scholarly journals Effect of Salivary Exosomal miR-25-3p on Periodontitis With Insulin Resistance

2022 ◽  
Vol 12 ◽  
Author(s):  
Jin-Seok Byun ◽  
Ho Yeop Lee ◽  
Jingwen Tian ◽  
Ji Sun Moon ◽  
Jaejin Choi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
T Cells ◽  
Immune Cells ◽  
Γδ T Cells ◽  
Healthy Individuals ◽  
Local Inflammation ◽  
Diet Induced Obesity ◽  
Exosomal Mirna

Periodontitis is caused by an oral microbial dysbiosis-mediated imbalance of the local immune microenvironment, which is promoted by insulin resistance and obesity. The prevalence and severity of periodontitis is higher in patients with type 2 diabetes than in healthy individuals, possibly because of differences in immune responses. The level of glycemic control also affects the saliva profile, which may further promote periodontal disease in diabetes patients. Therefore, we compared the salivary exosomal miRNA profiles of patients with type 2 diabetes with those of healthy individuals, and we found that exosomal miR-25-3p in saliva is significantly enriched (by approximately 2-fold, p < 0.01) in obese patients with type 2 diabetes. We also identified CD69 mRNA as a miR-25-3p target that regulates both activation of γδ T cells and the inflammatory response. Knockdown of CD69 increased (by approximately 2-fold) interleukin-17A production of γδ T cells in vitro. To evaluate the role of exosomal miRNA on progression of periodontitis, we analyzed regional immune cells in both periodontal tissues and lymph nodes from mice with periodontitis. We found that diet-induced obesity increased the population of infiltrating pro-inflammatory immune cells in the gingiva and regional lymph nodes of these mice. Treatment with miR-25-3p inhibitors prevented the local in vivo inflammatory response in mice with periodontitis and diet-induced obesity. Finally, we showed that suppression of interleukin 17-mediated local inflammation by a miR-25-3p inhibitor alleviated (by approximately 34%) ligature-induced periodontal alveolar bone loss in mice. Taken together, these data suggest that exosomal miR-25-3p in saliva contributes to development and progression of diabetes-associated periodontitis. Discovery of additional miR-25-3p targets may provide critical insights into developing drugs to treat periodontitis by regulating γδ T cell-mediated local inflammation.

scholarly journals Adipose Tissue Dendritic Cells: Critical Regulators of Obesity-Induced Inflammation and Insulin Resistance

2021 ◽  
Vol 22 (16) ◽  
pp. 8666
Author(s):  
Shindy Soedono ◽  
Kae Won Cho
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
T Cells ◽  
Dendritic Cells ◽  
Adipose Tissue ◽  
Immune Responses ◽  
Immune Cells ◽  
Critical Component ◽  
Exact Role

Chronic inflammation of the adipose tissue (AT) is a critical component of obesity-induced insulin resistance and type 2 diabetes. Adipose tissue immune cells, including AT macrophages (ATMs), AT dendritic cells (ATDCs), and T cells, are dynamically regulated by obesity and participate in obesity-induced inflammation. Among AT resident immune cells, ATDCs are master immune regulators and engage in crosstalk with various immune cells to initiate and regulate immune responses. However, due to confounding markers and lack of animal models, their exact role and contribution to the initiation and maintenance of AT inflammation and insulin resistance have not been clearly elucidated. This paper reviews the current understanding of ATDCs and their role in obesity-induced AT inflammation. We also provide the potential mechanisms by which ATDCs regulate AT inflammation and insulin resistance in obesity. Finally, this review offers perspectives on ways to better dissect the distinct functions and contributions of ATDCs to obesity.

Increasing endogenous PPARγ ligands improves insulin sensitivity and protects against diet-induced obesity without side effects of thiazolidinediones

2021 ◽  
Author(s):  
Yu-Hua Tseng ◽  
Lee-Ming Chuang ◽  
Yi-Cheng Chang ◽  
Meng-Lun Hsieh ◽  
Lun Tsou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Side Effects ◽  
Knockout Mice ◽  
Fasting Glucose ◽  
Binding Mode ◽  
Fluid Retention ◽  
Diet Induced Obesity

