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1.
Front Immunol ; 13: 977413, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36090989

RESUMO

Latent autoimmune diabetes in adults (LADA) is a type of diabetes caused by slow progression of autoimmune damage to pancreatic beta cells. According to the etiological classification, LADA should belong to the autoimmune subtype of type 1 diabetes (T1D). Previous studies have found general immune genetic effects associated with LADA, but there are also some racial differences. Multicenter studies have been conducted in different countries worldwide, but it is still unclear how the Chinese and Caucasian populations differ. The epidemiology and phenotypic characteristics of LADA may vary between Caucasian and Chinese diabetic patients as lifestyle, food habits, and body mass index differ between these two populations. The prevalence of LADA in China has reached a high level compared to other countries. The prevalence of LADA in China has reached a high level compared to other countries, and the number of patients with LADA ranks first in the world. Previous studies have found general immune genetic effects associated with LADA, but some racial differences also exist. The prevalence of LADA among newly diagnosed type 2 diabetes patients over the age of 30 years in China is 5.9%, and LADA patients account for 65% of the newly diagnosed T1D patients in the country. As a country with a large population, China has many people with LADA. A summary and analysis of these studies will enhance further understanding of LADA in China. In addition, comparing the similarities and differences between the Chinese and the Caucasian population from the perspectives of epidemiology, clinical, immunology and genetics will help to improve the understanding of LADA, and then promote LADA studies in individual populations.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Autoimune Latente em Adultos , Adulto , Asiáticos , China/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Humanos , Diabetes Autoimune Latente em Adultos/epidemiologia , Diabetes Autoimune Latente em Adultos/genética
2.
Ann Transl Med ; 10(16): 851, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36111021

RESUMO

Background: A high seropositive rate of thyroid autoantibodies is often reported in patients with type 1 diabetes mellitus (T1DM), latent autoimmune diabetes in adults (LADA) and type 2 diabetes mellitus (T2DM). However, the positive rate of thyroid autoantibodies in latent autoimmune diabetes in youth (LADY) patients has not been reported in China. Thus, the purpose of the current study was to clarify the thyroid autoantibody distribution in patients with LADY to provide evidence for the clinical screening of autoimmune thyroid diseases (AITD). Methods: This nationwide, multicenter and cross-sectional study included 1,723 younger patients (<30 years old) and 2,000 older patients (≥30 years old) aged 15 to 79 years. The patients were grouped into younger T1DM (n=281), LADY (n=130), younger T2DM (n=200), older T1DM (n=287), LADA (n=129), and older T2DM (n=200) groups. Autoantibodies against thyroid peroxidase (TPOA) and thyroglobulin (TGA) prevalence were analyzed in each group. Results: The prevalence of TGA or TPOA in LADY patients was similar to that in younger T1DM patients. The seropositive rate of TPOA in LADY patients was higher than that in LADA patients (36.2% vs. 23.3%, respectively; P=0.023); the risk of TPOA was higher in LADY patients than in LADA patients, even after adjusting for sex, glutamic acid decarboxylase (GADA)- and insulinoma-associated-2 (IA-2A)-positivity (OR =1.94, P=0.023). LADY patients with high GADA titers exhibited a higher frequency of thyroid autoantibodies than patients with low GADA titers did (TPOA, P=0.005; TGA, P=0.023; TPOA or TGA, P=0.004). Further analysis showed that only male patients showed a strong association between high GADA titers and thyroid autoantibodies positivity, and the association remained significant after adjustment for age (OR =11.14, P=0.025 for TGA; OR =4.99, P=0.011 for TPOA; OR =5.52, P=0.007 for TPOA or TGA). Conclusions: Routine screening for thyroid autoantibodies is recommended in LADY patients, and special clinical attention should be paid to the thyroid autoantibodies status of male patients of LADY with high GADA titers to identify patients at high risk of developing AITD.

