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Lei Y, Wang Y, Tang S, Yang J, Lai D, Qiu Q. The adaptive immune system in the retina of diabetics. Surv Ophthalmol 2025; 70:241-254. [PMID: 39566563 DOI: 10.1016/j.survophthal.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 11/07/2024] [Accepted: 11/13/2024] [Indexed: 11/22/2024]
Abstract
As the prevalence of diabetes mellitus increases each year, its most common microvascular complication, diabetic retinopathy (DR), is also on the rise. DR is now regarded as an inflammatory disease in which innate immunity plays a crucial role, and a large number of innate immune cells with associated cytokines are involved in the pathologic process of DR. The role of adaptive immunity in DR is seldom mentioned, probably due to the general perception of the immune privileged environment of the retina; however, in recent years there has been a gradual increase in research on the role of adaptive immunity in DR, and with the discovery of the retinal lymphatic system, it seems that the role of adaptive immunity can no longer be ignored. Here, we discuss the immunosuppressive environment of the retina, the phenomenon and potential mechanisms of lymphocyte infiltration in DR, and the role of the adaptive immune system in the diabetic retina, which may point the way for future research.
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Affiliation(s)
- Yiou Lei
- Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China
| | - Yani Wang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China
| | - Siao Tang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China
| | - Jiaqi Yang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China
| | - Dongwei Lai
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China.
| | - Qinghua Qiu
- Department of Ophthalmology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Poon F, Sambathkumar R, Korytnikov R, Aghazadeh Y, Oakie A, Misra PS, Sarangi F, Nostro MC. Tankyrase inhibition promotes endocrine commitment of hPSC-derived pancreatic progenitors. Nat Commun 2024; 15:8754. [PMID: 39384787 PMCID: PMC11464881 DOI: 10.1038/s41467-024-53068-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 09/27/2024] [Indexed: 10/11/2024] Open
Abstract
Human pluripotent stem cells (hPSCs) have the potential to differentiate into various cell types, including pancreatic insulin-producing β cells, which are crucial for developing therapies for diabetes. However, current methods for directing hPSC differentiation towards pancreatic β-like cells are often inefficient and produce cells that do not fully resemble the native counterparts. Here, we report that highly selective tankyrase inhibitors, such as WIKI4, significantly enhances pancreatic differentiation from hPSCs. Our results show that WIKI4 promotes the formation of pancreatic progenitors that give rise to islet-like cells with improved β-like cell frequencies and glucose responsiveness compared to our standard cultures. These findings not only advance our understanding of pancreatic development, but also provide a promising new tool for generating pancreatic cells for research and potential therapeutic applications.
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Affiliation(s)
- Frankie Poon
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada
- Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Sana Biotechnology, 300 Technology Square, Cambridge, MA, 02139, USA
| | - Rangarajan Sambathkumar
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada
- Allarta Life Science Inc., 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - Roman Korytnikov
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada
- Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Yasaman Aghazadeh
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada
- Montreal Clinical Research Institute (IRCM), University of Montreal, Department of Medicine, Montreal, H2W 1R7, QC, Canada
| | - Amanda Oakie
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada
| | - Paraish S Misra
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada
- Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Farida Sarangi
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada
| | - M Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada.
- Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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Yue M, He X, Min X, Yang H, Xu H, Wu W, Zhong J, Mei A, Chen J. The role of islet autoantigen-specific T cells in the onset and treatment of type 1 diabetes mellitus. Front Immunol 2024; 15:1462384. [PMID: 39380988 PMCID: PMC11458421 DOI: 10.3389/fimmu.2024.1462384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/02/2024] [Indexed: 10/10/2024] Open
Abstract
Type 1 diabetes mellitus (T1DM), a complex chronic disease with an intricate etiology and pathogenesis, involves the recognition of self-antigens by pancreatic islet autoantigen-specific T cells and plays crucial roles in both early- and late-stage destruction of beta cells, thus impacting disease progression. Antigen-specific T cells regulate and execute immune responses by recognizing particular antigens, playing broad roles in the treatment of various diseases. Immunotherapy targeting antigen-specific T cells holds promising potential as a targeted treatment approach. This review outlines the pathogenesis of diabetes, emphasizing the pivotal role of pancreatic islet autoantigen-specific T cells in the progression and treatment of T1DM. Exploring this avenue in research holds promise for identifying novel therapeutic targets for effectively managing diabetes.
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Affiliation(s)
- Mengmeng Yue
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Xianzhen He
- Children’s Medical Center, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xinwen Min
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Handong Yang
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Hao Xu
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Wenwen Wu
- School of Public Health, Hubei University of Medicine, Shiyan, Hubei, China
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Aihua Mei
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Jun Chen
- Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan, China
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Yang K, Zhang Y, Ding J, Li Z, Zhang H, Zou F. Autoimmune CD8+ T cells in type 1 diabetes: from single-cell RNA sequencing to T-cell receptor redirection. Front Endocrinol (Lausanne) 2024; 15:1377322. [PMID: 38800484 PMCID: PMC11116783 DOI: 10.3389/fendo.2024.1377322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 04/18/2024] [Indexed: 05/29/2024] Open
Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by pancreatic β cell destruction and mediated primarily by autoreactive CD8+ T cells. It has been shown that only a small number of stem cell-like β cell-specific CD8+ T cells are needed to convert normal mice into T1D mice; thus, it is likely that T1D can be cured or significantly improved by modulating or altering self-reactive CD8+ T cells. However, stem cell-type, effector and exhausted CD8+ T cells play intricate and important roles in T1D. The highly diverse T-cell receptors (TCRs) also make precise and stable targeted therapy more difficult. Therefore, this review will investigate the mechanisms of autoimmune CD8+ T cells and TCRs in T1D, as well as the related single-cell RNA sequencing (ScRNA-Seq), CRISPR/Cas9, chimeric antigen receptor T-cell (CAR-T) and T-cell receptor-gene engineered T cells (TCR-T), for a detailed and clear overview. This review highlights that targeting CD8+ T cells and their TCRs may be a potential strategy for predicting or treating T1D.
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Affiliation(s)
- Kangping Yang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yihan Zhang
- The Second Clinical Medicine School, Nanchang University, Nanchang, China
| | - Jiatong Ding
- The Second Clinical Medicine School, Nanchang University, Nanchang, China
| | - Zelin Li
- The First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Hejin Zhang
- The Second Clinical Medicine School, Nanchang University, Nanchang, China
| | - Fang Zou
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Li J, Yang Y, Xia Y, Luo S, Lin J, Xiao Y, Li X, Huang G, Yang L, Xie Z, Zhou Z. Effect of SIRT1 gene single-nucleotide polymorphisms on susceptibility to type 1 diabetes in a Han Chinese population. J Endocrinol Invest 2024; 47:819-826. [PMID: 37695462 DOI: 10.1007/s40618-023-02190-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 08/25/2023] [Indexed: 09/12/2023]
Abstract
AIMS SIRT1 deficiency has been associated with diabetes, and a variant of the SIRT1 gene has been found to be involved in human autoimmune diabetes; however, it is unclear whether this genetic variation exists in Han Chinese with type 1 diabetes (T1D) and whether it contributes to development of T1D. Therefore, we aimed to explore the association of the SIRT1 gene single-nucleotide polymorphisms (SNPs) rs10997866 and rs3818292 in a Han Chinese population with T1D. METHODS This study recruited 2653 unrelated Han Chinese individuals, of whom 1289 had T1D and 1364 were healthy controls. Allelic and genotypic distributions of SIRT1 polymorphisms (rs10997866 and rs3818292) were determined by MassARRAY. Basic characteristics, genotype and allele frequencies of selected SNPs were compared between the T1D patients and healthy controls. Further genotype-phenotype association analysis of the SNPs was performed on the T1D patients divided into three groups according to genotype. Statistical analyses included the chi-square test, Mann‒Whitney U test, Kruskal‒Wallis H test and logistic regression. RESULTS The allelic (G vs. A) and genotypic (GA vs. AA) distributions of SIRT1 rs10997866 were significantly different in T1D patients and healthy controls (P = 0.039, P = 0.027), and rs10997866 was associated with T1D susceptibility under dominant, overdominant and additive models (P = 0.026, P = 0.030 and P = 0.027, respectively). Moreover, genotype-phenotype association analysis showed the GG genotype of rs10997866 and the GG genotype of rs3818292 to be associated with higher titers of IA-2A (P = 0.013 and P = 0.038, respectively). CONCLUSION SIRT1 rs10997866 is significantly associated with T1D susceptibility, with the minor allele G conferring a higher risk of T1D. Moreover, SIRT1 gene rs10997866 and rs3818292 correlate with the titer of IA-2A in Han Chinese individuals with T1D.
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Affiliation(s)
- J Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Y Yang
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Y Xia
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - S Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - J Lin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Y Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - X Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - G Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - L Yang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Z Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
| | - Z Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes, Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
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Trevizol JS, Buzalaf NR, Dionizio A, Delgado AQ, de Lara JPZ, Magalhães AC, Bosqueiro JR, Buzalaf MAR. Adaptive responses of the ileum of NOD mice to low-dose fluoride: A proteomic exploratory study. Cell Biochem Funct 2024; 42:e3976. [PMID: 38489223 DOI: 10.1002/cbf.3976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/20/2024] [Accepted: 02/29/2024] [Indexed: 03/17/2024]
Abstract
Fluoride (F) has been employed worldwide to control dental caries. More recently, it has been suggested that the consumption of low doses of F in the drinking water may reduce blood glucose levels, introducing a new perspective for the use of F for the management of blood glucose. However, the exact mechanism by which F affects blood glucose levels remains largely unexplored. Given that the small gut plays a pivotal role in glucose homeostasis, the aim of this study was to investigate the proteomic changes induced by low doses of F in the ileum of female nonobese-diabetic (NOD) mice. Forty-two female NOD mice were divided into two groups based on the F concentration in their drinking water for 14 weeks: 0 (control) or 10 mgF/L. At the end of the experimental period, the ileum was collected for proteomic and Western blot analyses. Proteomic analysis indicated an increase in isoforms of actin, gastrotropin, several H2B histones, and enzymes involved in antioxidant processes, as well as a decrease in enzymes essential for energy metabolism. In summary, our data indicates an adaptive response of organism to preserve protein synthesis in the ileum, despite significant alterations in energy metabolism typically induced by F, therefore highlighting the safety of controlled fluoridation in water supplies.
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Affiliation(s)
- Juliana S Trevizol
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, Brazil
| | - Nathalia R Buzalaf
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, Brazil
| | - Aline Dionizio
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, Brazil
| | - Aislan Q Delgado
- Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - João P Z de Lara
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, Brazil
| | - Ana C Magalhães
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, Brazil
| | - José R Bosqueiro
- Department of Physical Education, Faculty of Science, São Paulo State University, Bauru, Brazil
| | - Marília A R Buzalaf
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, Brazil
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Montaser E, Brown SA, DeBoer MD, Farhy LS. Predicting the Risk of Developing Type 1 Diabetes Using a One-Week Continuous Glucose Monitoring Home Test With Classification Enhanced by Machine Learning: An Exploratory Study. J Diabetes Sci Technol 2024; 18:257-265. [PMID: 37946401 PMCID: PMC10973864 DOI: 10.1177/19322968231209302] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
BACKGROUND Detection of two or more autoantibodies (Ab) in the blood might describe those individuals at increased risk of developing type 1 diabetes (T1D) during the following years. The aim of this exploratory study is to propose a high versus low T1D risk classifier using machine learning technology based on continuous glucose monitoring (CGM) home data. METHODS Forty-two healthy relatives of people with T1D with mean ± SD age of 23.8 ± 10.5 years, HbA1c (glycated hemoglobin) of 5.3% ± 0.3%, and BMI (body mass index) of 23.2 ± 5.2 kg/m2 with zero (low risk; N = 21), and ≥2 (high risk; N = 21) Ab, were enrolled in an NIH (National Institutes of Health)-funded TrialNet ancillary study. Participants wore a CGM for a week and consumed three standardized liquid mixed meals (SLMM) instead of three breakfasts. Glycemic features were extracted from two-hour post-SLMM CGM traces, compared across groups, and used in four supervised machine learning Ab risk status classifiers. Recursive Feature Elimination (RFE) algorithm was used for feature selection; classifiers were evaluated through 10-fold cross-validation, using the receiver operating characteristic area under the curve (AUC-ROC) to select the best classification model. RESULTS The percent time of glucose >180 mg/dL (T180), glucose range, and glucose CV (coefficient of variation) were the only significant differences between the glycemic features in the two groups with P values of .040, .035, and .028 respectively. The linear SVM (Support Vector Machine) model with RFE features achieved the best performance of classifying low-risk versus high-risk individuals with AUC-ROC = 0.88. CONCLUSIONS A machine learning technology, combining a potentially self-administered one-week CGM home test, has the potential to reliably assess the T1D risk.
