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1.
JAMA ; 323(4): 339-351, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31990315

RESUMO

Importance: Public health screening for type 1 diabetes in its presymptomatic stages may reduce disease severity and burden on a population level. Objective: To determine the prevalence of presymptomatic type 1 diabetes in children participating in a public health screening program for islet autoantibodies and the risk for progression to clinical diabetes. Design, Setting, and Participants: Screening for islet autoantibodies was offered to children aged 1.75 to 5.99 years in Bavaria, Germany, between 2015 and 2019 by primary care pediatricians during well-baby visits. Families of children with multiple islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019. Exposures: Measurement of islet autoantibodies. Main Outcomes and Measures: The primary outcome was presymptomatic type 1 diabetes, defined by 2 or more islet autoantibodies, with categorization into stages 1 (normoglycemia), 2 (dysglycemia), or 3 (clinical) type 1 diabetes. Secondary outcomes were the frequency of diabetic ketoacidosis and parental psychological stress, assessed by the Patient Health Questionnaire-9 (range, 0-27; higher scores indicate worse depression; ≤4 indicates no to minimal depression; >20 indicates severe depression). Results: Of 90 632 children screened (median [interquartile range {IQR}] age, 3.1 [2.1-4.2] years; 48.5% girls), 280 (0.31%; 95% CI, 0.27-0.35) had presymptomatic type 1 diabetes, including 196 (0.22%) with stage 1, 17 (0.02%) with stage 2, 26 (0.03%) with stage 3, and 41 who were not staged. After a median (IQR) follow-up of 2.4 (1.0-3.2) years, another 36 children developed stage 3 type 1 diabetes. The 3-year cumulative risk for stage 3 type 1 diabetes in the 280 children with presymptomatic type 1 diabetes was 24.9% ([95% CI, 18.5%-30.7%]; 54 cases; annualized rate, 9.0%). Two children had diabetic ketoacidosis. Median (IQR) psychological stress scores were significantly increased at the time of metabolic staging in mothers of children with presymptomatic type 1 diabetes (3 [1-7]) compared with mothers of children without islet autoantibodies (2 [1-4]) (P = .002), but declined after 12 months of follow-up (2 [0-4]) (P < .001). Conclusions and Relevance: Among children aged 2 to 5 years in Bavaria, Germany, a program of primary care-based screening showed an islet autoantibody prevalence of 0.31%. These findings may inform considerations of population-based screening of children for islet autoantibodies.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Ilhotas Pancreáticas/imunologia , Programas de Rastreamento , Doenças Assintomáticas/epidemiologia , Doenças Assintomáticas/psicologia , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/psicologia , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Pais , Inquéritos e Questionários
2.
Nat Med ; 25(12): 1865-1872, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792456

RESUMO

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. ß cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to ß cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/virologia , Enterovirus/isolamento & purificação , RNA Viral/isolamento & purificação , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Enterovirus/imunologia , Enterovirus/patogenicidade , Fezes/virologia , Feminino , Humanos , Lactente , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/virologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/virologia , Masculino , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/virologia
3.
Nat Commun ; 10(1): 3495, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375697

RESUMO

Immune tolerance to allografts has been pursued for decades as an important goal in transplantation. Administration of apoptotic donor splenocytes effectively induces antigen-specific tolerance to allografts in murine studies. Here we show that two peritransplant infusions of apoptotic donor leukocytes under short-term immunotherapy with antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor and anti-interleukin 6 receptor antibody induce long-term (≥1 year) tolerance to islet allografts in 5 of 5 nonsensitized, MHC class I-disparate, and one MHC class II DRB allele-matched rhesus macaques. Tolerance in our preclinical model is associated with a regulatory network, involving antigen-specific Tr1 cells exhibiting a distinct transcriptome and indirect specificity for matched MHC class II and mismatched class I peptides. Apoptotic donor leukocyte infusions warrant continued investigation as a cellular, nonchimeric and translatable method for inducing antigen-specific tolerance in transplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica , Transplante das Ilhotas Pancreáticas/efeitos adversos , Linfócitos T Reguladores/transplante , Transferência Adotiva , Aloenxertos/imunologia , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Ilhotas Pancreáticas/imunologia , Macaca mulatta , Masculino , Linfócitos T Reguladores/imunologia , Doadores de Tecidos , Transplante Homólogo/efeitos adversos
4.
Endocr J ; 66(5): 459-468, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30842364