3.
Front Immunol ; 13: 974864, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091068

RESUMO

T lymphocytes are key players in the pathogenesis of autoimmune diabetes. We recruited subjects with T1D (n=81), LADA (n=82), T2D (n=95) and NGT (n=218) and analyzed the percentages of T-lymphocyte subsets, including T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), T cytotoxic 1 (Tc1), regulatory T cells (Tregs), effector T (Teff), naïve T, central memory T (Tcm), and effector memory T (Tem) cells by flow cytometry. LADA patients possessed similar frequencies of IFN-γ+CD4+ T (Th1), IFN-γ+CD8+ T and CD4+ Teff cells compared with T1D patients, but much lower than those of NGT subjects. Like T2D patients, LADA patients had increased frequencies of CD4+ Tem and CD8+ Tem cells with respect to T1D and NGT subjects. In LADA patients, Th2 cells were decreased while CD4+ Tcm cells were increased compared with NGT subjects. Notably, we observed significant negative correlations between the CD4+ Tcm cell frequency and C-peptide in LADA subjects. These data demonstrates that LADA patients possess T-cell subset changes resembling both T1D and T2D and represent the middle of the diabetes spectrum between T1D and T2D. Based on these T-cell subset alterations, we speculate that autoimmunity-induced ß-cell destruction and inflammation-induced insulin resistance might both be involved in the pathogenesis of LADA.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Diabetes Autoimune Latente em Adultos , Adulto , Humanos , Subpopulações de Linfócitos T/patologia , Linfócitos T Reguladores
4.
Materials (Basel) ; 15(16)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36013653

RESUMO

Utilizing scrap tire rubber by incorporating it into concrete is a valuable option. Many researchers are interested in using rubber tire waste in concrete. The possible uses of rubber tires in concrete, however, are dispersed and unclear. Therefore, a compressive analysis is necessary to identify the benefits and drawbacks of rubber tires for concrete performance. For examination, the important areas of concrete freshness, durability, and strength properties were considered. Additionally, several treatments and a microstructure investigation were included. Although it has much promise, there are certain obstacles that prevent it from being used as an aggregate in large numbers, such as the rubber's weak structural strength and poor binding performance with the cement matrix. Rubber, however, exhibits mechanical strength comparable to reference concrete up to 20%. The evaluation also emphasizes the need for new research to advance rubberized concrete for future generations.

5.
Front Endocrinol (Lausanne) ; 13: 959011, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35992113

RESUMO

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease sharing some phenotypic, genetic, and immunological features with both type 1 and 2 diabetes. Patients with LADA have a relatively slow autoimmune process and more residual islet ß-cell function at onset, allowing a time window to protect residual islet ß cells and delay or inhibit disease progression. It is crucial to discover various heterogeneous factors affecting islet ß-cell function for precise LADA therapy. In this review, we first describe the natural history of LADA. Thereafter, we summarize ß-cell function-related heterogeneous factors in LADA, including the age of onset, body mass index, genetic background, and immune, lifestyle, and environmental factors. In parallel, we evaluate the impact of current hypoglycemic agents and immune intervention therapies for islet ß-cell protection. Finally, we discuss the opportunities and challenges of LADA treatment from the perspective of islet ß-cell function protection.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Diabetes Autoimune Latente em Adultos , Adulto , Citoproteção , Diabetes Mellitus Tipo 1/terapia , Progressão da Doença , Humanos , Diabetes Autoimune Latente em Adultos/terapia
6.
Front Endocrinol (Lausanne) ; 13: 885650, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35979435

RESUMO

Diabetes mellitus (DM) is an endocrine disorder characterized by a relative or absolute lack of insulin due to the dysfunction or destruction of ß-cells. DM is one of the fastest growing challenges to global health in the 21st century and places a tremendous burden on affected individuals and their families and countries. Although insulin and antidiabetic drugs have been used to treat DM, a radical cure for the disease is unavailable. The pathogenesis of DM remains unclear. Emerging roles of circular RNAs (circRNAs) in DM have become a subject of global research. CircRNAs have been verified to participate in the onset and progression of DM, implying their potential roles as novel biomarkers and treatment tools. In the present review, we briefly introduce the characteristics of circRNAs. Next, we focus on specific roles of circRNAs in type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus and diabetes-associated complications.


Assuntos
Complicações do Diabetes , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , RNA Circular/genética
7.
Front Immunol ; 13: 946119, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958585

RESUMO

T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.