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Affiliation(s)
- Eslam Montaser
- Center for Diabetes Technology, School
of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Sue A. Brown
- Center for Diabetes Technology, School
of Medicine, University of Virginia, Charlottesville, VA, USA
- Division of Endocrinology and
Metabolism, Department of Medicine, School of Medicine, University of Virginia,
Charlottesville, VA, USA
| | - Mark D. DeBoer
- Center for Diabetes Technology, School
of Medicine, University of Virginia, Charlottesville, VA, USA
- Division of Pediatric Endocrinology,
Department of Pediatrics School of Medicine, University of Virginia,
Charlottesville, VA, USA
| | - Leon S. Farhy
- Center for Diabetes Technology, School
of Medicine, University of Virginia, Charlottesville, VA, USA
- Division of Endocrinology and
Metabolism, Department of Medicine, School of Medicine, University of Virginia,
Charlottesville, VA, USA
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YILDIRIM R, GÜNBEY C. Electroencephalographic abnormalities in children with type 1 diabetes mellitus: a prospective study. Turk J Med Sci 2023; 53:1794-1798. [PMID: 38813513 PMCID: PMC10760570 DOI: 10.55730/1300-0144.5749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 12/12/2022] [Accepted: 10/12/2023] [Indexed: 05/31/2024] Open
Abstract
Background/aim The aim herein was to investigate epileptiform discharges on electroencephalogram (EEG), their correlation with glutamic acid decarboxylase 65 autoantibody (GAD-ab) in newly diagnosed pediatric type 1 diabetes mellitus (T1DM) patients and interpret their medium-term utility in predicting epilepsy. Materials and methods Children presenting with T1DM between July 2018 and December 2019 were included in this prospective longitudinal study. Patients with a history of head injury, chronic illness, neurological disorder, seizure, autism, or encephalopathy were excluded. EEGs were obtained within the first 7 days of diagnosis and later reviewed by a pediatric neurologist. All of the children were clinically followed-up in pediatric endocrinology and neurology clinics for 2 years after their diagnosis. Results A total of 105 children (46 male, 43.8%) were included. The mean age at the time of diagnosis was 9.6 ± 4.1 years (range: 11 months-17.5 years). At the time of admission, 24 (22.9%), 29 (27.6%), and 52 (49.5%) patients had hyperglycemia, ketosis, and diabetic ketoacidosis, respectively. GAD-ab was positive in 55 children (52.4%). No background or sleep architecture abnormalities or focal slowing were present on the EEGs. Of the patients, 3 (2.9%) had focal epileptiform discharges. The mean GAD-ab levels of the remaining 102 patients were 7.48 ± 11.97 U/mL (range: 0.01-50.54) (p = 0.2). All 3 children with EEG abnormality had higher levels of GAD-ab (3.59 U/mL, 31.3 U/mL, and 7.09 U/mL, respectively). None of the patients developed epilepsy during the follow-up, although 1 patient experienced Guillain-Barré syndrome (GBS). Conclusion The prevalence of epileptiform discharges in the patients was similar to those of previous studies, in which healthy children were also included. No relationship was found between the epileptiform discharges and GAD-ab, and none of the patients manifested seizures during the first 2 years of follow-up of T1DM. These data support the findings of previous studies reporting that T1DM patients with confirmed electroencephalographic abnormalities do not have an increased risk of epilepsy. On the other hand, GBS might be considered as another autoimmune disease that may be associated with T1DM in children.
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Affiliation(s)
- Ruken YILDIRIM
- Department of Pediatric Endocrinology, Diyarbakır Children’s Hospital, Diyarbakır,
Turkiye
| | - Ceren GÜNBEY
- Department of Pediatric Neurology, Diyarbakır Children’s Hospital, Diyarbakır,
Turkiye
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9
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Trevizol JS, Dionizio A, Delgado AQ, Ventura TMO, Ribeiro CFDS, Ribeiro L, Buzalaf NR, Cestari TM, Magalhães AC, Suzuki M, Bosqueiro JR, Buzalaf MAR. Metabolic effect of low fluoride levels in the islets of NOD mice: integrative morphological, immunohistochemical, and proteomic analyses. J Appl Oral Sci 2023; 31:e20230036. [PMID: 37283331 PMCID: PMC10247282 DOI: 10.1590/1678-7757-2023-0036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/31/2023] [Accepted: 05/03/2023] [Indexed: 06/08/2023] Open
Abstract
OBJECTIVES Fluoride (F) has been widely used to control dental caries, and studies suggest beneficial effects against diabetes when a low dose of F is added to the drinking water (10 mgF/L). This study evaluated metabolic changes in pancreatic islets of NOD mice exposed to low doses of F and the main pathways altered by the treatment. METHODOLOGY In total, 42 female NOD mice were randomly divided into two groups, considering the concentration of F administered in the drinking water for 14 weeks: 0 or 10 mgF/L. After the experimental period, the pancreas was collected for morphological and immunohistochemical analysis, and the islets for proteomic analysis. RESULTS In the morphological and immunohistochemical analysis, no significant differences were found in the percentage of cells labelled for insulin, glucagon, and acetylated histone H3, although the treated group had higher percentages than the control group. Moreover, no significant differences were found for the mean percentages of pancreatic areas occupied by islets and for the pancreatic inflammatory infiltrate between the control and treated groups. Proteomic analysis showed large increases in histones H3 and, to a lesser extent, in histone acetyltransferases, concomitant with a decrease in enzymes involved in the formation of acetyl-CoA, besides many changes in proteins involved in several metabolic pathways, especially energy metabolism. The conjunction analysis of these data showed an attempt by the organism to maintain protein synthesis in the islets, even with the dramatic changes in energy metabolism. CONCLUSION Our data suggests epigenetic alterations in the islets of NOD mice exposed to F levels comparable to those found in public supply water consumed by humans.
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Affiliation(s)
- Juliana Sanches Trevizol
- Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Bauru, SP, Brasil
| | - Aline Dionizio
- Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Bauru, SP, Brasil
| | | | | | | | - Laura Ribeiro
- Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Bauru, SP, Brasil
| | - Nathalia Rabelo Buzalaf
- Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Bauru, SP, Brasil
| | - Tânia Mary Cestari
- Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Bauru, SP, Brasil
| | - Ana Carolina Magalhães
- Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Bauru, SP, Brasil
| | - Maiko Suzuki
- The Dental College of Georgia, Department of Oral Biology and Diagnostic Sciences, Augusta, Georgia, United States
| | - José Roberto Bosqueiro
- Universidade Estadual Paulista, Faculdade de Ciências, Departamento de Educação Física, Bauru, São Paulo, Brasil
| | - Marília Afonso Rabelo Buzalaf
- Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Bauru, SP, Brasil
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10
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Liu Y, Ping F, Yu J, Lv L, Zhao Y, Qi M, Li W, Xu L, Yu M, Li M, Zhang H, Li Y. Hypoglycemia Caused by Exogenous Insulin Antibody Syndrome: A Large Single-Center Case Series From China. J Clin Endocrinol Metab 2023; 108:713-717. [PMID: 36219196 DOI: 10.1210/clinem/dgac578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 09/10/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT Exogenous insulin antibody syndrome (EIAS) can lead to unexpected and potentially life-threatening recurrent hypoglycemia. OBJECTIVE We aimed to better define autoimmune hypoglycemia caused by EIAS in patients with diabetes and shed light on the improvements in the identification and intervention for this rare but possibly life-threatening condition. METHODS We summarized the clinical characteristics of autoimmune hypoglycemia caused by EIAS in 23 patients with diabetes. Furthermore, we performed human leukocyte antigen (HLA) genotyping of 10 patients. RESULTS We identified a high frequency of autoimmune comorbidities (21.7%), food or drug allergy (48%), insulin allergy (30%), lipodystrophy at the insulin injection sites (22%), and antinuclear antibodies (25%) in the patients. Alternation between hyperglycemia and hypoglycemia was observed in more than 90% of the patients. Most patients showed a high insulin autoantibody titer (>90%) and inappropriately increased insulin concentration (insulin/C-peptide molar ratio >7, >85%). We detected similar frequencies of DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 compared with previously reported frequencies in type 1 diabetes, and a lower frequency of DRB1*0406 compared with insulin autoimmune syndrome. The spontaneous remission rate exceeded 70%. CONCLUSION Predisposing factors for autoimmune hypoglycemia caused by EIAS include a strong autoimmune background. Susceptible HLA genotypes for type 1 diabetes or insulin autoimmune syndrome might not explain susceptibility to this condition. Additionally, insulin autoantibodies and the insulin/C-peptide molar ratio are reliable screening options. The prognosis for this condition is favorable. Monitoring of insulin and insulin autoantibodies may contribute to treatment effectiveness.
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Affiliation(s)
- Yiwen Liu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jie Yu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Lu Lv
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yuan Zhao
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Mengya Qi
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Miao Yu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Ming Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
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11
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Rodrigues Oliveira SM, Rebocho A, Ahmadpour E, Nissapatorn V, de Lourdes Pereira M. Type 1 Diabetes Mellitus: A Review on Advances and Challenges in Creating Insulin Producing Devices. MICROMACHINES 2023; 14:151. [PMID: 36677212 PMCID: PMC9867263 DOI: 10.3390/mi14010151] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/25/2022] [Accepted: 12/30/2022] [Indexed: 06/17/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is the most common autoimmune chronic disease in young patients. It is caused by the destruction of pancreatic endocrine β-cells that produce insulin in specific areas of the pancreas, known as islets of Langerhans. As a result, the body becomes insulin deficient and hyperglycemic. Complications associated with diabetes are life-threatening and the current standard of care for T1DM consists still of insulin injections. Lifesaving, exogenous insulin replacement is a chronic and costly burden of care for diabetic patients. Alternative therapeutic options have been the focus in these fields. Advances in molecular biology technologies and in microfabrication have enabled promising new therapeutic options. For example, islet transplantation has emerged as an effective treatment to restore the normal regulation of blood glucose in patients with T1DM. However, this technique has been hampered by obstacles, such as limited islet availability, extensive islet apoptosis, and poor islet vascular engraftment. Many of these unsolved issues need to be addressed before a potential cure for T1DM can be a possibility. New technologies like organ-on-a-chip platforms (OoC), multiplexed assessment tools and emergent stem cell approaches promise to enhance therapeutic outcomes. This review will introduce the disorder of type 1 diabetes mellitus, an overview of advances and challenges in the areas of microfluidic devices, monitoring tools, and prominent use of stem cells, and how they can be linked together to create a viable model for the T1DM treatment. Microfluidic devices like OoC platforms can establish a crucial platform for pathophysiological and pharmacological studies as they recreate the pancreatic environment. Stem cell use opens the possibility to hypothetically generate a limitless number of functional pancreatic cells. Additionally, the integration of stem cells into OoC models may allow personalized or patient-specific therapies.