RESUMO

Pancreatic polypeptide (PP) is a 36-amino acid peptide encoded by the Ppy gene, which is produced by a small population of cells located in the periphery of the islets of Langerhans. Owing to the high amino acid sequence similarity among neuropeptide Y family members, antibodies against PP that are currently available are not convincingly specific to PP. Here we report the development of mouse monoclonal antibodies that specifically bind to PP. We generated Ppy knockout (Ppy-KO) mice in which the Ppy-coding region was replaced by Cre recombinase. The Ppy-KO mice were immunized with mouse PP peptide, and stable hybridoma cell lines producing anti-PP antibodies were isolated. Firstly, positive clones were selected in an enzyme-linked immunosorbent assay for reactivity with PP coupled to bovine serum albumin. During the screening, hybridoma clones producing antibodies that cross-react to the peptide YY (PYY) were excluded. In the second screening, hybridoma clones in which their culture media produce no signal in Ppy-KO islets but detect specific cells in the peripheral region of wild-type islets, were selected. Further studies demonstrated that the selected monoclonal antibody (23-2D3) specifically recognizes PP-producing cells, not only in mouse, but also in human and rat islets. The monoclonal antibodies with high binding specificity for PP developed in this study will be fundamental for future studies towards elucidating the expression profiles and the physiological roles of PP.


Assuntos
Anticorpos Monoclonais , Ilhotas Pancreáticas/imunologia , Polipeptídeo Pancreático/imunologia , Animais , Camundongos , Camundongos Knockout , Neuropeptídeo Y/imunologia , Peptídeo YY/imunologia
5.
Nature ; 567(7746): 43-48, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30760930

RESUMO

Cell-identity switches, in which terminally differentiated cells are converted into different cell types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic α-cells and somatostatin-producing δ-cells become insulin-expressing cells after the ablation of insulin-secreting ß-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-ß-cells, namely α-cells and pancreatic polypeptide (PPY)-producing γ-cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing α-cells maintain expression of α-cell markers, as seen by deep transcriptomic and proteomic characterization. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a treatment for diabetes and other degenerative diseases.


Assuntos
Diabetes Mellitus/patologia , Diabetes Mellitus/terapia , Células Secretoras de Glucagon/citologia , Células Secretoras de Glucagon/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/patologia , Animais , Biomarcadores/análise , Linhagem da Célula/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Feminino , Glucagon/metabolismo , Células Secretoras de Glucagon/efeitos dos fármacos , Células Secretoras de Glucagon/transplante , Glucose/farmacologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Fatores de Transcrição Maf Maior/genética , Fatores de Transcrição Maf Maior/metabolismo , Masculino , Camundongos , Especificidade de Órgãos/efeitos dos fármacos , Polipeptídeo Pancreático/metabolismo , Células Secretoras de Polipeptídeo Pancreático/citologia , Células Secretoras de Polipeptídeo Pancreático/efeitos dos fármacos , Células Secretoras de Polipeptídeo Pancreático/metabolismo , Proteômica , Análise de Sequência de RNA , Transativadores/genética , Transativadores/metabolismo , Transcriptoma , Transdução Genética
6.
Front Immunol ; 10: 99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30766536