Assuntos
Subpopulações de Linfócitos T , Timócitos , Diferenciação Celular , Transdução de Sinais
8.
Front Immunol ; 13: 941962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990660

RESUMO

As an important form of posttranslational modification, protein ubiquitination regulates a wide variety of biological processes, including different aspects of T cell development and differentiation. During T cell development, thymic seeding progenitor cells (TSPs) in the thymus undergo multistep maturation programs and checkpoints, which are critical to build a functional and tolerant immune system. Currently, a tremendous amount of research has focused on the transcriptional regulation of thymocyte development. However, in the past few years, compelling evidence has revealed that the ubiquitination system also plays a crucial role in the regulation of thymocyte developmental programs. In this review, we summarize recent findings on the molecular mechanisms and cellular pathways that regulate thymocyte ubiquitination and discuss the roles of E3 ligases and deubiquitinating enzymes (DUBs) involved in these processes. Understanding how T cell development is regulated by ubiquitination and deubiquitination will not only enhance our understanding of cell fate determination via gene regulatory networks but also provide potential novel therapeutic strategies for treating autoimmune diseases and cancer.


Assuntos
Doenças Autoimunes , Ubiquitina-Proteína Ligases , Diferenciação Celular , Humanos , Linfócitos T , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
10.
Endokrynol Pol ; 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35971929

RESUMO

INTRODUCTION: Fasting proinsulin (FPI) and fasting insulin (FI) have been demonstrated to be associated with impaired b cell function, T2DM, and insulin resistance. This genome-wide association study (GWAS) was performed to contribute to our understanding of the genetic basis of FPI, FI, 2-hour postprandial proinsulin (2hPI), and 2-hour postprandial insulin (2hI) of the pathophysiology of prediabetes in the Chinese population. MATERIAL AND METHODS: The levels of fasting plasma glucose (FPG), FPI, FI, 2hPI, and 2hI were examined by an automatic biochemical analyser. The Applied BiosystemsTM AxiomTM Precision Medicine Diversity Array, the Gene Titan Multi-Channel instrument, and Axiom Analysis Suite 6.0 Software were used for genotyping. Imputation was performed with IMPUTE 2.0 software from HapMap, 1000 Genomes Phase 3 as a reference panel. RESULTS: Six single nucleotide polymorphisms (SNPs) in DLG1-AS1, SORCS1, and CTAGE11P for FPI, and 27 SNPs in ZNF718, MARCHF2, and HNRNPM for 2hPI reached genome-wide significance. Genome-wide significance was reached for associations of 6 SNPs in KRT71 to FI. Also, 14 SNPs in UBE2U, ABO, and GRID1-AS1 were genome-wide significant in their relationship with 2hI. Among these, the genetic loci of CTAGE11P, MARCHF2, KRT71, and ABO have the strongest association with FPI, 2hPI, FI, and 2hI. CONCLUSIONS: The genetic variants of CTAGE11P, MARCHF2, KRT71, and ABO are significantly correlated with FPI, 2hPI, FI, and 2hI, respectively, in Chinese Han people. These genetic variants may serve as new biomarkers for the prevention of prediabetes.

11.
Front Endocrinol (Lausanne) ; 13: 917169, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937817

RESUMO

Latent autoimmune diabetes in adults (LADA) is a type of diabetes characterized by slow autoimmune damage of pancreatic ß cells without insulin treatment in the early clinical stage. There are differences between LADA and classical type 1 diabetes (T1D) and type 2 diabetes (T2D) in genetic background, autoimmune response, rate of islet function decline, clinical metabolic characteristics, and so on. The disease progression and drug response of patients with LADA are closely related to the level of islet autoimmunity, thus exploring the pathogenesis of LADA is of great significance for its prevention and treatment. Previous studies reported that adaptive immunity and innate immunity play a critical role in the etiology of LADA. Recent studies have shown that the intestinal microbiota which impacts host immunity hugely, participates in the pathogenesis of LADA. In addition, the progression of autoimmune pancreatic ß cell destruction in LADA is slower than in classical T1D, providing a wider window of opportunities for intervention. Therefore, therapies including antidiabetic drugs with immune-regulation effects and immunomodulators could contribute to promising interventions for LADA. We also shed light on potential interventions targeting the gut microbiota and gut-associated immunity, which may be envisaged to halt or delay the process of autoimmunity in LADA.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Diabetes Autoimune Latente em Adultos , Adulto , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Diabetes Autoimune Latente em Adultos/terapia
12.
Front Endocrinol (Lausanne) ; 13: 937109, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35966054