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Affiliation(s)
- Sonia M. Rodrigues Oliveira
- HMRI-Hunter Medical Research Institute, New Lambton, NSW 2305, Australia
- CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - António Rebocho
- Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ehsan Ahmadpour
- Drug Applied Research Center, Department of Parasitology and Mycology, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
- Department of Parasitology and Mycology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
| | - Veeranoot Nissapatorn
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand
- School of Allied Health Sciences, Southeast Asia Water Team (SEAWater Team), World Union for Herbal Drug Discovery (WUHeDD), Research Excellence Center for Innovation and Health Products, Walailak University, Nakhon Si Thammarat 80160, Thailand
| | - Maria de Lourdes Pereira
- CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
- Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
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12
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Makam AA, Biswas A, Kothegala L, Gandasi NR. Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit? Biomedicines 2022; 10:2695. [PMID: 36359215 PMCID: PMC9687317 DOI: 10.3390/biomedicines10112695] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/07/2022] [Accepted: 10/19/2022] [Indexed: 02/06/2025] Open
Abstract
Type-1-diabetes (T1D) is a multifactorial disorder with a global incidence of about 8.4 million individuals in 2021. It is primarily classified as an autoimmune disorder, where the pancreatic β-cells are unable to secrete sufficient insulin. This leads to elevated blood glucose levels (hyperglycemia). The development of T1D is an intricate interplay between various risk factors, such as genetic, environmental, and cellular elements. In this review, we focus on the cellular elements, such as ER (endoplasmic reticulum) stress and its consequences for T1D pathogenesis. One of the major repercussions of ER stress is defective protein processing. A well-studied example is that of islet amyloid polypeptide (IAPP), which is known to form cytotoxic amyloid plaques when misfolded. This review discusses the possible association between ER stress, IAPP, and amyloid formation in β-cells and its consequences in T1D. Additionally, ER stress also leads to autoantigen generation. This is driven by the loss of Ca++ ion homeostasis. Imbalanced Ca++ levels lead to abnormal activation of enzymes, causing post-translational modification of β-cell proteins. These modified proteins act as autoantigens and trigger the autoimmune response seen in T1D islets. Several of these autoantigens are also crucial for insulin granule biogenesis, processing, and release. Here, we explore the possible associations between ER stress leading to defects in insulin secretion and ultimately β-cell destruction.
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Affiliation(s)
- Aishwarya A. Makam
- Cell metabolism Lab (GA-08), Department of Molecular Reproduction, Development and Genetics (MRDG), Indian Institute of Science (IISc), Bengaluru 560012, India
| | - Anusmita Biswas
- Cell metabolism Lab (GA-08), Department of Molecular Reproduction, Development and Genetics (MRDG), Indian Institute of Science (IISc), Bengaluru 560012, India
| | - Lakshmi Kothegala
- Cell metabolism Lab (GA-08), Department of Molecular Reproduction, Development and Genetics (MRDG), Indian Institute of Science (IISc), Bengaluru 560012, India
- Unit of Metabolic Physiology, University of Gothenburg, 405 30 Gothenburg, Sweden
| | - Nikhil R. Gandasi
- Cell metabolism Lab (GA-08), Department of Molecular Reproduction, Development and Genetics (MRDG), Indian Institute of Science (IISc), Bengaluru 560012, India
- Unit of Metabolic Physiology, University of Gothenburg, 405 30 Gothenburg, Sweden
- Department of Medical Cell Biology, Uppsala University, BMC 571, 751 23 Uppsala, Sweden
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13
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Pang H, Lin J, Luo S, Huang G, Li X, Xie Z, Zhou Z. The missing heritability in type 1 diabetes. Diabetes Obes Metab 2022; 24:1901-1911. [PMID: 35603907 PMCID: PMC9545639 DOI: 10.1111/dom.14777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/04/2022] [Accepted: 05/17/2022] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) is a complex autoimmune disease characterized by an absolute deficiency of insulin. It affects more than 20 million people worldwide and imposes an enormous financial burden on patients. The underlying pathogenic mechanisms of T1D are still obscure, but it is widely accepted that both genetics and the environment play an important role in its onset and development. Previous studies have identified more than 60 susceptible loci associated with T1D, explaining approximately 80%-85% of the heritability. However, most identified variants confer only small increases in risk, which restricts their potential clinical application. In addition, there is still a so-called 'missing heritability' phenomenon. While the gap between known heritability and true heritability in T1D is small compared with that in other complex traits and disorders, further elucidation of T1D genetics has the potential to bring novel insights into its aetiology and provide new therapeutic targets. Many hypotheses have been proposed to explain the missing heritability, including variants remaining to be found (variants with small effect sizes, rare variants and structural variants) and interactions (gene-gene and gene-environment interactions; e.g. epigenetic effects). In the following review, we introduce the possible sources of missing heritability and discuss the existing related knowledge in the context of T1D.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jian Lin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
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Fuentes P, Torres MJ, Arancibia R, Aulestia F, Vergara M, Carrión F, Osses N, Altamirano C. Dynamic Culture of Mesenchymal Stromal/Stem Cell Spheroids and Secretion of Paracrine Factors. Front Bioeng Biotechnol 2022; 10:916229. [PMID: 36046670 PMCID: PMC9421039 DOI: 10.3389/fbioe.2022.916229] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
In recent years, conditioned medium (CM) obtained from the culture of mesenchymal stromal/stem cells (MSCs) has been shown to effectively promote tissue repair and modulate the immune response in vitro and in different animal models, with potential for application in regenerative medicine. Using CM offers multiple advantages over the implantation of MSCs themselves: 1) simpler storage, transport, and preservation requirements, 2) avoidance of the inherent risks of cell transplantation, and 3) potential application as a ready-to-go biologic product. For these reasons, a large amount of MSCs research has focused on the characterization of the obtained CM, including soluble trophic factors and vesicles, preconditioning strategies for enhancing paracrine secretion, such as hypoxia, a three-dimensional (3D) environment, and biochemical stimuli, and potential clinical applications. In vitro preconditioning strategies can increase the viability, proliferation, and paracrine properties of MSCs and therefore improve the therapeutic potential of the cells and their derived products. Specifically, dynamic cultivation conditions, such as fluid flow and 3D aggregate culture, substantially impact cellular behaviour. Increased levels of growth factors and cytokines were observed in 3D cultures of MSC grown on orbital or rotatory shaking platforms, in stirred systems, such as spinner flasks or stirred tank reactors, and in microgravity bioreactors. However, only a few studies have established dynamic culture conditions and protocols for 3D aggregate cultivation of MSCs as a scalable and reproducible strategy for CM production. This review summarizes significant advances into the upstream processing, mainly the dynamic generation and cultivation of MSC aggregates, for de CM manufacture and focuses on the standardization of the soluble factor production.
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Affiliation(s)
- Paloma Fuentes
- Escuela de Ingeniería Bioquímica, Facultad de Ingeniería, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - María José Torres
- Escuela de Ingeniería Bioquímica, Facultad de Ingeniería, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Rodrigo Arancibia
- Cellus Medicina Regenerativa S.A., Santiago, Chile
- Cellus Biomédica, Parque Tecnológico de León, León, Spain
| | - Francisco Aulestia
- Cellus Medicina Regenerativa S.A., Santiago, Chile
- Cellus Biomédica, Parque Tecnológico de León, León, Spain
| | - Mauricio Vergara
- Escuela de Ingeniería Bioquímica, Facultad de Ingeniería, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Flavio Carrión
- Cellus Medicina Regenerativa S.A., Santiago, Chile
- Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile
| | - Nelson Osses
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Claudia Altamirano
- Escuela de Ingeniería Bioquímica, Facultad de Ingeniería, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
- CREAS, Centro Regional de Estudios en Alimentos Saludables, Valparaíso, Chile
- *Correspondence: Claudia Altamirano,
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Winiarska-Mieczan A, Tomaszewska E, Donaldson J, Jachimowicz K. The Role of Nutritional Factors in the Modulation of the Composition of the Gut Microbiota in People with Autoimmune Diabetes. Nutrients 2022; 14:2498. [PMID: 35745227 PMCID: PMC9227140 DOI: 10.3390/nu14122498] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 12/14/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a disease marked by oxidative stress, chronic inflammation, and the presence of autoantibodies. The gut microbiota has been shown to be involved in the alleviation of oxidative stress and inflammation as well as strengthening immunity, thus its' possible involvement in the pathogenesis of T1DM has been highlighted. The goal of the present study is to analyze information on the relationship between the structure of the intestinal microbiome and the occurrence of T1DM. The modification of the intestinal microbiota can increase the proportion of SCFA-producing bacteria, which could in turn be effective in the prevention and/or treatment of T1DM. The increased daily intake of soluble and non-soluble fibers, as well as the inclusion of pro-biotics, prebiotics, herbs, spices, and teas that are sources of phytobiotics, in the diet, could be important in improving the composition and activity of the microbiota and thus in the prevention of metabolic disorders. Understanding how the microbiota interacts with immune cells to create immune tolerance could enable the development of new therapeutic strategies for T1DM and improve the quality of life of people with T1DM.
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Affiliation(s)
- Anna Winiarska-Mieczan
- Department of Bromatology and Nutrition Physiology, Institute of Animal Nutrition and Bromatology, University of Life Sciences in Lublin, Akademicka St. 13, 20-950 Lublin, Poland;
| | - Ewa Tomaszewska
- Department of Animal Physiology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka St. 12, 20-950 Lublin, Poland
| | - Janine Donaldson
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa;
| | - Karolina Jachimowicz
- Department of Bromatology and Nutrition Physiology, Institute of Animal Nutrition and Bromatology, University of Life Sciences in Lublin, Akademicka St. 13, 20-950 Lublin, Poland;
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Zaccaron RP, Barbieri RT, Mendes C, Venturini LM, Alves N, Mariano SDS, de Andrade TAM, Hermes de Araújo PH, Feuser PE, Thirupathi A, Machado-de-Ávila RA, Lock Silveira PC. Photobiomodulation associated with lipid nanoparticles and hyaluronic acid accelerate the healing of excisional wounds. J Biomater Appl 2022; 37:668-682. [PMID: 35705485 DOI: 10.1177/08853282221109344] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objectives: This article aimed to investigate the effects of the association between photobiomodulation and hyaluronic acid incorporated in lipid nanoparticles in an epithelial lesion model in inflammatory parameters and oxidative stress. Methods: Eighty Wistar rats were randomly assigned to the following groups: epithelial lesion group (EL); EL+PBM; EL+HA; EL+SLNs; EL+SLNs-HA; EL+PBM+HA; EL+PBM+SLNs; EL+PBM+SLNs-HA. The animals were anesthetized with 4% isofluorane after shaving and induced to an epithelial lesion. Topical treatment with a gel containing HA (0.9%) and/or SLNs (10 mg/mL) and with laser irradiation occurred daily for 1 week. Results: The results showed an increase in wound contraction on the seventh day in the LE + LBM + AH-NPL group, a reduction in pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), an increase in anti-inflammatory cytokines (IL- 4 and IL-10) and TGF-β. The levels of pro-inflammatory cytokine IL-4 and TGF-β also showed an increase in the LE + NPL-AH, LE + FBM + AH, LE + FBM + NPL and LE + FBM + NPL-AH groups. Regarding oxidative stress parameters, the levels of DCF and nitrite decreased in the combined therapy group when compared to the control group, as well as oxidative damage (carbonyl and sulfhydryl). In the antioxidant defense, there was an increase in GSH and SOD in the combination therapy group. Histological analysis showed a reduction in inflammatory infiltrate in the combination therapy group. The number of fibroblasts and the compaction of collagen fibers did not obtain significant responses. Conclusions: Results analyzed together showed that the combined therapy favored the repair process, and that studies can be carried out to enhance the histological analysis therapy favored the tissue repair process and that studies can be carried out to enhance the histological analysis.