RESUMO

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that affects more than 19 million people with incidence increasing rapidly worldwide. For T cells to effectively drive T1D, they must first traffic to the islets and extravasate through the islet vasculature. Understanding the cues that lead to T cell entry into inflamed islets is important because diagnosed T1D patients already have established immune infiltration of their islets. Here we show that CD11c+ cells are a key mediator of T cell trafficking to infiltrated islets in non-obese diabetic (NOD) mice. Using intravital 2-photon islet imaging we show that T cell extravasation into the islets is an extended process, with T cells arresting in the islet vasculature in close proximity to perivascular CD11c+ cells. Antigen is not required for T cell trafficking to infiltrated islets, but T cell chemokine receptor signaling is necessary. Using RNAseq, we show that islet CD11c+ cells express over 20 different chemokines that bind chemokine receptors expressed on islet T cells. One highly expressed chemokine-receptor pair is CXCL16-CXCR6. However, NOD. CXCR6-/- mice progressed normally to T1D and CXCR6 deficient T cells trafficked normally to the islets. Even with CXCR3 and CXCR6 dual deficiency, T cells trafficked to infiltrated islets. These data reinforce that chemokine receptor signaling is highly redundant for T cell trafficking to inflamed islets. Importantly, depletion of CD11c+ cells strongly inhibited T cell trafficking to infiltrated islets of NOD mice. We suggest that targeted depletion of CD11c+ cells associated with the islet vasculature may yield a therapeutic target to inhibit T cell trafficking to inflamed islets to prevent progression of T1D.


Assuntos
Antígeno CD11c/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Linfócitos T/imunologia , Animais , Feminino , Camundongos Endogâmicos NOD , Camundongos Knockout
7.
Diabetes Care ; 42(5): 789-796, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796108

RESUMO

OBJECTIVE: To study the association of gluten intake with development of islet autoimmunity and progression to type 1 diabetes. RESEARCH DESIGN AND METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) follows children with an increased risk of type 1 diabetes. Blood samples were collected at 9, 15, and 24 months of age, and annually thereafter. Islet autoimmunity was defined by the appearance of at least one autoantibody against insulin, IA2, GAD, or ZnT8 (zinc transporter 8) in at least two consecutive blood samples. Using food frequency questionnaires, we estimated the gluten intake (in grams per day) annually from 1 year of age. Cox regression modeling early gluten intake, and joint modeling of the cumulative gluten intake during follow-up, were used to estimate hazard ratios adjusted for confounders (aHR). RESULTS: By August 2017, 1,916 subjects were included (median age at end of follow-up 13.5 years), islet autoimmunity had developed in 178 participants, and 56 of these progressed to type 1 diabetes. We found no association between islet autoimmunity and gluten intake at 1-2 years of age or during follow-up (aHR per 4 g/day increase in gluten intake 1.00, 95% CI 0.85-1.17 and 1.01, 0.99-1.02, respectively). We found similar null results for progression from islet autoimmunity to type 1 diabetes. Introduction of gluten at <4 months of age was associated with an increased risk of progressing from islet autoimmunity to type 1 diabetes compared with introduction at 4-5.9 months (aHR 8.69, 95% CI 1.69-44.8). CONCLUSIONS: Our findings indicate no strong rationale to reduce the amount of gluten in high-risk children to prevent development of type 1 diabetes.


Assuntos
Autoimunidade , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Ingestão de Alimentos/fisiologia , Glutens/administração & dosagem , Ilhotas Pancreáticas/imunologia , Autoanticorpos/sangue , Pré-Escolar , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Inquéritos sobre Dietas , Progressão da Doença , Feminino , Seguimentos , Humanos , Lactente , Ilhotas Pancreáticas/patologia , Estudos Longitudinais , Masculino , Fatores de Risco
8.
J Neuroimmunol ; 327: 1-9, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30685070

RESUMO

Type 1 Diabetes (T1D) is an autoimmune disease in which insulin producing beta cells of the pancreas are selectively destroyed. Glial Fibrillary Acidic Protein (GFAP) expressed in peri-islet Schwann cells (pSCs) and in the ductal cells of the pancreas is one of the candidate autoantigens for T1D. Immune responses to GFAP expressing cell types precede the islet autoimmunity in Non-Obese Diabetic (NOD) mice. By removing MHC class I from GFAP expressing cell types, we tested the role of autoantigens presented by these cell types in the development of invasive insulitis. Our findings indicate that antigens expressed by pancreatic ductal cells are important in the development of invasive insulitis in NOD mice.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Ilhotas Pancreáticas/imunologia , Animais , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout
9.
Diabetes Metab Res Rev ; 35(4): e3132, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30693639