Abstract Insulin resistance and obesity are pivotal features of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones are potent synthetic PPARγ ligands and insulin sensitizers with undesirable side effects including increased adiposity, fluid retention, and osteoporosis, which limit their clinical use. We and others have proved that 15-keto-PGE2 is an endogenous natural PPARγ ligand. 15-keto-PGE2 is catalyzed by prostaglandin reductase 2 (PTGR2) to become inactive metabolites. We found that 15-keto-PGE2 level is increased in Ptgr2 knockout mice. Ptgr2 knockout mice were protected from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention nor reduced bone mineral density. Diet-induced obese mice have drastically reduced 15-keto-PGE2 levels compared to lean mice. Administration of 15-keto-PGE2 markedly improved insulin sensitivity and prevented diet-induced obesity in mice. We demonstrated that 15-keto-PGE2 activates PPARγ through covalent binding to its cysteine 285 residue at helix 3, which restrained its binding pocket between helix 3 and β-sheets of the PPARγ ligand binding domain. This binding mode differs from the helix12-dependent binding mode of thiazolidinediones. We further identified a small-molecule PTGR2 inhibitor BPRPT245, which interferes the interaction between the substrate-binding sites of PTGR2 and 15-keto-PGE2. BPRPT245 increased 15-keto-PGE2 concentration, activated PPARγ, and promoted glucose uptake in adipocytes. BPRPT245 also prevented diet-induced obesity, improved insulin sensitivity and glucose tolerance, lowers fasting glucose without fluid retention and osteoporosis. In humans, reduced serum 15-keto-PGE2 levels were observed in patients with type 2 diabetes compared with controls. Furthermore, serum 15-keto-PGE2 levels correlate inversely with insulin resistance and fasting glucose in non-diabetic humans. In conclusion, we identified a new therapeutic approach to improve insulin sensitivity and protect diet-induced obesity through increasing endogenous natural PPARγ ligands without side effects of thiazolidinediones.

scholarly journals Role of T Lymphocytes in Type 2 Diabetes and Diabetes-Associated Inflammation

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Chang Xia ◽  
Xiaoquan Rao ◽  
Jixin Zhong
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
T Cells ◽  
Immune System ◽  
Critical Role ◽  
Adaptive Immune System ◽  
Metabolic Inflammation ◽  
Adaptive Immune

Although a critical role of adaptive immune system has been confirmed in driving local and systemic inflammation in type 2 diabetes and promoting insulin resistance, the underlying mechanism is not completely understood. Inflammatory regulation has been focused on innate immunity especially macrophage for a long time, while increasing evidence suggests T cells are crucial for the development of metabolic inflammation and insulin resistance since 2009. There was growing evidence supporting the critical implication of T cells in the pathogenesis of type 2 diabetes. We will discuss the available effect of T cells subsets in adaptive immune system associated with the procession of T2DM, which may unveil several potential strategies that could provide successful therapies in the future.

scholarly journals Reprogrammed Functional Brown Adipocytes Ameliorate Insulin Resistance and Dyslipidemia in Diet-Induced Obesity and Type 2 Diabetes

2015 ◽  
Vol 5 (4) ◽  
pp. 569-581 ◽  
Author(s):  
Tsunao Kishida ◽  
Akika Ejima ◽  
Kenta Yamamoto ◽  
Seiji Tanaka ◽  
Toshiro Yamamoto ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Brown Adipocytes ◽  
Diet Induced Obesity ◽  
Ameliorate Insulin Resistance

scholarly journals AB0083 STUDY OF THE ROLE OF ANGIOPOIETIN-LIKE PROTEIN TYPE 4 IN METABOLIC DISORDERS CAUSED BY INFLAMMATION IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1341.2-1341
Author(s):  
A. Aleksandrov ◽  
V. Aleksandrov ◽  
L. Shilova
Keyword(s):  
Rheumatoid Arthritis ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Blood Serum ◽  
Disease Activity ◽  
Metabolic Disorders ◽  
Healthy Individuals