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Affiliation(s)
- Rubya Pereira Zaccaron
- Laboratory of Experimental Phisiopatology, Program of postgraduate in Science of Health, 97853Universidade do Extremo Sul Catarinense, Criciúma, Brazil
| | - Rusilania Tozi Barbieri
- Laboratory of Experimental Phisiopatology, Program of postgraduate in Science of Health, 97853Universidade do Extremo Sul Catarinense, Criciúma, Brazil
| | - Carolini Mendes
- Laboratory of Experimental Phisiopatology, Program of postgraduate in Science of Health, 97853Universidade do Extremo Sul Catarinense, Criciúma, Brazil
| | - Ligia Milanez Venturini
- Laboratory of Experimental Phisiopatology, Program of postgraduate in Science of Health, 97853Universidade do Extremo Sul Catarinense, Criciúma, Brazil
| | - Naiara Alves
- Graduate Program of Biomedical Science, Herminio Ometto Foundation, Araras-SP, Brazil
| | | | | | | | - Paulo Emílio Feuser
- Laboratory of Experimental Phisiopatology, Program of postgraduate in Science of Health, 97853Universidade do Extremo Sul Catarinense, Criciúma, Brazil.,Department of Chemical Engineering and Food Engineering, 28117Federal University of Santa Catarina, Florianopolis, Brazil
| | - Anand Thirupathi
- Faculty of Sports Science, 47862Ningbo University, Ningbo, China
| | - Ricardo Andrez Machado-de-Ávila
- Laboratory of Experimental Phisiopatology, Program of postgraduate in Science of Health, 97853Universidade do Extremo Sul Catarinense, Criciúma, Brazil
| | - Paulo Cesar Lock Silveira
- Laboratory of Experimental Phisiopatology, Program of postgraduate in Science of Health, 97853Universidade do Extremo Sul Catarinense, Criciúma, Brazil
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Pang H, Fan W, Shi X, Li J, Wang Y, Luo S, Lin J, Huang G, Li X, Xie Z, Zhou Z. Characterization of lncRNA Profiles of Plasma-Derived Exosomes From Type 1 Diabetes Mellitus. Front Endocrinol (Lausanne) 2022; 13:822221. [PMID: 35634499 PMCID: PMC9135040 DOI: 10.3389/fendo.2022.822221] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/28/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUNDS Exosomes contain several types of transcripts, including long non-coding RNAs (lncRNAs), and have been shown to exert important effects in human diseases. However, the roles of exosomal lncRNAs in type 1 diabetes mellitus (T1DM) have not been well investigated. In the present study, we characterized the plasma-derived exosomal lncRNAs expression profiles of T1DM and predict their potential function in the pathogenesis of T1DM. MATERIAL AND METHODS Exosomal lncRNA expression profiles were detected by Illumina Hiseq platform (T1DM subjects N=10; age-, sex- matched Control subjects N=10). Six exosomal lncRNAs were selected to validate their expression level by using quantitative real-time PCR (qRT-PCR) (T1DM subjects N=30; age-, sex- matched Control subjects N=30). Bioinformatics analysis approaches were carried out to explore the potential biological function of differentially expressed lncRNAs. RESULTS A total of 162 differentially expressed exosomal lncRNAs were identified in T1DM patients compared with control subjects, among which 77 up-regulated and 85 down-regulated. The expression level of the selected six lncRNAs didn't show significant difference in the following qRT-PCR analysis. Gene Ontology analysis enriched terms such as activation of phospholipase D activity, neuronal cell body membrane, and calcium sensitive guanylate cyclase activator activity for cis-acting genes of lncRNAs, and metal ion binding for trans-acting genes. The most enriched Kyoto Encyclopedia of Genes and Genomes pathways for the lncRNAs were associated with oxidative phosphorylation and Parkinson's disease for cis-acting genes, and pathways in cancer as well as focal adhesion for trans-acting genes. CONCLUSIONS This study characterized the lncRNA profiles of plasma-derived exosomes from T1DM for the first time and these results highlighted the potential role of exosomal lncRNAs in T1DM pathogenesis. A better understanding of exosomal lncRNA profiling will provide novel insights into its molecular mechanisms.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Streptozotocin-Induced Diabetes Causes Changes in Serotonin-Positive Neurons in the Small Intestine in Pig Model. Int J Mol Sci 2022; 23:ijms23094564. [PMID: 35562954 PMCID: PMC9099899 DOI: 10.3390/ijms23094564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/19/2022] [Accepted: 04/19/2022] [Indexed: 12/03/2022] Open
Abstract
Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter of the central and peripheral nervous systems, predominantly secreted in the gastrointestinal tract, especially in the gut. 5-HT is a crucial enteric signaling molecule and is well known for playing a key role in sensory-motor and secretory functions in the gut. Gastroenteropathy is one of the most clinical problems in diabetic patients with frequent episodes of hyperglycemia. Changes in 5-HT expression may mediate gastrointestinal tract disturbances seen in diabetes, such as nausea and diarrhea. Based on the double immunohistochemical staining, this study determined the variability in the population of 5-HT-positive neurons in the porcine small intestinal enteric neurons in the course of streptozotocin-induced diabetes. The results show changes in the number of 5-HT-positive neurons in the examined intestinal sections. The greatest changes were observed in the jejunum, particularly within the myenteric plexus. In the ileum, both de novo 5-HT synthesis in the inner submucosal plexus neurons and an increase in the number of neurons in the outer submucosal plexus were noted. The changes observed in the duodenum were also increasing in nature. The results of the current study confirm the previous observations concerning the involvement of 5-HT in inflammatory processes, and an increase in the number of 5-HT -positive neurons may also be a result of increased concentration of the 5-HT in the gastrointestinal tract wall and affects the motor and secretory processes, which are particularly intense in the small intestines.
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Zhu M, Wu J, Gao JQ. Exosomes for diabetes syndrome: ongoing applications and perspective. Biomater Sci 2022; 10:2154-2171. [DOI: 10.1039/d2bm00161f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Diabetes mellitus, ranking the ninth death cause in the world, is a kind of metabolic disease characterized by hyperglycemia. Without timely and effective treatment, many ensuing complications involved with heart,...
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Sun X, Xu L, Xia Y, Luo S, Lin J, Xiao Y, Huang G, Li X, Xie Z, Zhou Z. rs3806265 and rs4612666 of the NLRP3 Gene Are Associated With the Titer of Glutamic Acid Decarboxylase Antibody in Type 1 Diabetes. Front Endocrinol (Lausanne) 2022; 13:835054. [PMID: 35528000 PMCID: PMC9068986 DOI: 10.3389/fendo.2022.835054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND AND AIMS The NLRP3 gene is reportedly associated with several autoimmune diseases. However, in the Chinese Han population, whether NLRP3 polymorphisms are associated with type 1 diabetes (T1D) is unclear. Therefore, this study examined the associations of rs3806265 and rs4612666 of the NLRP3 gene with T1D susceptibility and the clinical characteristics of Chinese Han T1D patients. METHODS In total, 510 classic T1D patients and 531 healthy controls from the Chinese Han population were recruited for a case-control study. rs3806265 and rs4612666 of the NLRP3 gene were genotyped by MassARRAY. Logistic regression analysis and the chi-square test were used to compare the distributions of the alleles and genotypes of rs3806265 and rs4612666. The relationships between rs3806265 and rs4612666 and the clinical characteristics of T1D patients were analyzed by Kruskal-Wallis one-way ANOVA. Student's t test was used to analyze normally distributed data. Bonferroni correction was used for multiple comparisons. RESULTS 1) rs3806265 was associated with glutamic acid decarboxylase antibody (GADA) titers (P = 0.02), and patients with the CC genotype had higher GADA titers than patients with the TT genotype. 2) rs4612666 was also associated with GADA titers (P=0.041). Compared with patients with the CC genotype, patients with the TT genotype had higher GADA titers. 3) rs3806265 and rs4612666 of the NLRP3 gene were not significantly associated with T1D susceptibility under different genetic models. CONCLUSION rs3806265 and rs4612666 of the NLRP3 gene were significantly associated with GADA titers in Chinese Han T1D patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Zhiguo Xie
- *Correspondence: Zhiguang Zhou, ; Zhiguo Xie,
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Houeiss P, Luce S, Boitard C. Environmental Triggering of Type 1 Diabetes Autoimmunity. Front Endocrinol (Lausanne) 2022; 13:933965. [PMID: 35937815 PMCID: PMC9353023 DOI: 10.3389/fendo.2022.933965] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/20/2022] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic islet β cells are destroyed by immune cells, ultimately leading to overt diabetes. The progressive increase in T1D incidence over the years points to the role of environmental factors in triggering or accelerating the disease process which develops on a highly multigenic susceptibility background. Evidence that environmental factors induce T1D has mostly been obtained in animal models. In the human, associations between viruses, dietary habits or changes in the microbiota and the development of islet cell autoantibodies or overt diabetes have been reported. So far, prediction of T1D development is mostly based on autoantibody detection. Future work should focus on identifying a causality between the different environmental risk factors and T1D development to improve prediction scores. This should allow developing preventive strategies to limit the T1D burden in the future.
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Affiliation(s)
- Pamela Houeiss
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Sandrine Luce
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Christian Boitard
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
- *Correspondence: Christian Boitard,
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Li J, Sun X, Luo S, Lin J, Xiao Y, Yu H, Huang G, Li X, Xie Z, Zhou Z. The Positivity Rate of IA-2A and ZnT8A in the Chinese Han Population With Type 1 Diabetes Mellitus: Association With rs1143627 and rs1143643 Polymorphisms in the IL1B Gene. Front Pharmacol 2021; 12:729890. [PMID: 34867336 PMCID: PMC8636020 DOI: 10.3389/fphar.2021.729890] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Objective: To investigate the association between susceptibility to type 1 diabetes mellitus (T1DM) and polymorphisms (rs1143627 and rs1143643) in the interleukin 1 beta (IL1B) gene in the Chinese Han population. Methods: The Meso Scale Discovery (MSD) method was used to detect the concentration of IL-1β in 24 T1DM patients and 27 healthy controls. MassARRAY was used to analyze the polymorphisms in the IL1B gene in 510 patients with classic T1DM and 531 healthy controls. The general data of the T1DM patients and healthy controls were compared by the chi-square test and Mann-Whitney U test. The chi-square test and logistic regression were used to analyze the frequency distributions of alleles and genotypes of polymorphisms in the IL1B gene. The Kruskal-Wallis H test and chi-square test were used for the genotype-phenotype analysis of rs1143627 and rs1143643 in the IL1B gene. Results: ① The concentration of IL-1β in T1DM patients was significantly higher than that in healthy controls. ② rs1143627 and rs1143643 in the IL1B gene were significantly correlated with the positivity rates for IA-2A and ZnT8A; genotype GG at rs1143627 and genotype CC at rs1143643 in the case group showed lower positivity rates for IA-2A and ZnT8A. ③ There was no significant difference in the genotypes or allele frequencies at rs1143627 (GG/GA/AA) or rs1143643 (CC/CT/TT) between the case group and control group (p > 0.05). ④ rs1143627 and rs1143643 were not found to be linked to T1DM susceptibility under different genetic models. Conclusion: rs1143627 and rs1143643 in the IL1B gene correlate with the positivity rate of IA-2A and ZnT8A in Chinese Han individuals with T1DM.