RESUMO

Background: T-cell immunoglobulin and mucin domain (Tim) proteins are immunomodulatory molecules that play key roles in the regulation of T-cell activation. Published studies have reported that Tim molecules are involved in the pathogenesis of certain autoimmune diseases. Type 1 diabetes (T1D) is an autoimmune disease in which T cells mediate the destruction of islet ß cells. However, the expression of Tim molecules in T1D remains unclear. In this study, we measured the expression of Tim family molecules as well as T-cell subset-specific transcription factors in T1D patients, and we explored the possible involvement of Tim molecules in the pathogenesis of T1D. Methods: Ninety T1D patients, Thirty-six type 2 diabetes (T2D) patients and forty healthy controls (HCs) were recruited for this study. Peripheral blood mononuclear cells (PBMCs) were isolated, RNA was extracted from the PBMCs and reverse transcribed into cDNA, and gene expression patterns were analysed by RT-qPCR. The expression of Tim molecules in different T-cell subsets was analysed by flow cytometry. Results: Compared with that in HCs, the mRNA expression of Tim-1 and RORC was increased in T1D patients (P=0.0355 and P=0.0423, respectively), while the expression of Tim-3 was decreased (P=0.0013). In addition, compared with HCs, the ratio of Tim-3 to Tim-1 expression in diabetic patients was decreased (P<0.0001 for T1D and P=0.0387 for T2D). The ratios of T-Bet to GATA3 expression and RORC to FOXP3 expression were higher in T1D patients than in HCs (P=0.0042 and P=0.0066, respectively). Furthermore, the T1D patients with defective islet function had more significant imbalances in the Tim-3/Tim-1 and RORC/FOXP3 ratios (P<0.0001, and P=0.001, respectively). Moreover, Both Tim-3 expression in CD4+ T cells and the Tim-3 to Tim-1 ratio were elevated in T1D in the remission phase compared to T1D. Conclusion: Our study revealed altered expression of Tim molecules in T1D patients. The imbalanced ratios of Tim-3/Tim-1 expression were more pronounced in T1D patients with defective islet function. However, alterations in Tim molecule expression are mitigated in T1D in the remission phase. All these findings suggest that Tim family molecules may be involved in the pathogenesis of T1D.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Fatores de Transcrição Forkhead , Receptor Celular 2 do Vírus da Hepatite A/genética , Humanos , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
13.
Front Med (Lausanne) ; 9: 918721, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935798

RESUMO

Background: Subacute thyroiditis, an inflammatory disease, has been reported caused by vaccines in rare cases. In the context of the coronavirus disease 19 pandemic, various SARS-CoV-2 vaccines have been developed and may be potential triggers for subacute thyroiditis. Case presentation: We report a case of subacute thyroiditis 3 days after receiving the second dose of inactivated SARS-CoV-2 vaccine (BBIBP-CorV). The patient did not report a previous history of thyroid disease, upper respiratory tract infection, or COVID-19. Physical examination, laboratory testing, ultrasonography, and radioactive iodine uptake were consistent with subacute thyroiditis. During follow-up, the patient recovered from symptoms and signs, and imaging changes except for hypothyroidism, requiring an ongoing thyroxine replacement. Conclusions: Inactivated SARS-CoV-2 vaccine may be a causal trigger leading to subacute thyroiditis. Clinicians should be aware of subacute thyroiditis as a possible thyroid-related side effect of an inactivated SARS-CoV-2 vaccine.

14.
Front Endocrinol (Lausanne) ; 13: 915482, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35837316

RESUMO

Aims: There is limited evidence that evaluates the glycemic control of type 1 diabetes mellitus (T1DM) during the Chinese New Year public holiday in China. The Chinese New Year public holiday represents various challenges to glycemic control, especially in T1DM patients, in China. We aimed to assess the effect of the Chinese New Year public holiday on several glucose metrics using flash glucose monitoring (FGM) in patients with T1DM. Methods: Complete FGM data for 1 week before, 1 week during and 1 week after the Chinese New Year public holiday were available for 71 T1DM patients treated with multiple daily insulin injection (MDI) therapy (n = 51) or continuous subcutaneous insulin infusion (CSII) treatment (n = 20). The mean age of the study participants was 13 (9, 30) years. Of note, 59.2% of the patients (n = 42) were adults, and 40.8% of the patients (n = 29) were minors. The interval between each two adjacent periods was one week. The indicators of mean glucose, glucose variability and time in different glycemic ranges were analyzed. Results: The Chinese New Year public holiday was associated with an increase in mean blood glucose (8.4 ± 1.7 vs. 9.2 ± 2.5; P < 0.001) and time above range (TAR) (27.9% ± 16.6% vs. 35.0% ± 22.3%; P< 0.001) but a decrease in time in range (TIR) (65.1% ± 15.5% vs. 58.0% ± 19.0%; P < 0.001) and coefficient of variation (CV) (65.1% ± 15.5% vs. 58.0% ± 19.0%; P < 0.001). There was no significant difference in time below range (TBR). The glycemic control deteriorated during the Chinese New Year public holiday in our study population regardless of age. Interestingly, in the CSII group, none of the metrics of glucose control significantly changed during the Chinese New Year public holiday. Conclusions: These results suggested that less self-management may worsen glycemic control in the short term, indicating a need for more refined management algorithms during the Chinese New Year public holiday for T1DM patients.