RESUMO

BACKGROUND: Antibodies to posttranslationally modified insulin (oxPTM-INS-Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM-INS-Ab can improve T1D prediction in children with positive standard islet autoantibodies (AAB). METHODS: We evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM-INS-Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA-2A) in a cohort of islet AAB-positive (AAB+ ) children from the general population (median follow-up 8.8 years). RESULTS: oxPTM-INS-Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA-2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM-INS-Ab was higher than GADA and IAA (P = 0.003 and P = 0.017, respectively), and similar to IA-2A (P = 0.896). oxPTM-INS-Ab and IA-2A were more effective than IAA for detecting progr-T1D when used as second-line biomarker in GADA+ children. Risk for diabetes was higher (P = 0.03) among multiple AAB+ who were also oxPTM-INS-Ab+ compared with those who were oxPTM-INS-Ab- . Importantly, when replacing IAA with oxPTM-INS-Ab, diabetes risk increased to 100% in children with oxPTM-INS-Ab+ in combination with GADA+ and IA-2A+ , compared with 84.37% in those with IAA+ , GADA+ , and IA-2A+ (P = 0.04). CONCLUSIONS: Antibodies to oxidized insulin (oxPTM-INS-Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB+ children.


Assuntos
Autoanticorpos/sangue , Biomarcadores/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Anticorpos Anti-Insulina/imunologia , Insulina Regular Humana/química , Insulina Regular Humana/imunologia , Ilhotas Pancreáticas/imunologia , Autoanticorpos/imunologia , Glicemia/análise , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Oxirredução , Prognóstico , Estudos Prospectivos , Processamento de Proteína Pós-Traducional
10.
Biomolecules ; 9(1)2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30669674

RESUMO

Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Sangue Fetal/metabolismo , Ilhotas Pancreáticas/imunologia , Lipídeos/análise , Área Sob a Curva , Autoanticorpos/análise , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Análise Discriminante , Progressão da Doença , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Espectrometria de Massas , Curva ROC , Esfingomielinas/metabolismo
11.
Pediatr Diabetes ; 20(3): 263-270, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30628751

RESUMO

OBJECTIVE: The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high-risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: Logistic regression and 4-fold cross-validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data. TEDDY subjects with at least one persistent, confirmed autoantibody at age 3 were analyzed with progression to T1D by age 6 serving as the primary endpoint. The logistic regression prediction model was compared to two non-statistical predictors, multiple autoantibody status, and presence of insulinoma-associated-2 autoantibodies (IA-2A). RESULTS: A total of 363 subjects had at least one autoantibody at age 3. Twenty-one percent of subjects developed T1D by age 6. Logistic regression modeling identified 5 significant predictors - IA-2A status, hemoglobin A1c, body mass index Z-score, single-nucleotide polymorphism rs12708716_G, and a combination marker of autoantibody number plus fasting insulin level. The logistic model yielded a receiver operating characteristic area under the curve (AUC) of 0.80, higher than the two other predictors; however, the differences in AUC, sensitivity, and specificity were small across models. CONCLUSIONS: This study highlights the application of precision medicine techniques to predict progression to diabetes over a 3-year window in TEDDY subjects. This multifaceted model provides preliminary improvement in prediction over simpler prediction tools. Additional tools are needed to maximize the predictive value of these approaches.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Ilhotas Pancreáticas/imunologia , Fatores Etários , Autoanticorpos/análise , Autoimunidade/genética , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Feminino , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico
12.
Xenotransplantation ; 26(2): e12461, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30230032