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Affiliation(s)
- Jiaqi Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiaoxiao Sun
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jian Lin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Haibo Yu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Pang H, Luo S, Huang G, Li X, Xie Z, Zhou Z. The Association of CTLA-4 rs231775 and rs3087243 Polymorphisms with Latent Autoimmune Diabetes in Adults: A Meta-Analysis. Biochem Genet 2021; 60:1222-1235. [PMID: 34822071 DOI: 10.1007/s10528-021-10152-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 11/03/2021] [Indexed: 12/13/2022]
Abstract
Polymorphisms rs231775 and rs3087243 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene have been associated with risk of latent autoimmune diabetes in adults (LADA). However, the results were inconsistent. The purpose of this study was to quantitatively assess the relationship between polymorphisms rs231775 and rs3087243 of CTLA-4 and LADA in a larger pooled population by performing a meta-analysis. Systematic search for eligible studies was conducted in PubMed, Web of Science, and Embase. Case-control studies containing genotype frequencies of polymorphisms rs231775 or rs3087243 were selected, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between polymorphisms of CTLA-4 and LADA in allelic, dominant and recessive genetic model. A total of eleven studies, in which five studies reported rs231775, two studies reported rs3087342, and four studies reported both rs231775 and rs3087243, were identified. Among them, one study wasn't included in the following meta-analysis because the distribution of genotypes in the control group didn't comply with Hardy-Weinberg equilibrium. Significant associations with susceptibility to LADA were detected for rs231775 (785 cases and 3435 controls) and for rs3087243 (820 cases and 4824 controls) in overall population. Further subgroup analyses for ethnicity (Asian, Caucasian, and African) have also indicated the positive association between rs231775 and LADA. As for rs3087243, subgroup analyses detected the association between polymorphism and LADA in Caucasian population under recessive model. Polymorphisms rs231775 and rs3087243 of CTLA-4 gene are potential risk factors for LADA and may serve as novel genetic biomarkers of LADA.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
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Li J, Li L, Wang Y, Huang G, Li X, Xie Z, Zhou Z. Insights Into the Role of DNA Methylation in Immune Cell Development and Autoimmune Disease. Front Cell Dev Biol 2021; 9:757318. [PMID: 34790667 PMCID: PMC8591242 DOI: 10.3389/fcell.2021.757318] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/07/2021] [Indexed: 12/26/2022] Open
Abstract
To date, nearly 100 autoimmune diseases have been an area of focus, and these diseases bring health challenges to approximately 5% of the population worldwide. As a type of disease caused by tolerance breakdown, both environmental and genetic risk factors contribute to autoimmune disease development. However, in most cases, there are still gaps in our understanding of disease pathogenesis, diagnosis, and treatment. Therefore, more detailed knowledge of disease pathogenesis and potential therapies is indispensable. DNA methylation, which does not affect the DNA sequence, is one of the key epigenetic silencing mechanisms and has been indicated to play a key role in gene expression regulation and to participate in the development of certain autoimmune diseases. Potential epigenetic regulation via DNA methylation has garnered more attention as a disease biomarker in recent years. In this review, we clarify the basic function and distribution of DNA methylation, evaluate its effects on gene expression and discuss related key enzymes. In addition, we summarize recent aberrant DNA methylation modifications identified in the most important cell types related to several autoimmune diseases and then provide potential directions for better diagnosing and monitoring disease progression driven by epigenetic control, which may broaden our understanding and contribute to further epigenetic research in autoimmune diseases.
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Affiliation(s)
- Jiaqi Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lifang Li
- Department of Ultrasound, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yimeng Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Winiarska-Mieczan A, Tomaszewska E, Jachimowicz K. Antioxidant, Anti-Inflammatory, and Immunomodulatory Properties of Tea-The Positive Impact of Tea Consumption on Patients with Autoimmune Diabetes. Nutrients 2021; 13:nu13113972. [PMID: 34836227 PMCID: PMC8625657 DOI: 10.3390/nu13113972] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 01/08/2023] Open
Abstract
The physiological markers of autoimmune diabetes include functional disorders of the antioxidative system as well as progressing inflammation and the presence of autoantibodies. Even though people with type 1 diabetes show genetic predispositions facilitating the onset of the disease, it is believed that dietary factors can stimulate the initiation and progression of the disease. This paper analyses the possibility of using tea as an element of diet therapy in the treatment of type 1 diabetes. Based on information available in literature covering the last 10 years, the impact of regular tea consumption or diet supplements containing tea polyphenols on the oxidative status as well as inflammatory and autoimmune response of the organism was analyzed. Studies conducted on laboratory animals, human patients, and in vitro revealed positive effects of the consumption of tea or polyphenols isolated therefrom on the diabetic body. Few reports available in the literature pertain to the impact of tea on organisms affected by type 1 diabetes as most (over 85%) have focused on cases of type 2 diabetes. It has been concluded that by introducing tea into the diet, it is possible to alleviate some of the consequences of oxidative stress and inflammation, thus limiting their destructive impact on the patients' organisms, consequently improving their quality of life, regardless of the type of diabetes. Furthermore, elimination of inflammation should reduce the incidence of immune response. One should consider more widespread promotion of tea consumption by individuals genetically predisposed to diabetes, especially considering the drink's low price, easy availability, overall benefits to human health, and above all, the fact that it can be safely used over extended periods of time, regardless of the patient's age.
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Affiliation(s)
- Anna Winiarska-Mieczan
- Institute of Animal Nutrition and Bromatology, University of Life Sciences in Lublin, Akademicka St. 13, 20-950 Lublin, Poland;
- Correspondence: (A.W.-M.); (E.T.); Tel.: +48-81-445-67-44 (A.W.-M.); +48-81-445-69-63 (E.T.)
| | - Ewa Tomaszewska
- Department of Animal Physiology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka St. 12, 20-950 Lublin, Poland
- Correspondence: (A.W.-M.); (E.T.); Tel.: +48-81-445-67-44 (A.W.-M.); +48-81-445-69-63 (E.T.)
| | - Karolina Jachimowicz
- Institute of Animal Nutrition and Bromatology, University of Life Sciences in Lublin, Akademicka St. 13, 20-950 Lublin, Poland;
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Pang H, Sun X, Luo S, Lin J, Shi X, Xiao Y, Huang G, Li X, Xie Z, Zhou Z. The polymorphism of the CARD8 inflammasome-related gene is associated with glutamic-acid-decarboxylase-antibody positivity in patients with type 1 diabetes mellitus. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1131. [PMID: 34430572 PMCID: PMC8350628 DOI: 10.21037/atm-21-1126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/17/2021] [Indexed: 11/20/2022]
Abstract
Background This study sought to examine the correlation between 2 single-nucleotide polymorphisms (SNPs; rs10403848 and rs2043211) in the caspase recruitment domain-containing protein 8 (CARD8) gene and the risks and clinical features of patients with type 1 diabetes mellitus (T1DM) in the Han Chinese population. Methods A case-control study involving the Han Chinese population was designed, and individuals diagnosed with classical T1DM and healthy controls were enrolled in this study. MassARRAY genotyped the SNPs of rs10403848 and rs2043211. Logistic regression and chi-square analyses were conducted to compare the allele distributions and genotypes of the T1DM and healthy control participants. A Kruskal-Wallis 1-way analysis of variance was used to perform the genotype-phenotype analysis for the T1DM patients. Results In total, 510 participants with classical T1DM and 531 sex-matched healthy control participants participated in this study. The CARD8 SNP of rs2043211 was significantly associated with the rate of glutamic-acid-decarboxylase-antibody (GADA) positivity among T1DM patients (P=0.021). However, no significant differences in the distributions of alleles or the genotypes of rs10403848 and rs2043211 were observed between the case and control groups, and these 2 SNPs were not associated with T1DM under various inheritance models. Conclusions The rs10403848 and rs2043211 polymorphisms of CARD8 were not associated with susceptibility to T1DM. However, rs2043211 was found to be correlated with GADA positivity in participants with T1DM.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiaoxiao Sun
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jian Lin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiajie Shi
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Bauer W, Gyenesei A, Krętowski A. The Multifactorial Progression from the Islet Autoimmunity to Type 1 Diabetes in Children. Int J Mol Sci 2021; 22:7493. [PMID: 34299114 PMCID: PMC8305179 DOI: 10.3390/ijms22147493] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/04/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022] Open
Abstract
Type 1 Diabetes (T1D) results from autoimmune destruction of insulin producing pancreatic ß-cells. This disease, with a peak incidence in childhood, causes the lifelong need for insulin injections and necessitates careful monitoring of blood glucose levels. However, despite the current insulin therapies, it still shortens life expectancy due to complications affecting multiple organs. Recently, the incidence of T1D in childhood has increased by 3-5% per year in most developed Western countries. The heterogeneity of the disease process is supported by the findings of follow-up studies started early in infancy. The development of T1D is usually preceded by the appearance of autoantibodies targeted against antigens expressed in the pancreatic islets. The risk of T1D increases significantly with an increasing number of positive autoantibodies. The order of autoantibody appearance affects the disease risk. Genetic susceptibility, mainly defined by the human leukocyte antigen (HLA) class II gene region and environmental factors, is important in the development of islet autoimmunity and T1D. Environmental factors, mainly those linked to the changes in the gut microbiome as well as several pathogens, especially viruses, and diet are key modulators of T1D. The aim of this paper is to expand the understanding of the aetiology and pathogenesis of T1D in childhood by detailed description and comparison of factors affecting the progression from the islet autoimmunity to T1D in children.
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Affiliation(s)
- Witold Bauer
- Clinical Research Centre, Medical University of Białystok, Marii Skłodowskiej-Curie 24a, 15-276 Białystok, Poland; (A.G.); (A.K.)
| | - Attila Gyenesei
- Clinical Research Centre, Medical University of Białystok, Marii Skłodowskiej-Curie 24a, 15-276 Białystok, Poland; (A.G.); (A.K.)
- Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, 7624 Pécs, Hungary
| | - Adam Krętowski
- Clinical Research Centre, Medical University of Białystok, Marii Skłodowskiej-Curie 24a, 15-276 Białystok, Poland; (A.G.); (A.K.)
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Białystok, Marii Skłodowskiej-Curie 24a, 15-276 Białystok, Poland
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Sun ZY, Yu TY, Jiang FX, Wang W. Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes. World J Stem Cells 2021; 13:193-207. [PMID: 33815669 PMCID: PMC8006013 DOI: 10.4252/wjsc.v13.i3.193] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/19/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.
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Affiliation(s)
- Zi-Yi Sun
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Ting-Yan Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Fang-Xu Jiang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Wei Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China.
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Pang H, Xia Y, Luo S, Huang G, Li X, Xie Z, Zhou Z. Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus. J Med Genet 2021; 58:289-296. [PMID: 33753534 PMCID: PMC8086251 DOI: 10.1136/jmedgenet-2020-107350] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 01/06/2021] [Accepted: 01/10/2021] [Indexed: 12/12/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%–85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ying Xia
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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Volfson-Sedletsky V, Jones A, Hernandez-Escalante J, Dooms H. Emerging Therapeutic Strategies to Restore Regulatory T Cell Control of Islet Autoimmunity in Type 1 Diabetes. Front Immunol 2021; 12:635767. [PMID: 33815387 PMCID: PMC8015774 DOI: 10.3389/fimmu.2021.635767] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/02/2021] [Indexed: 12/15/2022] Open
Abstract
Despite many decades of investigation uncovering the autoimmune mechanisms underlying Type 1 Diabetes (T1D), translating these findings into effective therapeutics has proven extremely challenging. T1D is caused by autoreactive T cells that become inappropriately activated and kill the β cells in the pancreas, resulting in insulin insufficiency and hyperglycemia. A large body of evidence supports the idea that the unchecked activation and expansion of autoreactive T cells in T1D is due to defects in immunosuppressive regulatory T cells (Tregs) that are critical for maintaining peripheral tolerance to islet autoantigens. Hence, repairing these Treg deficiencies is a much sought-after strategy to treat the disease. To accomplish this goal in the most precise, effective and safest way possible, restored Treg functions will need to be targeted towards suppressing the autoantigen-specific immune responses only and/or be localized in the pancreas. Here we review the most recent developments in designing Treg therapies that go beyond broad activation or expansion of non-specific polyclonal Treg populations. We focus on two cutting-edge strategies namely ex vivo generation of optimized Tregs for re-introduction in T1D patients vs direct in situ stimulation and restoration of endogenous Treg function.