Background:Objectives:To assess the potential role of angiopoietin-like protein type 4 (ANGPTL4) in metabolic disorders caused by inflammation in rheumatoid arthritis (RA).Methods:The study included 88 patients with significant RA, 64 patients with other rheumatic diseases (RD) (36 patients with osteoarthritis (OA); 28 patients with psoriatic arthritis (PsA); 17 patients with ankylosing spondylitis (AS)) and 32 healthy individuals. Estimation of ANGPTL4 was carried out by enzyme immunoassay using the commercial test system “RayBio Human ANGPTL4 ELISA Kit” (RayBiotech, USA) in blood serum. Levels of ESR, CRP, RF, antibodies to cyclic citrullinated peptide (anti-CCP) and modified vimentin (anti-MCV) in the ELISA test were determined for all patients with RA.Results:The level of ANGPTL4 in the blood serum of patients with RA was significantly higher than in healthy people (p <0.001) and patients with other RD (p = 0.012 compared with OA; p = 0.046 with PsA; p = 0.008 with AS). ANGPTL4 indices in patients with RA correlated with the age of onset of RA (r = -0.658, p <0.001), disease activity according to DAS-28 (r = 0.449, p = 0.001), level of education (r = 0.235, p = 0.029), dose of glucocorticoid hormones (r = 0.321, p = 0.009) and methotrexate (r = -0.496, p = 0.05), the presence of osteopenia (r = 0.44), signs of kidney damage - proteinuria (r = 0.309, p = 0.037) and hypoalbuminemia (r = 0.386, p = 0.022), as well as with CRP levels (r = 0.488, p = 0.003), ESR (r = 0.458, p = 0.002), serum vitamin D (r = -0.417) and urinary calcium when recalculated to creatinine (r = 0.797, p = 0.032).Patients with RA showed a high frequency of insulin resistance (according to the HOMA-IR index) (1.27 [0.84–1.62] in patients with RA; 0.76 [0.44–1.02] in healthy individuals; p <0.001) and the presence of coronary heart disease, as well as a positive correlation between disease activity (according to DAS-28) and insulin resistance (according to the HOMA-IR index) (p = 0.033).Higher values of C-reactive protein (p = 0.04) and serum ANGPTL4 levels (p = 0.042, compared with patients with RA without type 2 diabetes; p = 0.026, compared with healthy individuals) were determined in the group of patients with RA with the presence of type 2 diabetes. ANGPTL4 acts as an inhibitor of lipoprotein lipase. His contribution to the development of dyslipidemia in RA can be demonstrated by the results we obtained when comparing groups of patients with / without signs of metabolic syndrome (MS). A positive correlation between ANGPTL4 and triglyceride levels (r = 0.42, p = 0.018) was found. An increase in the level of ANGPTL4 in blood serum of patients with RA with MS (p = 0.027 compared with RA without MS) can predict the development of cardiac pathology in this group of patients.Conclusion:ANGPTL4 is directly involved in the regulation of glucose homeostasis, lipid metabolism, and insulin sensitivity. Cardiovascular diseases associated with atherosclerosis, insulin resistance and metabolic syndrome are known as the most common extraarticular manifestations of RA; the study of the role of ANGPTL4 in metabolic disorders caused by inflammation can show a new direction in the development of laboratory and therapeutic technologies in RA.Disclosure of Interests:None declared

scholarly journals Exploring the role of ATP10A in diet‐induced obesity, insulin resistance, and type 2 diabetes

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Adriana Norris ◽  
Todd Graham ◽  
John Stafford ◽  
Lin Zhu
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Diet Induced Obesity

scholarly journals RGC32 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

2014 ◽  
Vol 224 (2) ◽  
pp. 127-137 ◽  
Author(s):  
Xiao-Bing Cui ◽  
Jun-Na Luan ◽  
Jianping Ye ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Tolerance Test ◽  
High Fat ◽  
Diet Induced Obesity

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases and many other chronic diseases. Adipose tissue inflammation is a critical link between obesity and insulin resistance and type 2 diabetes and a contributor to disease susceptibility and progression. The objective of this study was to determine the role of response gene to complement 32 (RGC32) in the development of obesity and insulin resistance. WT and RGC32 knockout (Rgc32−/− (Rgcc)) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical, and histologic analyses were performed. 3T3-L1 preadipocytes were used to study the role of RGC32 in adipocytes in vitro. Rgc32−/− mice fed with HFD exhibited a lean phenotype with reduced epididymal fat weight compared with WT controls. Blood biochemical analysis and insulin tolerance test showed that RGC32 deficiency improved HFD-induced dyslipidemia and insulin resistance. Although it had no effect on adipocyte differentiation, RGC32 deficiency ameliorated adipose tissue and systemic inflammation. Moreover, Rgc32−/− induced browning of adipose tissues and increased energy expenditure. Our data indicated that RGC32 plays an important role in diet-induced obesity and insulin resistance, and thus it may serve as a potential novel drug target for developing therapeutics to treat obesity and metabolic disorders.

scholarly journals CD26/DPP4 Levels in Peripheral Blood and T Cells in Patients With Type 2 Diabetes Mellitus