Assuntos
Diabetes Mellitus Tipo 1 , Adulto , Glicemia , Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucose , Hemoglobina A Glicada/análise , Controle Glicêmico , Férias e Feriados , Humanos , Hipoglicemiantes/efeitos adversos , Insulina , Sistemas de Infusão de Insulina
15.
Front Endocrinol (Lausanne) ; 13: 876657, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784546

RESUMO

Background: Latent autoimmune diabetes in adults (LADA) is a heterogeneous form of diabetes, characterized by autoimmune destruction of pancreatic ß-cells as well as insulin resistance and is triggered by environmental factors in the context of genetic susceptibility. Berberine (BBR), a small alkaloid isolated from medicinal plants, has antidiabetic, anti-inflammatory, and antibacterial effects. Inulin is a common prebiotic that has been shown to improve glycemic control, alter the gut microbiota and suppress inflammation. The primary purpose of this study was to evaluate the effects of oral BBR and inulin combined with insulin therapy on diabetes care in patients with LADA. Methods and Analysis: We will conduct a single-center, prospective, randomized, double-blind, placebo-controlled trial. A total of 240 patients with LADA who have started insulin therapy will be randomly allocated either to the intervention or control group. After a 1-week run-in period, they will complete a 3-month treatment of BBR alone, inulin plus BBR, inulin alone, or placebo. Anthropometric and clinical data will be collected at five time points: baseline, 3 months, 6 months, 9 months, and 12 months from baseline. The primary outcome was the change in glycated hemoglobin levels. Dynamic blood glucose parameters, ß-cell function, and gut microbiota, as well as adverse events and quality of life will be monitored. Discussion: Glycemic control is critical for preventing the progression of diabetes. Although insulin is a recommended treatment for patients with LADA, there are currently no drugs that can effectively prevent the progressive destruction of pancreatic ß-cells or maintain their function. Several studies have found that when berberine and prebiotics are used alone, they have beneficial metabolic effects. This clinical research protocol will assess the efficacy of the combined treatment of berberine plus inulin and provide new ideas for future pharmacological research and clinical practices in diabetes care and glycemic control for LADA patients. Ethics and Dissemination: This study has been approved by the Ethics Committee of National Clinical Research Center of the Second Xiangya Hospital of Central South University (approval number: 2021-046). Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04698330.


Assuntos
Berberina , Diabetes Mellitus Tipo 1 , Intolerância à Glucose , Diabetes Autoimune Latente em Adultos , Adulto , Berberina/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Insulina , Inulina/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Front Endocrinol (Lausanne) ; 13: 914136, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757405

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells and is becoming a serious public health threat. Despite the increasing incidence rate of T1D worldwide, our understanding of why T1D develops and how T cells lose their self-tolerance in this process remain limited. Recent advances in immunometabolism have shown that cellular metabolism plays a fundamental role in shaping T cell responses. T cell activation and proliferation are supported by metabolic reprogramming to meet the increased energy and biomass demand, and deregulation in immune metabolism can lead to autoimmune disorders. Specific metabolic pathways and factors have been investigated to rectify known deficiencies in several autoimmune diseases, including T1D. Most therapeutic strategies have concentrated on aerobic glycolysis to limit T cell responses, whereas glycolysis is the main metabolic pathway for T cell activation and proliferation. The use of metabolic inhibitors, especially glycolysis inhibitors may largely leave T cell function intact but primarily target those autoreactive T cells with hyperactivated metabolism. In this review, we provide an overview of metabolic reprogramming used by T cells, summarize the recent findings of key metabolic pathways and regulators modulating T cell homeostasis, differentiation, and function in the context of T1D, and discuss the opportunities for metabolic intervention to be employed to suppress autoreactive T cells and limit the progression of ß-cell destruction.