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Affiliation(s)
- Victoria Volfson-Sedletsky
- Arthritis and Autoimmune Diseases Research Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.,Department of Microbiology, Boston University School of Medicine, Boston, MA, United States
| | - Albert Jones
- Arthritis and Autoimmune Diseases Research Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.,Department of Microbiology, Boston University School of Medicine, Boston, MA, United States
| | - Jaileene Hernandez-Escalante
- Arthritis and Autoimmune Diseases Research Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.,Department of Microbiology, Boston University School of Medicine, Boston, MA, United States
| | - Hans Dooms
- Arthritis and Autoimmune Diseases Research Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.,Department of Microbiology, Boston University School of Medicine, Boston, MA, United States
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Pan S, Li M, Yu H, Xie Z, Li X, Duan X, Huang G, Zhou Z. microRNA-143-3p contributes to inflammatory reactions by targeting FOSL2 in PBMCs from patients with autoimmune diabetes mellitus. Acta Diabetol 2021; 58:63-72. [PMID: 32815005 DOI: 10.1007/s00592-020-01591-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 08/05/2020] [Indexed: 12/17/2022]
Abstract
AIM Autoimmune diabetes mellitus (defined as ADM) comprises classical type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA). In this study, microRNAs (miRNAs) expression profiles and functions in peripheral blood mononuclear cells (PBMCs) of ADM patients were mapped and used to explore epigenetic regulation of the pathogenesis of ADM. METHODS PBMCs samples from T1DM patients, LADA patients, and type 2 diabetes mellitus (T2DM) patients, as well as age- and sex-matched healthy controls for T1DM and T2DM, respectively, were collected and were sequenced to screen the miRNAs expression profiles. The target genes were verified by dual-luciferase reporter assay. Silencing or overexpressing of the differentially expressed miRNAs, or simultaneously silencing the miRNAs and it's target gene, and then levels of the mRNAs, protein and cytokines were detected. RESULTS miR-143-3p expression was upregulated in ADM patients. The target gene of miR-143-3p was identified as Fos-related antigen 2 (FOSL2). Transfection of a miR-143-3p inhibitor into PBMCs upregulated FOSL2 expression, resulting in a downregulated expression of the IL-2, TNF-α, and IFN-γ, and an upregulated expression of IL-6. Transfection of a miR-143-3p mimic into PBMCs downregulated FOSL2 expression, leading to an upregulation of IL-2 and TNF-α expression and a downregulation of IL-6 expression. When silencing FOSL2 while inhibiting miR-143-3p in PBMCs, there was no significant change in expression of the FOSL2 mRNA, protein and cytokines. CONCLUSION The expression of miR-143-3p in PBMCs from ADM patients is upregulated. miR-143-3p could function in the pathogenesis of ADM by modulating the inflammatory reaction through FOSL2.
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MESH Headings
- Adolescent
- Adult
- Case-Control Studies
- Cells, Cultured
- Child
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Epigenesis, Genetic/genetics
- Female
- Fos-Related Antigen-2/genetics
- Gene Expression Regulation
- HEK293 Cells
- Humans
- Leukocytes, Mononuclear/metabolism
- Leukocytes, Mononuclear/pathology
- Male
- MicroRNAs/physiology
- Middle Aged
- Young Adult
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Affiliation(s)
- Shan Pan
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Mengyu Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Haibo Yu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Xianlan Duan
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China.
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
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Yahaya TO, Salisu T, Abdulrahman YB, Umar AK. Update on the genetic and epigenetic etiology of gestational diabetes mellitus: a review. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020; 21:13. [DOI: 10.1186/s43042-020-00054-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 02/11/2020] [Indexed: 02/08/2023] Open
Abstract
Abstract
Background
Many studies have been conducted on the genetic and epigenetic etiology of gestational diabetes mellitus (GDM) in the last two decades because of the disease’s increasing prevalence and role in global diabetes mellitus (DM) explosion. An update on the genetic and epigenetic etiology of GDM then becomes imperative to better understand and stem the rising incidence of the disease. This review, therefore, articulated GDM candidate genes and their pathophysiology for the awareness of stakeholders.
Main body (genetic and epigenetic etiology, GDM)
The search discovered 83 GDM candidate genes, of which TCF7L2, MTNR1B, CDKAL1, IRS1, and KCNQ1 are the most prevalent. Certain polymorphisms of these genes can modulate beta-cell dysfunction, adiposity, obesity, and insulin resistance through several mechanisms. Environmental triggers such as diets, pollutants, and microbes may also cause epigenetic changes in these genes, resulting in a loss of insulin-boosting and glucose metabolism functions. Early detection and adequate management may resolve the condition after delivery; otherwise, it will progress to maternal type 2 diabetes mellitus (T2DM) and fetal configuration to future obesity and DM. This shows that GDM is a strong risk factor for T2DM and, in rare cases, type 1 diabetes mellitus (T1DM) and maturity-onset diabetes of the young (MODY). This further shows that GDM significantly contributes to the rising incidence and burden of DM worldwide and its prevention may reverse the trend.
Conclusion
Mutations and epigenetic changes in certain genes are strong risk factors for GDM. For affected individuals with such etiologies, medical practitioners should formulate drugs and treatment procedures that target these genes and their pathophysiology.
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Pang H, Luo S, Xiao Y, Xia Y, Li X, Huang G, Xie Z, Zhou Z. Emerging Roles of Exosomes in T1DM. Front Immunol 2020; 11:593348. [PMID: 33324409 PMCID: PMC7725901 DOI: 10.3389/fimmu.2020.593348] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/02/2020] [Indexed: 12/17/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ying Xia
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Identification of the Key Genes Involved in the Effect of Folic Acid on Endothelial Progenitor Cell Transcriptome of Patients with Type 1 Diabetes. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2020; 2020:4542689. [PMID: 33029194 PMCID: PMC7532406 DOI: 10.1155/2020/4542689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/19/2020] [Accepted: 09/11/2020] [Indexed: 11/18/2022]
Abstract
Type 1 diabetes (T1D) is one of the most common autoimmune diseases in children. Previous studies have suggested that endothelial progenitor cells (EPCs) might be engaged in the regulating of the biological processes in T1D and folic acid (FA) might be engaged in regulating EPC function. The present study has identified 716 downregulated genes and 617 upregulated genes in T1D EPC cases after treated with FA. Bioinformatics analysis has shown that these DEGs were engaged in regulating metabolic processes, cell proliferation-related processes, bone marrow development, cell adhesion, platelet degranulation, and cellular response to growth factor stimulus. Furthermore, we have conducted and identified hub PPI networks. Importantly, we have identified 6 upregulated genes (POLR2A, BDNF, CDC27, LTN1, RAB1A, and CUL2) and 8 downregulated genes (SHC1, GRIN2B, TTN, GNAL, GNB2, PTK2, TF, and TLR9) as key regulators involved in the effect of FA on endothelial progenitor cell transcriptome of patients with T1D. We think that this study could provide novel information to understand the roles of FA in regulating EPCs of T1D patients.
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Qiu R, Zhou L, Ma Y, Zhou L, Liang T, Shi L, Long J, Yuan D. Regulatory T Cell Plasticity and Stability and Autoimmune Diseases. Clin Rev Allergy Immunol 2020; 58:52-70. [PMID: 30449014 DOI: 10.1007/s12016-018-8721-0] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
CD4+CD25+ regulatory T cells (Tregs) are a class of CD4+ T cells with immunosuppressive functions that play a critical role in maintaining immune homeostasis. However, in certain disease settings, Tregs demonstrate plastic differentiation, and the stability of these Tregs, which is characterized by the stable expression or protective epigenetic modifications of the transcription factor Foxp3, becomes abnormal. Plastic Tregs have some features of helper T (Th) cells, such as the secretion of Th-related cytokines and the expression of specific transcription factors in Th cells, but also still retain the expression of Foxp3, a feature of Tregs. Although such Th-like Tregs can secrete pro-inflammatory cytokines, they still possess a strong ability to inhibit specific Th cell responses. Therefore, the plastic differentiation of Tregs not only increases the complexity of the immune circumstances under pathological conditions, especially autoimmune diseases, but also shows an association with changes in the stability of Tregs. The plastic differentiation and stability change of Tregs play vital roles in the progression of diseases. This review focuses on the phenotypic characteristics, functions, and formation conditions of several plastic Tregs and also summarizes the changes of Treg stability and their effects on inhibitory function. Additionally, the effects of Treg plasticity and stability on disease prognosis for several autoimmune diseases were also investigated in order to better understand the relationship between Tregs and autoimmune diseases.
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Affiliation(s)
- Runze Qiu
- School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023, People's Republic of China
| | - Liyu Zhou
- School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023, People's Republic of China
| | - Yuanjing Ma
- School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023, People's Republic of China
| | - Lingling Zhou
- School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023, People's Republic of China
| | - Tao Liang
- School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023, People's Republic of China
| | - Le Shi
- School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023, People's Republic of China
| | - Jun Long
- School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023, People's Republic of China.
| | - Dongping Yuan
- School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023, People's Republic of China.
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Bulc M, Całka J, Palus K. Effect of Streptozotocin-Inducted Diabetes on the Pathophysiology of Enteric Neurons in the Small Intestine Based on the Porcine Diabetes Model. Int J Mol Sci 2020; 21:E2047. [PMID: 32192078 PMCID: PMC7139978 DOI: 10.3390/ijms21062047] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/13/2020] [Accepted: 03/14/2020] [Indexed: 12/31/2022] Open
Abstract
Hyperglycemia is one of the main causes of diabetes complications. Gastrointestinal (GI) disturbances are one of the most frequent complications during diabetes. The porcine digestive tract possesses physiological and pathological similarities to the human digestive tract. This also applies to the innervation of the gastrointestinal tract. In this study, the influence of experimentally-inducted hyperglycemia was examined on the expression of vesicular acetylcholine transporter (VAChT), cocaine- and amphetamine-regulated transcript (CART), galanin (GAL), vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP) in the enteric nervous system (ENS) neurons in the small intestine of the pig. During the current study, an increased number of neurons containing CART, VIP, GAL, and CGRP under streptozotocin injection were observed. The augmentation of expression included all enteric plexuses present in the small intestine. The same results were obtained in the case of VAChT; namely, chronic hyperglycemia led to an increase in the number of neurons utilizing VAChT in all investigated plexuses. The obtained results suggested that the function of neuropeptides studied in this experiment depended on their localization in the ENS structures, as well as part of the GI tract. Diabetes led to alterations in the neurochemical phenotype of small intestine enteric neurons.
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Affiliation(s)
- Michał Bulc
- Department of Clinical Physiology Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Str. 13, 10-719 Olsztyn, Poland; (J.C.); (K.P.)
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Zhang L, Wu H, Zhao M, Lu Q. Identifying the differentially expressed microRNAs in autoimmunity: A systemic review and meta-analysis. Autoimmunity 2020; 53:122-136. [DOI: 10.1080/08916934.2019.1710135] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Lian Zhang
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Central South University, Changsha, China
| | - Haijing Wu
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Central South University, Changsha, China
| | - Ming Zhao
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Central South University, Changsha, China
| | - Qianjin Lu
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Central South University, Changsha, China
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Xu L, Sun X, Xia Y, Luo S, Lin J, Xiao Y, Liu Y, Wang Y, Huang G, Li X, Xie Z, Zhou Z. Polymorphisms of the NLRC4 Gene are Associated with the Onset Age, Positive Rate of GADA and 2-h Postprandial C-Peptide in Patients with Type 1 Diabetes. Diabetes Metab Syndr Obes 2020; 13:811-818. [PMID: 32256096 PMCID: PMC7090150 DOI: 10.2147/dmso.s244882] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 02/15/2020] [Indexed: 12/16/2022] Open
Abstract
PURPOSE The purpose of this study was to clarify the association between the NLRC4 gene and the susceptibility and clinical characteristics of type 1 diabetes (T1D) in a Chinese Han population. PATIENTS AND METHODS A case-control study was performed in a Chinese Han population including 510 classical T1D patients and 531 healthy controls. rs212704 and rs385076 of the NLRC4 gene were genotyped by MassARRAY. The frequency distributions of alleles and genotypes of polymorphisms in the NLRC4 gene were compared by logistic regression and the chi-square test. The relationships between the polymorphisms of the NLRC4 gene and various clinical characteristics were analyzed by Kruskal-Wallis one-way ANOVA. The statistical power was calculated by Quanto software. RESULTS 1) rs385076 of the NLRC4 gene was significantly correlated with the onset age of T1D patients and the positive rate of GADA. The relationship between rs212704 and 2-h postprandial C-peptide was statistically significant. 2) There was no significant difference in the frequency distributions of the genotypes and alleles of rs212704 and rs385076 between T1D patients and controls. 3) rs212704 and rs385076 were not correlated with T1D susceptibility under different genetic models. CONCLUSION rs212704 was associated with 2-h postprandial C-peptide, while rs385076 of the NLRC4 gene was associated with the onset age and positive rate of GADA in patients with T1D.
