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1.
Cell ; 183(6): 1650-1664.e15, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33125898

RESUMO

Correction of disease-causing mutations in human embryos holds the potential to reduce the burden of inherited genetic disorders and improve fertility treatments for couples with disease-causing mutations in lieu of embryo selection. Here, we evaluate repair outcomes of a Cas9-induced double-strand break (DSB) introduced on the paternal chromosome at the EYS locus, which carries a frameshift mutation causing blindness. We show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame. Notably, about half of the breaks remain unrepaired, resulting in an undetectable paternal allele and, after mitosis, loss of one or both chromosomal arms. Correspondingly, Cas9 off-target cleavage results in chromosomal losses and hemizygous indels because of cleavage of both alleles. These results demonstrate the ability to manipulate chromosome content and reveal significant challenges for mutation correction in human embryos.


Assuntos
Alelos , Proteína 9 Associada à CRISPR/metabolismo , Cromossomos Humanos/genética , Embrião de Mamíferos/metabolismo , Animais , Sequência de Bases , Blastocisto/metabolismo , Ciclo Celular/genética , Linhagem Celular , Deleção Cromossômica , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades/genética , Implantação do Embrião/genética , Proteínas do Olho/genética , Fertilização , Edição de Genes , Rearranjo Gênico/genética , Loci Gênicos , Genoma Humano , Genótipo , Heterozigoto , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Mutação INDEL/genética , Camundongos , Mitose , Fases de Leitura Aberta/genética , Polimorfismo de Nucleotídeo Único/genética
2.
N Engl J Med ; 387(13): 1161-1172, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36170500

RESUMO

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).


Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemiantes , Insulina Aspart , Sistemas de Infusão de Insulina , Insulina Lispro , Adolescente , Adulto , Idoso , Biônica/instrumentação , Glicemia/análise , Automonitorização da Glicemia/instrumentação , Automonitorização da Glicemia/métodos , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina/uso terapêutico , Insulina Aspart/administração & dosagem , Insulina Aspart/efeitos adversos , Insulina Aspart/uso terapêutico , Sistemas de Infusão de Insulina/efeitos adversos , Insulina Lispro/administração & dosagem , Insulina Lispro/efeitos adversos , Insulina Lispro/uso terapêutico , Pessoa de Meia-Idade , Adulto Jovem
3.
Diabetologia ; 63(3): 588-596, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31768570

RESUMO

AIMS/HYPOTHESIS: Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status. METHODS: Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39 years; range, 1-49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study. RESULTS: Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%. CONCLUSIONS/INTERPRETATION: Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Estado Pré-Diabético/patologia , Adolescente , Adulto , Autoanticorpos/análise , Doenças Autoimunes/sangue , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , 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 , Seguimentos , Predisposição Genética para Doença , Teste de Tolerância a Glucose , Humanos , Individualidade , Lactente , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Estado Pré-Diabético/sangue , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/genética , Prognóstico , Fatores de Risco , Adulto Jovem
4.
Nature ; 510(7506): 533-6, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24776804

RESUMO

The transfer of somatic cell nuclei into oocytes can give rise to pluripotent stem cells that are consistently equivalent to embryonic stem cells, holding promise for autologous cell replacement therapy. Although methods to induce pluripotent stem cells from somatic cells by transcription factors are widely used in basic research, numerous differences between induced pluripotent stem cells and embryonic stem cells have been reported, potentially affecting their clinical use. Because of the therapeutic potential of diploid embryonic stem-cell lines derived from adult cells of diseased human subjects, we have systematically investigated the parameters affecting efficiency of blastocyst development and stem-cell derivation. Here we show that improvements to the oocyte activation protocol, including the use of both kinase and translation inhibitors, and cell culture in the presence of histone deacetylase inhibitors, promote development to the blastocyst stage. Developmental efficiency varied between oocyte donors, and was inversely related to the number of days of hormonal stimulation required for oocyte maturation, whereas the daily dose of gonadotropin or the total number of metaphase II oocytes retrieved did not affect developmental outcome. Because the use of concentrated Sendai virus for cell fusion induced an increase in intracellular calcium concentration, causing premature oocyte activation, we used diluted Sendai virus in calcium-free medium. Using this modified nuclear transfer protocol, we derived diploid pluripotent stem-cell lines from somatic cells of a newborn and, for the first time, an adult, a female with type 1 diabetes.


Assuntos
Núcleo Celular/genética , Reprogramação Celular , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diploide , Oócitos/citologia , Células-Tronco Pluripotentes/citologia , Adulto , Blastocisto/efeitos dos fármacos , Fusão Celular , Cromossomos de Mamíferos/metabolismo , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Recém-Nascido , Metáfase , Oócitos/metabolismo , Oogênese , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/patologia , Vírus Sendai , Fuso Acromático/metabolismo
5.
JAMA ; 323(23): 2388-2396, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32543683