2013 ◽  
Vol 98 (6) ◽  
pp. 2553-2561 ◽  
Author(s):  
Sang Ah Lee ◽  
Young Ree Kim ◽  
Eun Jin Yang ◽  
Eun-Jeong Kwon ◽  
Sun Hyung Kim ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
T Cells ◽  
Cd8 T Cells ◽  
Hemoglobin A1c ◽  
Control Group ◽  
Model Assessment ◽  
Homeostasis Model Assessment

Context: Dipeptidyl peptidase 4 (CD26/DPP4) is expressed on blood T cells and also circulates in a soluble form (sCD26/DPP4). Objective: We aimed to evaluate blood T cell and circulating CD26/DPP4 and its association with metabolic parameters in patients with type 2 diabetes mellitus (T2DM). Designs: We measured CD26/DPP4 expression (percentage of CD26+ cells using flow cytometry) on CD4+ and CD8+ T cells, serum CD26/DPP4 level and activity, and various metabolic parameters in T2DM patients not on DPP4 inhibitor therapy (n = 148). Nondiabetic subjects (n = 50) were included as a control group. Results: Compared with the healthy controls, CD26/DPP4 expression on CD4+ T cells and CD8+ T cells was higher in T2DM patients. Serum CD26/DPP4 levels and enzymatic activities were also higher in patients with T2DM than in the control group only when metformin and/or thiazolidinedione-treated T2DM patients were excluded; metformin and/or thiazolidinedione-treated T2DM patients had lower values compared with other T2DM patients. Various parameters in T2DM patients were related to CD26/DPP4 expression on the T cells (hemoglobin A1c), serum sCD26/DPP4 (hemoglobin A1c and insulin resistance assessed by updated homeostasis model assessment), and serum CD26/DPP4 activity (insulin resistance assessed by updated homeostasis model assessment, γ-glutamyl transferase, and alanine aminotransferase) by multivariate analyses. After active glucose control for 12 weeks in drug-naive T2DM patients (n = 50), CD26/DPP4 expression on blood T cells was significantly decreased. Conclusions: Our results suggest that the CD26/DPP4 level on blood T cells was associated with glucose control status in patients with T2DM.

scholarly journals Elimination of the NLRP3-ASC Inflammasome Protects against Chronic Obesity-Induced Pancreatic Damage

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4039-4045 ◽  
Author(s):  
Yun-Hee Youm ◽  
Ayinuer Adijiang ◽  
Bolormaa Vandanmagsar ◽  
David Burk ◽  
Anthony Ravussin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Nlrp3 Inflammasome ◽  
Diabetic Patients ◽  
Inflammasome Activation ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Diet Induced Obesity ◽  
Pancreatic Damage

Clinical evidence that the blockade of IL-1β in type-2 diabetic patients improves glycemia is indicative of an autoinflammatory mechanism that may trigger adiposity-driven pancreatic damage. IL-1β is a key contributor to the obesity-induced inflammation and subsequent insulin resistance, pancreatic β-cell dysfunction, and the onset of type 2 diabetes. Our previous studies demonstrated that the ceramides activate the Nod-like receptor family, pyrin domain containing 3 (Nlrp3) inflammasome to cause the generation of mature IL-1β and ablation of the Nlrp3 inflammasome in diet-induced obesity improves insulin signaling. However, it remains unclear whether the posttranslational processing of active IL-1β in pancreas is regulated by the NLRP3 inflammasome or whether the alternate mechanisms play a dominant role in chronic obesity-induced pancreatic β-cell exhaustion. Here we show that loss of ASC, a critical adaptor required for the assembly of the NLRP3 and absent in melanoma 2 inflammasome substantially improves the insulin action. Surprisingly, despite lower insulin resistance in the chronically obese NLRP3 and ASC knockout mice, the insulin levels were substantially higher when the inflammasome pathway was eliminated. The obesity-induced increase in maturation of pancreatic IL-1β and pancreatic islet fibrosis was dependent on the NLRP3 inflammasome activation. Furthermore, elimination of NLRP3 inflammasome protected the pancreatic β-cells from cell death caused by long-term high-fat feeding during obesity with significant increase in the size of the islets of Langerhans. Collectively, this study provides direct in vivo evidence that activation of the NLRP3 inflammasome in diet-induced obesity is a critical trigger in causing pancreatic damage and is an important mechanism of progression toward type 2 diabetes.

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