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Affiliation(s)
- Linling Xu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Xiaoxiao Sun
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Ying Xia
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Shuoming Luo
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Jian Lin
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Yang Xiao
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Yue Liu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Yanfei Wang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of China
- Correspondence: Zhiguang Zhou; Zhiguo Xie Email ;
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Xie Z, Chang C, Huang G, Zhou Z. The Role of Epigenetics in Type 1 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1253:223-257. [PMID: 32445098 DOI: 10.1007/978-981-15-3449-2_9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the interaction between genetic alterations and environmental factors. More than 60 susceptible genes or loci of T1D have been identified. Among them, HLA regions are reported to contribute about 50% of genetic susceptibility in Caucasians. There are many environmental factors involved in the pathogenesis of T1D. Environmental factors may change the expression of genes through epigenetic mechanisms, thus inducing individuals with susceptible genes to develop T1D; however, the underlying mechanisms remain poorly understood. The major epigenetic modifications include DNA methylation, histone modification, and non-coding RNA. There has been extensive research on the role of epigenetic mechanisms including aberrant DNA methylation, histone modification, and microRNA in the pathogenesis of T1D. DNA methylation and microRNA have been proposed as biomarkers to predict islet β cell death, which needs further confirmation before any clinical application can be developed. Small molecule inhibitors of histone deacetylases, histone methylation, and DNA methylation are potentially important for preventing T1D or in the reprogramming of insulin-producing cells. This chapter mainly focuses on T1D-related DNA methylation, histone modification, and non-coding RNA, as well as their possible translational potential in the early diagnosis and treatment of T1D.
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Affiliation(s)
- Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Christopher Chang
- Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, Hollywood, FL, 33021, USA.,Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA, 95616, USA
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. .,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China.
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Abstract
Diabetes mellitus (DM) is the most common endocrine and metabolic disease caused by absolute or insufficient insulin secretion. Under the context of an aging population worldwide, the number of diabetic patients is increasing year by year. Most patients with diabetes have multiple complications that severely threaten their survival and living quality. DM is mainly divided into type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM is caused by absolute lack of insulin secretion, so the current treatment for T1DM patients is exogenous insulin replacement therapy. At present, exercise therapy has been widely recognized in the prevention and treatment of diabetes, and regular aerobic exercise has become an important part of T1DM treatment. At the same time, exercise therapy is also used in conjunction with other treatments in the prevention and treatment of diabetic complications. However, for patients with T1DM, exercise still has the risk of hypoglycemia or hyperglycemia. T1DM Patients and specialist physician need to fully understand the effects of exercise on metabolism and implement individualized exercise programs. This chapter reviews the related content of exercise and T1DM.
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Affiliation(s)
- Xiya Lu
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Cuimei Zhao
- Department of Cardiology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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Pang H, Luo S, Huang G, Xia Y, Xie Z, Zhou Z. Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM. Front Endocrinol (Lausanne) 2020; 11:119. [PMID: 32226409 PMCID: PMC7080653 DOI: 10.3389/fendo.2020.00119] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 02/24/2020] [Indexed: 12/12/2022] Open
Abstract
T1DM (type 1 diabetes mellitus), which results from the irreversible elimination of beta-cells mediated by autoreactive T cells, is defined as an autoimmune disease. It is widely accepted that T1DM is caused by a combination of genetic and environmental factors, but the precise underlying molecular mechanisms are still unknown. To date, more than 50 genetic risk regions contributing to the pathogenesis of T1DM have been identified by GWAS (genome-wide association studies). Notably, more than 60% of the identified candidate genes are expressed in islets and beta-cells, which makes it plausible that these genes act at the beta-cell level and play a key role in the pathogenesis of T1DM. In this review, we focus on the current status of candidate genes that act at the beta-cell level by regulating the innate immune response and antiviral activity, affecting susceptibility to proapoptotic stimuli and influencing the pancreatic beta-cell phenotype.
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Affiliation(s)
- Haipeng Pang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Shuoming Luo
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Ying Xia
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
- *Correspondence: Zhiguo Xie
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
- Zhiguang Zhou
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Expression Pattern of microRNAs, miR-21, miR-155 and miR-338 in Patients with Type 1 Diabetes. Arch Med Res 2019; 50:79-85. [PMID: 31495393 DOI: 10.1016/j.arcmed.2019.07.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 06/04/2019] [Accepted: 07/03/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Type 1 diabetes (T1D) is a multifactorial disease identified by a deficiency in the production of insulin. MicroRNAs (miRNAs) are identified as important epigenetic regulators in T1D. Many studies highlight the differential expression of these small non-coding molecules in the pathogenesis of T1D. AIM OF THE STUDY In the present study, the expression pattern of miR-21, miR-155 and miR-338 were analyzed in the peripheral blood mononuclear cells (PBMCs) of T1D patients compared to healthy controls. METHODS The expression levels of miR-21, miR-155 and miR-338 were measured in the PBMCs of 30 T1D patients and 11 healthy controls by real time PCR method. The final results were statistically analyzed and ROC curves were created for miRNAs with significant differential expression. RESULTS Both miR-155 (p value: 0.021) and miR-21 (p value: 0.05) were upregulated in the PBMCs of T1D patients compared to healthy controls. There was no significant difference in the expression level of miR-338 between patients and controls. Furthermore, ROC curve analysis was performed for miR-21 (AUC: 0.65) and miR-155 (AUC: 0.73) which suggests the potential role of miR-155 as a biomarker in T1D patients. Using integrative computational analysis, a number of dysregulated miR155-mRNA and miR21-mRNA interactions were also suggested. CONCLUSION Our findings suggest the significant association between the expression levels of miR-21 and miR-155 with T1D. In addition, miR-155 (AUC: 0.73) could be considered as a possible biomarker to track disease in T1D patients.
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Stevenson MJ, Uyeda KS, Harder NHO, Heffern MC. Metal-dependent hormone function: the emerging interdisciplinary field of metalloendocrinology. Metallomics 2019; 11:85-110. [PMID: 30270362 PMCID: PMC10249669 DOI: 10.1039/c8mt00221e] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
For over 100 years, there has been an incredible amount of knowledge amassed concerning hormones in the endocrine system and their central role in human health. Hormones represent a diverse group of biomolecules that are released by glands, communicate signals to their target tissue, and are regulated by feedback loops to maintain organism health. Many disease states, such as diabetes and reproductive disorders, stem from misregulation or dysfunction of hormones. Increasing research is illuminating the intricate roles of metal ions in the endocrine system where they may act advantageously in concert with hormones or deleteriously catalyze hormone-associated disease states. As the critical role of metal ions in the endocrine system becomes more apparent, it is increasingly important to untangle the complex mechanisms underlying the connections between inorganic biochemistry and hormone function to understand and control endocrinological phenomena. This tutorial review harmonizes the interdisciplinary fields of endocrinology and inorganic chemistry in the newly-termed field of "metalloendocrinology". We describe examples linking metals to both normal and aberrant hormone function with a focus on highlighting insight to molecular mechanisms. Hormone activities related to both essential metal micronutrients, such as copper, iron, zinc, and calcium, and disruptive nonessential metals, such as lead and cadmium are discussed.
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Affiliation(s)
- Michael J Stevenson
- Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
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Yang J, Zhang LJ, Wang F, Hong T, Liu Z. Molecular imaging of diabetes and diabetic complications: Beyond pancreatic β-cell targeting. Adv Drug Deliv Rev 2019; 139:32-50. [PMID: 30529307 DOI: 10.1016/j.addr.2018.11.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 09/28/2018] [Accepted: 11/27/2018] [Indexed: 12/13/2022]
Abstract
Diabetes is a chronic non-communicable disease affecting over 400 million people worldwide. Diabetic patients are at a high risk of various complications, such as cardiovascular, renal, and other diseases. The pathogenesis of diabetes (both type 1 and type 2 diabetes) is associated with a functional impairment of pancreatic β-cells. Consequently, most efforts to manage and prevent diabetes have focused on preserving β-cells and their function. Advances in imaging techniques, such as magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography, and single-photon-emission computed tomography, have enabled noninvasive and quantitative detection and characterization of the population and function of β-cells in vivo. These advantages aid in defining and monitoring the progress of diabetes and determining the efficacy of anti-diabetic therapies. Beyond β-cell targeting, molecular imaging of biomarkers associated with the development of diabetes, e.g., lymphocyte infiltration, insulitis, and metabolic changes, may also be a promising strategy for early detection of diabetes, monitoring its progression, and occurrence of complications, as well as facilitating exploration of new therapeutic interventions. Moreover, molecular imaging of glucose uptake, production and excretion in specified tissues is critical for understanding the pathogenesis of diabetes. In the current review, we summarize and discuss recent advances in noninvasive imaging technologies for imaging of biomarkers beyond β-cells for early diagnosis of diabetes, investigation of glucose metabolism, and precise diagnosis and monitoring of diabetic complications for better management of diabetic patients.
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Affiliation(s)
- Jichun Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Beijing 100191, China.
| | - Long Jiang Zhang
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China
| | - Fan Wang
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China.
| | - Zhaofei Liu
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
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Lin J, Cai Q, Liang B, Wu L, Zhuang Y, He Y, Lin W. Berberine, a Traditional Chinese Medicine, Reduces Inflammation in Adipose Tissue, Polarizes M2 Macrophages, and Increases Energy Expenditure in Mice Fed a High-Fat Diet. Med Sci Monit 2019; 25:87-97. [PMID: 30606998 PMCID: PMC6330261 DOI: 10.12659/msm.911849] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The uncoupling protein 1 (UCP1) gene has a role in mitochondrial energy expenditure in brown adipose tissue. This study aimed to investigate the effects of berberine, a benzylisoquinoline alkaloid used in traditional Chinese medicine, on energy expenditure, expression of the UCP1 gene, the cell stress protein inositol-requiring enzyme 1α (IRE1α), apoptosis genes, and macrophage phenotype (M1 and M2) in white and brown adipose tissue in an obese mouse model fed a high-fat diet. MATERIAL AND METHODS Four-week-old C57BL/6J male mice (n=20) were divided into a high-fat diet group, a normal diet group, a group treated with berberine at 100 mg/kg/d in 0.9% normal saline, and a non-treated group. Whole-body fat mass, blood glucose, insulin resistance, and oxygen expenditure during physical activity were measured. After 16 weeks, the mice were euthanized for examination of liver and adipose tissue. The expression of pro-inflammatory cytokines, apoptosis genes, thermogenic genes (including UCP1), and IRE1α, were investigated using immunohistochemistry, Western blot, and quantitative reverse transcription polymerase chain reaction (qRT-PCR), in white and brown adipose tissue. Magnetic cell sorting harvested M1 and M2 macrophages in adipose tissue. Clodronate liposomes were used to inhibit macrophage recruitment. RESULTS Berberine treatment in mice fed a high-fat diet increased energy metabolism, glucose tolerance, and expression of UCP1, and reduced expression of pro-inflammatory cytokines, macrophage recruitment, and resulted in M2 macrophage polarization in white adipose tissue. Polarized M2 macrophages showed reduced expression of apoptotic genes and IRE1α. CONCLUSIONS Berberine improved metabolic function in a mouse model fed a high-fat diet.