RESUMO

Encapsulated porcine islets could be used to treat type I diabetes without necessitating severe immunosuppression. Islet survival and secretory function in the encapsulation device need to be preserved to ensure efficient insulin output in response to surrounding stimuli. In the present study, we evaluated stimulated insulin secretion from adult and neonatal pig islets seeded on an acellular collagen matrix and encapsulated in alginate during long-term culture. Pig islets survived longer and secreted more insulin when cultured on acellular porcine dermis compared to human fascia. Islets from neonatal pigs could survive up to 33 weeks in vitro, and their insulin secretion increased during the first 5 weeks of culture in a beta-cell maturation medium. In fact, by the 4th week of culture, insulin secretion from neonatal islets attained the same level as adult islets and even surpassed it by the 18th week. Our results show that in vitro maturation of encapsulated neonatal porcine islets is possible and can actually compensate the initial low insulin secretion from these islets while allowing enough time to perform complete functional and biosafety characterization of islets before transplantation.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Insulina/metabolismo , Transplante das Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/citologia , Tempo , Alginatos , Animais , Colágeno/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Insulina/imunologia , Secreção de Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Transplante das Ilhotas Pancreáticas/métodos , Suínos , Transplante Heterólogo/métodos
13.
Curr Diabetes Rev ; 15(3): 188-193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30009709

RESUMO

Latent Autoimmune Diabetes in Adults (LADA), although formally classified as Type 1 Diabetes (T1D), very often (at least in Western countries) appear clinically with Type 2 Diabetes (T2D)-like features as overweight and insulin resistance. LADA patients do not need exogenous insulin at the time they are diagnosed with diabetes, but a large percentage will within a few years develop need for such treatment. The decline in beta cell function progresses much faster in LADA than in T2D, presumably because of the ongoing autoimmune assault in LADA, and therefore necessitates insulin therapy much earlier in LADA than in T2D. Despite high prevalence of LADA (about 10% of the total diabetic population in many countries), the treatment of LADA patients is far less elucidated than is the case for T1D and T2D. Finding a treatment strategy for LADA from the time of diagnosis, that can reduce the decline of beta cell function, ensure adequate metabolic control and thereby reduce the risk of diabetic complications is thus an important clinical challenge. Conclusions from the randomized treatment studies so far do not indicate an optimal treatment strategy in LADA. This review aims to give an overview of current practices for the medical treatment of LADA as well as an update on results from recent studies on the treatment of the disease.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Autoimune Latente em Adultos/tratamento farmacológico , Adulto , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glutamato Descarboxilase/uso terapêutico , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/uso terapêutico , Ilhotas Pancreáticas/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Curr Diabetes Rev ; 15(3): 174-177, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30009711

RESUMO

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than "classical" type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis have been challenged. Despite the absence of a genetic background that is exclusive for LADA this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems to therapy and follow-up, perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.


Assuntos
Diabetes Autoimune Latente em Adultos/diagnóstico , Adulto , Idade de Início , Autoanticorpos/sangue , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Diagnóstico Diferencial , Humanos , Ilhotas Pancreáticas/imunologia , Diabetes Autoimune Latente em Adultos/classificação
15.
Diabetes Care ; 42(2): 192-199, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30061316

RESUMO

OBJECTIVE: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS: Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS: At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS: Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.


Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas/imunologia , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Adolescente , Adulto , Autoanticorpos/análise , Autoanticorpos/sangue , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/prevenção & controle , Progressão da Doença , Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/genética , Doenças em Gêmeos/imunologia , Meio Ambiente , Feminino , Predisposição Genética para Doença , Glutamato Descarboxilase/imunologia , Humanos , Insulina/metabolismo , Masculino , Programas de Rastreamento/métodos , Fatores de Risco , Estudos Soroepidemiológicos , Irmãos , Gêmeos/genética , Gêmeos Dizigóticos/genética , Gêmeos Dizigóticos/estatística & dados numéricos , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/estatística & dados numéricos , Adulto Jovem
16.
Pediatr Diabetes ; 20(1): 86-92, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30411443

