontitis has a significant negative impact on the daily lives of patients. Detailed exploration of the molecular mechanisms underlying the physiopathology of periodontitis may contribute to the development of new therapeutic strategies for periodontitis and the associated systematic diseases. Pyroptosis, as one of the inflammatory programmed cell death pathways, is implicated in the pathogenesis of periodontitis. Progress in the field of pyroptosis has greatly enhanced our understanding of its role in inflammatory diseases. This review first summarizes the mechanisms underlying the activation of pyroptosis in periodontitis and the pathological role of pyroptosis in the progression of periodontitis. Then, the crosstalk between pyroptosis with apoptosis, necroptosis, and NETosis in periodontitis is discussed. Moreover, pyroptosis, as a novel link that connects periodontitis with systemic disease, is also reviewed. Finally, the current challenges associated with pyroptosis as a potential therapeutic target for periodontitis are highlighted.

Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies.

Objective: GPHB5 has been found to be associated with glucose and lipid metabolism in animal studies. However, the association of GPHB5 with IR and metabolic disorders remains unknown, and there is a lack of research in humans. Our aim in this study was to investigate the relationship between circulating GPHB5 and metabolic disorders in humans. Methods: Bioinformatics analysis was performed to understand the relationship between GPHB5 and metabolic disorders. GPHB5 mRNA expression in mice and rats was determined using RT-qPCR. Circulating GPHB5 concentrations were measured with an ELISA kit. EHC and OGTT were performed in humans. Results: Bioinformatics analysis shows that GPHB5 is associated with metabolic disorders and PCOS. GPHB5 mRNA expression levels in the metabolic-related tissues of HFD-fed mice, db/db and ob/ob mice, and PCOS rats were significantly higher than those of WT mice or rats. In human studies, we find that circulating GPHB5 levels were significantly higher in women with IR and PCOS. GPHB5 levels were positively correlated with age, BMI, WHR, BP, FBG, 2 h-BG, FIns, 2 h-Ins, TC, LDL-C, HbA1c, and FFA, but negatively correlated with adiponectin. Furthermore, GPHB5 was positively correlated with DHEAS and FAI, while negatively correlated with SHBG, FSH, SHBG and FSH. The increased GPHB5 concentration was related to IR and PCOS. After the treatment of metformin, GLP-1RA (Lira), and TZDs, circulating GPHB5 levels were decreased. Conclusions: Our results reveal that circulating GPHB5 could be a biomarker and potential therapeutic target for IR and PCOS in women.

Association of serum fetuin-B with insulin resistance and pre-diabetes in young Chinese women: evidence from a cross-sectional study and effect of liraglutide.

BACKGROUND AND AIMS: Fetuin-B has been reported to be involved in glucose and lipid metabolism and associated with the occurrence of diabetes. The main purpose of this study is to explore the changes of circulating fetuin-B in young women with pre-diabetes and to analyze the relationship between fetuin-B and the occurrence and development of IR. METHODS: A total of 304 women were enrolled in this study and subjected to both OGTT and EHC. A subgroup of 26 overweight/obese womenwas treated with Lira for 24 weeks. serum fetuin-B concentrations were measured by ELISA. RESULTS: In IGT and IR-NG groups, serum fetuin-B levels were higher than those in the NGT group. The serum fetuin-B levels in the IGT group were higher than those in the IR-NG group. serum fetuin-B was positively correlated with BMI, WHR, 2h-BG, FIns, HbA1c, and HOMA2-IR, but negatively correlated with the M-value in all study populations. Multiple stepwise regression analysis showed that the M-value was independently and inversely associated with serum fetuin-B. Logistic regression analysis showed that serum fetuin-B was independently associated with IGT and significantly increased the risk of IGT. During the OGTT, serum fetuin-B increased significantly in the NGT group, but there were no significant changes in other groups. During the EHC, serum fetuin-B increased in the IGT group, but there was no change in other groups. After Lira intervention, serum fetuin-B decreased significantly in IGT women. CONCLUSIONS: serum fetuin-B levels are elevated in young women with IR or IGT and may be associated with IR.