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Affiliation(s)
- Jiayu Lin
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China (mainland)
| | - Qingyan Cai
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China (mainland)
| | - Bo Liang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China (mainland)
| | - Lizhen Wu
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China (mainland)
| | - Yong Zhuang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China (mainland)
| | - Yuanfang He
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China (mainland)
| | - Wanrong Lin
- Department of Endocrinology, Shishi (Overseas Chinese) Hospital, Quanzhou, Fujian, China (mainland)
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Sun X, Xia Y, Liu Y, Wang Y, Luo S, Lin J, Huang G, Li X, Xie Z, Zhou Z. Polymorphisms in NLRP1 Gene Are Associated with Type 1 Diabetes. J Diabetes Res 2019; 2019:7405120. [PMID: 31396539 PMCID: PMC6664699 DOI: 10.1155/2019/7405120] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 06/27/2019] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE The aim of this study was to clarify the association of two single-nucleotide polymorphisms (SNPs) (rs11651270 and rs2670660) in the NLRP1 (NLR family pyrin domain containing 1) gene with type 1 diabetes (T1D) in the Chinese Han population. We hypothesize that mutations in the NLRP1 gene may affect the susceptibility to T1D. MATERIALS AND METHODS A case control study was designed, and participants fulfilling the diagnostic criteria of classical T1D as well as nondiabetic controls were enrolled in the study. The polymorphisms rs11651270 and rs2670660 were genotyped by polymerase chain reaction (PCR) and Sanger sequencing. Chi-squared test and logistic regression analysis were performed to compare the distributions of the allele and genotype between cases and controls. Kruskal-Wallis one-way ANOVA was used to compare the characteristics of different genotypes in participants with T1D. RESULTS A total of 510 participants with classical T1D as well as 531 nondiabetic controls were enrolled in the study. The two groups were matched in sex (p = 0.418). The age (p < 0.001) and BMI (p < 0.001) were significantly lower in cases compared to controls. Significantly higher values were observed for fasting plasma glucose (FPG) (p < 0.001) and 2 h postprandial plasma glucose (PPG) (p < 0.001) in individuals with T1D. Regarding the allelic model, the minor allele C of rs11651270 was significantly associated with lower risk of T1D compared with the T allele (OR = 0.714, 95% CI = 0.579-0.882). Both rs11651270 and rs2670660 polymorphisms were associated with T1D in the Chinese Han population under a dominant model (OR = 0.648, 95% CI = 0.503-0.834 and OR = 0.716, 95% CI = 0.549-0.934, respectively) and an overdominant model (OR = 0.663, 95% CI = 0.511-0.860 and OR = 0.711, 95% CI = 0.541-0.935, respectively). Additionally, the polymorphism rs11651270 was also related to T1D in an additive model (OR = 0.719, 95% CI = 0.583-0.887). Most importantly, when we analyzed the clinical characteristics of T1D individuals with different genotypes, we found that the age of onset with the TT genotype at rs11651270 was younger than those with the other two genotypes (p = 0.001). CONCLUSIONS SNPs in the NLRP1 gene were associated with T1D, as well as the age of onset in the Chinese Han T1D individuals. Our study indicated that the NLRP1 gene might play a pivotal role in the etiopathogenesis of T1D and could be applied to genetic screening of T1D in the Chinese Han population.
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Affiliation(s)
- Xiaoxiao Sun
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Ying Xia
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yue Liu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yanfei Wang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Shuoming Luo
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Jian Lin
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
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Xu YJ, Chen FP, Chen Y, Fu B, Liu EY, Zou L, Liu LX. A Possible Reason to Induce Acute Graft-vs.-Host Disease After Hematopoietic Stem Cell Transplantation: Lack of Sirtuin-1 in CD4 + T Cells. Front Immunol 2018; 9:3078. [PMID: 30622543 PMCID: PMC6308326 DOI: 10.3389/fimmu.2018.03078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 12/12/2018] [Indexed: 01/02/2023] Open
Abstract
Sirtuin 1 (SIRT1) is a critical suppressor of T cell immunity. However, whether SIRT1 is involved in the progression of acute graft-vs.-host disease (aGVHD) has still remained unclear. PI3K/Akt/mTOR pathway is a crucial element involved in the activation and functions of T cells. Over-activation of PI3K/Akt/mTOR signaling may be related to the occurrence of aGVHD. STAT3 activation requires phosphorylation and acetylation. A recent study showed that STAT3 hyperphosphorylation in CD4+ T cells may be a trigger of aGVHD. The role of the STAT3 acetylation in aGVHD pathogenesis is still unclear. The present study revealed that SIRT1 deficiency as a critical factor is involved in the excessive activation of mTOR pathway and upregulation of STAT3 acetylation and phosphorylation in CD4+ T cells from patients with aGVHD. Exorbitant activation of IL-1β signaling is the main reason for TAK1-dependent SIRT1 insufficiency. The findings of the present study might provide a new therapeutic target for treating aGVHD.
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Affiliation(s)
- Ya-Jing Xu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Fang-Ping Chen
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Chen
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Bin Fu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - En-Yi Liu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Lang Zou
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Lin-Xin Liu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
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Zheng P, Li Z, Zhou Z. Gut microbiome in type 1 diabetes: A comprehensive review. Diabetes Metab Res Rev 2018; 34:e3043. [PMID: 29929213 PMCID: PMC6220847 DOI: 10.1002/dmrr.3043] [Citation(s) in RCA: 137] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/06/2018] [Accepted: 06/14/2018] [Indexed: 12/17/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease, which is characterized by the destruction of islet β cells in the pancreas triggered by genetic and environmental factors. In past decades, extensive familial and genome-wide association studies have revealed more than 50 risk loci in the genome. However, genetic susceptibility cannot explain the increased incidence of T1D worldwide, which is very likely attributed by the growing impact of environmental factors, especially gut microbiome. Recently, the role of gut microbiome in the pathogenesis of T1D has been uncovered by the increasing evidence from both human subjects and animal models, strongly indicating that gut microbiome might be a pivotal hub of T1D-triggering factors, especially environmental factors. In this review, we summarize the current aetiological and mechanism studies of gut microbiome in T1D. A better understanding of the role of gut microbiome in T1D may provide us with powerful prognostic and therapeutic tools in the near future.
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Affiliation(s)
- Peilin Zheng
- Department of Metabolism and Endocrinology, The Second Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of EducationNational Clinical Research Center for Metabolic DiseasesChangshaChina
| | - Zhixia Li
- Department of Metabolism and Endocrinology, The Second Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of EducationNational Clinical Research Center for Metabolic DiseasesChangshaChina
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of EducationNational Clinical Research Center for Metabolic DiseasesChangshaChina
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Eddaikra A, Amroun H, Raache R, Galleze A, Abdallah-Elhadj N, Azzouz M, Meçabih F, Mechti B, Abbadi MC, Touil-Boukoffa C, Attal N. Clinical variables and ethnicity may influenced by polymorphism of CAT -262C/T and MnSOD 47C/T antioxidant enzymes in Algerian type1 diabetes without complications. Gene 2018; 670:182-192. [PMID: 29859283 DOI: 10.1016/j.gene.2018.05.105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/21/2018] [Accepted: 05/29/2018] [Indexed: 01/11/2023]
Abstract
The latest studies in Algeria show that the frequency of type 1 diabetes (T1D) without complications is lower than that with complications and represents a significant burden in terms of cost and treatment. For this reason, we are interested in uncomplicated type1 diabetes and risk factors that are related to polymorphisms of antioxidant enzymes in order to prevent its complications. A total of 260 blood samples of young Algerian adults were examined. The genotypic analysis of Catalase gene (CAT -262C/T, rs1001179) and the superoxide dismutase gene (MnSOD 47C/T, rs4880) was performed by real-time PCR using TaqMan technology. The genotypic distribution of the CAT -262C/T promoter gene's polymorphism showed a significant difference between control and T1D patients for the CC genotype (p = 0.009; OR = 0.30) and for the T allele (p = 0.002; OR = 2.82). In addition, the genotypic distribution of the MnSOD 47C/T gene showed an association with T1D for the CT genotype (p = 0.040; OR = 2.37). Our results revealed that polymorphisms of CAT and MnSOD may be associated with physiopathology causing the onset of T1D. Our data, suggest that the genotypic frequencies of these SNPs appear to be influenced by clinical variables and by the Arab-Berber ethnic origin of the Algerian population.
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Affiliation(s)
- A Eddaikra
- Department of Cellular Biology and Physiology, Faculty of Nature and Life, University Saad Dahleb, Blida, Algeria; Department of Cellular and Molecular Biology, Team Cytokines and Nitric Oxide Synthases, Faculty of Biology, University Houari Boumediene USTHB, Algiers, Algeria.
| | - H Amroun
- Department of Immunology, Institute Pasteur of Algeria, Algiers, Algeria
| | - R Raache
- Department of Cellular and Molecular Biology, Team Cytokines and Nitric Oxide Synthases, Faculty of Biology, University Houari Boumediene USTHB, Algiers, Algeria; Department of Immunology, Institute Pasteur of Algeria, Algiers, Algeria
| | - A Galleze
- Department of Cellular and Molecular Biology, Team Cytokines and Nitric Oxide Synthases, Faculty of Biology, University Houari Boumediene USTHB, Algiers, Algeria
| | - N Abdallah-Elhadj
- Diabetology Department, Trichine Ibrahime Fabore Hospital, Blida, Algeria
| | - M Azzouz
- Diabetology Department, Mustapha Pacha Hospital, Algiers, Algeria
| | - F Meçabih
- Department of Immunology, Institute Pasteur of Algeria, Algiers, Algeria
| | - B Mechti
- Department of Immunology, Institute Pasteur of Algeria, Algiers, Algeria
| | - M C Abbadi
- Department of Immunology, Institute Pasteur of Algeria, Algiers, Algeria
| | - C Touil-Boukoffa
- Department of Cellular and Molecular Biology, Team Cytokines and Nitric Oxide Synthases, Faculty of Biology, University Houari Boumediene USTHB, Algiers, Algeria
| | - N Attal
- Department of Immunology, Institute Pasteur of Algeria, Algiers, Algeria
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Wang Z, Long H, Chang C, Zhao M, Lu Q. Crosstalk between metabolism and epigenetic modifications in autoimmune diseases: a comprehensive overview. Cell Mol Life Sci 2018; 75:3353-3369. [PMID: 29974127 PMCID: PMC11105184 DOI: 10.1007/s00018-018-2864-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 06/20/2018] [Accepted: 06/25/2018] [Indexed: 12/11/2022]
Abstract
Little information is available regarding mechanistic links between epigenetic modifications and autoimmune diseases. It seems plausible to surmise that aberrant gene expression and energy metabolism would disrupt immune tolerance, which could ultimately result in autoimmune responses. Metaboloepigenetics is an emerging paradigm that defines the interrelationships between metabolism and epigenetics. Epigenetic modifications, such as the methylation/demethylation of DNA and histone proteins and histone acetylation/deacetylation can be dynamically produced and eliminated by a group of enzymes that consume several metabolites derived from various physiological pathways. Recent insights into cellular metabolism have demonstrated that environmental stimuli such as dietary exposure and nutritional status act through the variation in concentration of metabolites to affect epigenetic regulation and breakdown biochemical homeostasis. Metabolites, including S-adenosylmethionine, acetyl-CoA, nicotinamide adenine dinucleotide, α-ketoglutarate, and ATP serve as cofactors for chromatin-modifying enzymes, such as methyltransferases, deacetylases and kinases, which are responsible for chromatin remodelling. The concentration of crucial nutrients, such as glucose, glutamine, and oxygen, spatially and temporally modulate epigenetic modifications to regulate gene expression and the reaction to stressful microenvironments in disease pathology. In this review, we focus on the interaction between metabolic intermediates and epigenetic modifications, integrating environmental signals with programmes through modification of the epigenome-metabolome to speculate as to how this may influence autoimmune diseases.
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Affiliation(s)
- Zijun Wang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, No. 139 Renmin Middle Rd, Changsha, 410011, Hunan, China
| | - Hai Long
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, No. 139 Renmin Middle Rd, Changsha, 410011, Hunan, China
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Suite 6510, 451 Health Sciences Drive, Davis, CA, 95616, USA
| | - Ming Zhao
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, No. 139 Renmin Middle Rd, Changsha, 410011, Hunan, China.
| | - Qianjin Lu
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, No. 139 Renmin Middle Rd, Changsha, 410011, Hunan, China.
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