RESUMO

OBJECTIVE: We investigated the association between maternal use of vitamin D and omega-3 fatty acids (n-3 FAs) supplements during pregnancy and risk of islet autoimmunity (IA) in the offspring. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) Study is prospectively following 8676 children with increased genetic risk for type 1 diabetes in Finland, Germany, Sweden, and the United States. Blood samples were collected every 3 months between 3 and 48 months of age then every 6 months thereafter to determine persistent IA. Duration, frequency, and supplement dose during pregnancy were recalled by mothers at 3 to 4 months postpartum. Cumulative intakes of supplemental vitamin D and n-3 FAs were analyzed as continuous or binary variables. We applied time-to-event analysis to study the association between maternal supplement use and IA, adjusting for country, human leukocyte antigen-DR-DQ genotype, family history of type 1 diabetes and sex. Secondary outcomes included insulin autoantibodies (IAA) or glutamic acid decarboxylase (GADA) as the first appearing autoantibody. RESULTS: As of February 2018, there were 747 (9.0%) children with IA. Vitamin D supplement intake during pregnancy (any vs none) was not associated with risk for IA (hazard ratio [HR] 1.11; 95% confidence interval [CI] 0.94, 1.31); neither was cumulative vitamin D supplement intake. Supplemental n-3 FA intake was similarly not associated with IA risk (HR: 1.19, 95% CI 0.98, 1.45). Similar lack of association was observed for either IAA or GADA as the first appearing autoantibody. CONCLUSIONS: The TEDDY cohort showed no evidence of benefit regarding IA risk for vitamin D or n-3 FA supplementation during pregnancy.


Assuntos
Autoimunidade , Diabetes Mellitus Tipo 1/epidemiologia , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Ilhotas Pancreáticas/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Vitamina D/administração & dosagem , Autoanticorpos/sangue , Autoimunidade/efeitos dos fármacos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Suplementos Nutricionais/estatística & dados numéricos , Feminino , Finlândia/epidemiologia , Alemanha/epidemiologia , Glutamato Descarboxilase/imunologia , Humanos , Lactente , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Suécia/epidemiologia , Estados Unidos/epidemiologia
17.
Pediatr Diabetes ; 20(1): 73-77, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30338642

RESUMO

AIMS/HYPOTHESIS: Evidence of the role of cytomegalovirus (CMV) infection in the pathogenesis of type 1 diabetes (T1D) has remained inconclusive. Our aim was to elucidate the possible role of CMV infection in the initiation of islet autoimmunity and in the progression to clinical T1D among children with human leukocyte antigen (HLA)-conferred T1D risk. METHODS: A total of 1402 children from the prospective Type 1 Diabetes Prediction and Prevention (DIPP) study were analyzed for CMV-specific IgG antibodies during early childhood. All the children carried HLA-DQ genotypes associated with increased risk for T1D. The effect of CMV infection on the appearance of T1D-associated autoantibodies (insulin autoantibodies [IAA], glutamic acid decarboxylase [GADA], and insulinoma antigen-2 [IA-2A], n = 356) and on the progression rate to clinical T1D (n = 233) were analyzed with Kaplan-Meier survival analysis and Log-rank test. RESULTS: Early childhood CMV infection was inversely associated with the development of T1D during childhood. Cumulative progression to T1D was decreased in subjects with an early CMV infection (P = 0.035). In further analyses, the effect of early CMV infection on the initiation of islet autoimmunity and progression to clinical T1D were examined separately. Interestingly, early CMV infection did not affect the appearance of T1D-associated autoantibodies but a decelerating effect was observed on the progression rate from islet autoimmunity to clinical T1D (P = 0.015). CONCLUSION: Our results suggest that an early childhood CMV infection may decelerate the progression from islet autoimmunity to clinical T1D among at-risk children and may thus protect these children from progressing to T1D during childhood.


Assuntos
Infecções por Citomegalovirus/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/patologia , Adolescente , Idade de Início , Autoanticorpos/sangue , Autoimunidade/fisiologia , Criança , Pré-Escolar , Citomegalovirus/imunologia , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Finlândia/epidemiologia , Seguimentos , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Humanos , Lactente , Ilhotas Pancreáticas/imunologia , Masculino , Fatores de Risco
18.
Fetal Pediatr Pathol ; 38(2): 103-111, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30588857