Assuntos
Doenças Autoimunes , Diabetes Mellitus Tipo 1 , Doenças Autoimunes/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Glicólise , Humanos , Ativação Linfocitária , Linfócitos T
17.
Front Pharmacol ; 13: 907702, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721172

RESUMO

Type 2 diabetes mellitus (T2DM) is a major global health concern. Psidium guajava L. (guava) is widely used for food as well as a folk medicine. Previous studies have shown its anti-diabetic and anti-inflammatory properties. However, the underlying mechanisms remains to be elusive. In this study, we assessed the potential therapeutic effects of aqueous extract of guava leaves (GvAEx) on T2DM and explored their potential mechanisms in vivo and in vitro. GvAEx was gavage administered for 12 weeks in diabetic db/db mice. Our results have demonstrated that GvAEx significantly lowered fasting plasma glucose levels (p < 0.01) and improved glucose tolerance and insulin sensitivity (p < 0.01, p < 0.05, respectively). Additionally, GvAEx increased hepatic glycogen accumulation, glucose uptake and decreased the mRNA expression levels of gluconeogenic genes. Furthermore, GvAEx-treatment caused higher glucose transporter 2 (GLUT2) expression in the membrane in hepatocytes. Notably, for the first time, we have elaborated the possible mechanism of the hypoglycemic effect of GvAEx from the perspective of intestinal microbiota. GvAEx has significantly changed the composition of microbiota and increased short chain fatty acid (SCFA) -producing Lachnospiraceae family and Akkermansia genus in the gut. Taken together, GvAEx could alleviate hyperglycemia and insulin resistance of T2DM by regulating glucose metabolism in the liver and restoring the gut microbiota. Thus, GvAEx has the potential for drug development against T2DM.

18.
Diabetes Obes Metab ; 24(10): 1901-1911, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35603907

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos
19.
Acta Biomater ; 147: 403-413, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35605956

RESUMO

The central nervous system (CNS) is protected by the blood-brain barrier (BBB), which acts as a physical barrier to regulate and prevent the uptake of endogenous metabolites and xenobiotics. However, the BBB prevents most non-lipophilic drugs from reaching the CNS following systematic administration. Therefore, there is considerable interest in identifying drug carriers that can maintain the biostability of therapeutic molecules and target their transport across the BBB. In this regard, upconversion nanoparticles (UCNPs) have become popular as a nanoparticle-based solution to this problem, with the additional benefit that they display unique properties for in vivo visualization. The majority of studies to date have explored basic spherical UCNPs for drug delivery applications. However, the biophysical properties of UCNPs, cell uptake and BBB transport have not been thoroughly investigated. In this study, we described a one-pot seed-mediated approach to precisely control longitudinal growth to produce bright UCNPs with various aspect ratios. We have systematically evaluated the effects of the physical aspect ratios and PEGylation of UCNPs on cellular uptake in different cell lines and an in vivo zebrafish model. We found that PEGylated the original UCNPs can enhance their biostability and cell uptake capacity. We identify an optimal aspect ratio for UCNP uptake into several different types of cultured cells, finding that this is generally in the ratio of 2 (length/width). This data provides a crucial clue for further optimizing UCNPs as a drug carrier to deliver therapeutic agents into the CNS. STATEMENT OF SIGNIFICANCE: The central nervous system (CNS) is protected by the blood-brain barrier (BBB), which acts as a highly selective semipermeable barrier of endothelial cells to regulate and prevent the uptake of toxins and pathogens. However, the BBB prevents most non-lipophilic drugs from reaching the CNS following systematic administration. The proposed research is significant because identifying the aspect ratio of drug carriers that maintains the biostability of therapeutic molecules and targets their transport across the blood-brain barrier (BBB) is crucial for designing an efficient drug delivery system. Therefore, this research provides a vital clue for further optimizing UCNPs as drug carriers to deliver therapeutic molecules into the brain.


Assuntos
Nanopartículas , Peixe-Zebra , Animais , Barreira Hematoencefálica/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Células Endoteliais/metabolismo , Nanopartículas/química , Polietilenoglicóis/metabolismo , Polietilenoglicóis/farmacologia
20.
Front Endocrinol (Lausanne) ; 13: 822221, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634499

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1 , Exossomos , RNA Longo não Codificante , Diabetes Mellitus Tipo 1/genética , Exossomos/genética , Exossomos/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , RNA Longo não Codificante/genética , RNA Mensageiro/genética
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