RESUMO

BACKGROUND: Some studies implicate rotavirus infection as a trigger for the development of type 1 diabetes mellitus (T1DM) in children, however findings are controversial. OBJECTIVES: We investigated the link between rotavirus infection and autoantibodies against islet antigens and T1DM in children. METHODS: Serum samples from 80 new-onset diabetic and 80 nondiabetic children were screened for anti-rotavirus IgG, anti-GAD65 and anti-IA-2 autoantibodies using ELISA kits. RESULTS: Positivity percentages of anti-rotavirus IgG detection in diabetic and nondiabetic children were 51.3% and 35.0%, respectively (p = 0.03). The mean anti-GAD65 and anti-IA-2 antibody titers in anti-rotavirus IgG positive samples were statistically higher than that the anti-rotavirus IgG negative samples. A positive correlation was found between anti-rotavirus IgG and anti-GAD65 antibody levels (p = 0.004; r = 0.22). CONCLUSIONS: Our findings support the hypothesis that rotovirus infection may induce T1DM in children.


Assuntos
Autoanticorpos/sangue , Autoantígenos/sangue , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Infecções por Rotavirus/imunologia , Autoantígenos/imunologia , Criança , Pré-Escolar , Humanos , Lactente , Ilhotas Pancreáticas/imunologia , Masculino , Proteínas de Membrana/imunologia
19.
Front Immunol ; 9: 2800, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555479

RESUMO

Diabetogenic T cells infiltrate the pancreatic islets by transmigrating across the microcapillaries residing close to, or within, the pancreatic islets. Deficiency in IFNγ signaling prevents efficient migration of T cells into the pancreatic islets, but the IFNγ-regulated molecules that mediate this are uncertain. Homing of autoreactive T cells into target tissues may require antigen specificity through presentation of cognate antigen by MHC expressed on the vascular endothelium. We investigated the hypothesis that IFNγ promotes the migration of islet antigen-specific CD4+ T cells by upregulating MHC class II on islet endothelial cells (IEC), thereby providing an antigen-specific signal for islet infiltration. Upon IFNγ stimulation, MHC class II, which is not constitutively expressed on IEC, was induced. IFNγ-dependent upregulation of MHC class II was detected in IEC isolated from prediabetic NOD mice at the earliest stages of insulitis, before other markers of inflammation were present. Using a CD4+ T cell-mediated adoptive transfer model of autoimmune diabetes we observed that even though diabetes does not develop in recipient mice lacking IFNγ receptors, mice with MHC class II-deficient IEC were not protected from disease. Thus, IFNγ-regulated molecules, but not MHC class II or antigen presentation by IECs is required for the early migration of antigen-specific CD4+ T cells into the pancreatic islets.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Endoteliais/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Interferon gama/imunologia , Ilhotas Pancreáticas/imunologia , Estado Pré-Diabético/imunologia , Animais , Biomarcadores , Linfócitos T CD4-Positivos/patologia , Células Endoteliais/patologia , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Interferon gama/genética , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Estado Pré-Diabético/genética , Estado Pré-Diabético/patologia
20.
Sci Data ; 5: 180250, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30422126

RESUMO

Early prediction and prevention of type 1 diabetes (T1D) are currently unmet medical needs. Previous metabolomics studies suggest that children who develop T1D are characterised by a distinct metabolic profile already detectable during infancy, prior to the onset of islet autoimmunity. However, the specificity of persistent metabolic disturbances in relation T1D development has not yet been established. Here, we report a longitudinal plasma lipidomics dataset from (1) 40 children who progressed to T1D during follow-up, (2) 40 children who developed single islet autoantibody but did not develop T1D and (3) 40 matched controls (6 time points: 3, 6, 12, 18, 24 and 36 months of age). This dataset may help other researchers in studying age-dependent progression of islet autoimmunity and T1D as well as of the age-dependence of lipidomic profiles in general. Alternatively, this dataset could more broadly used for the development of methods for the analysis of longitudinal multivariate data.


Assuntos
Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Lipídeos/sangue , Autoanticorpos/sangue , Autoimunidade , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Progressão da Doença , Finlândia , Predisposição Genética para Doença , Humanos , Lactente , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Lipídeos/fisiologia , Estudos Longitudinais , Metabolômica
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