RESUMO

Importance: Adolescents and young adults with type 1 diabetes exhibit the worst glycemic control among individuals with type 1 diabetes across the lifespan. Although continuous glucose monitoring (CGM) has been shown to improve glycemic control in adults, its benefit in adolescents and young adults has not been demonstrated. Objective: To determine the effect of CGM on glycemic control in adolescents and young adults with type 1 diabetes. Design, Setting, and Participants: Randomized clinical trial conducted between January 2018 and May 2019 at 14 endocrinology practices in the US including 153 individuals aged 14 to 24 years with type 1 diabetes and screening hemoglobin A1c (HbA1c) of 7.5% to 10.9%. Interventions: Participants were randomized 1:1 to undergo CGM (CGM group; n = 74) or usual care using a blood glucose meter for glucose monitoring (blood glucose monitoring [BGM] group; n = 79). Main Outcomes and Measures: The primary outcome was change in HbA1c from baseline to 26 weeks. There were 20 secondary outcomes, including additional HbA1c outcomes, CGM glucose metrics, and patient-reported outcomes with adjustment for multiple comparisons to control for the false discovery rate. Results: Among the 153 participants (mean [SD] age, 17 [3] years; 76 [50%] were female; mean [SD] diabetes duration, 9 [5] years), 142 (93%) completed the study. In the CGM group, 68% of participants used CGM at least 5 days per week in month 6. Mean HbA1c was 8.9% at baseline and 8.5% at 26 weeks in the CGM group and 8.9% at both baseline and 26 weeks in the BGM group (adjusted between-group difference, -0.37% [95% CI, -0.66% to -0.08%]; P = .01). Of 20 prespecified secondary outcomes, there were statistically significant differences in 3 of 7 binary HbA1c outcomes, 8 of 9 CGM metrics, and 1 of 4 patient-reported outcomes. The most commonly reported adverse events in the CGM and BGM groups were severe hypoglycemia (3 participants with an event in the CGM group and 2 in the BGM group), hyperglycemia/ketosis (1 participant with an event in CGM group and 4 in the BGM group), and diabetic ketoacidosis (3 participants with an event in the CGM group and 1 in the BGM group). Conclusions and Relevance: Among adolescents and young adults with type 1 diabetes, continuous glucose monitoring compared with standard blood glucose monitoring resulted in a small but statistically significant improvement in glycemic control over 26 weeks. Further research is needed to understand the clinical importance of the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03263494.


Assuntos
Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 1/sangue , Hemoglobinas Glicadas/análise , Hipoglicemiantes/administração & dosagem , Adolescente , Glicemia/análise , Automonitorização da Glicemia/instrumentação , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética , Feminino , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/diagnóstico , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Masculino , Aplicativos Móveis , Monitorização Ambulatorial/instrumentação , Adulto Jovem
6.
JAMA ; 323(23): 2397-2406, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32543682

RESUMO

Importance: Continuous glucose monitoring (CGM) provides real-time assessment of glucose levels and may be beneficial in reducing hypoglycemia in older adults with type 1 diabetes. Objective: To determine whether CGM is effective in reducing hypoglycemia compared with standard blood glucose monitoring (BGM) in older adults with type 1 diabetes. Design, Setting, and Participants: Randomized clinical trial conducted at 22 endocrinology practices in the United States among 203 adults at least 60 years of age with type 1 diabetes. Interventions: Participants were randomly assigned in a 1:1 ratio to use CGM (n = 103) or standard BGM (n = 100). Main Outcomes and Measures: The primary outcome was CGM-measured percentage of time that sensor glucose values were less than 70 mg/dL during 6 months of follow-up. There were 31 prespecified secondary outcomes, including additional CGM metrics for hypoglycemia, hyperglycemia, and glucose control; hemoglobin A1c (HbA1c); and cognition and patient-reported outcomes, with adjustment for multiple comparisons to control for false-discovery rate. Results: Of the 203 participants (median age, 68 [interquartile range {IQR}, 65-71] years; median type 1 diabetes duration, 36 [IQR, 25-48] years; 52% female; 53% insulin pump use; mean HbA1c, 7.5% [SD, 0.9%]), 83% used CGM at least 6 days per week during month 6. Median time with glucose levels less than 70 mg/dL was 5.1% (73 minutes per day) at baseline and 2.7% (39 minutes per day) during follow-up in the CGM group vs 4.7% (68 minutes per day) and 4.9% (70 minutes per day), respectively, in the standard BGM group (adjusted treatment difference, -1.9% (-27 minutes per day); 95% CI, -2.8% to -1.1% [-40 to -16 minutes per day]; P <.001). Of the 31 prespecified secondary end points, there were statistically significant differences for all 9 CGM metrics, 6 of 7 HbA1c outcomes, and none of the 15 cognitive and patient-reported outcomes. Mean HbA1c decreased in the CGM group compared with the standard BGM group (adjusted group difference, -0.3%; 95% CI, -0.4% to -0.1%; P <.001). The most commonly reported adverse events using CGM and standard BGM, respectively, were severe hypoglycemia (1 and 10), fractures (5 and 1), falls (4 and 3), and emergency department visits (6 and 8). Conclusions and Relevance: Among adults aged 60 years or older with type 1 diabetes, continuous glucose monitoring compared with standard blood glucose monitoring resulted in a small but statistically significant improvement in hypoglycemia over 6 months. Further research is needed to understand the long-term clinical benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT03240432.


Assuntos
Automonitorização da Glicemia/métodos , Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Hemoglobinas Glicadas/análise , Hipoglicemia/prevenção & controle , Idoso , Automonitorização da Glicemia/instrumentação , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/psicologia , Feminino , Humanos , Hiperglicemia/diagnóstico , Hipoglicemia/induzido quimicamente , Hipoglicemia/diagnóstico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial/instrumentação , Medidas de Resultados Relatados pelo Paciente
7.
Am J Hum Genet ; 98(5): 934-955, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27153397

RESUMO

Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders. Targeted bis-seq confirmed hap-ASM in 12/13 loci tested, including CCDC155, CD69, FRMD1, IRF1, KBTBD11, and S100A(∗)-ILF2, associated with immune phenotypes, MYT1L, PTPRN2, CMTM8 and CELF2, associated with neurological disorders, NGFR and HLA-DRB6, associated with both immunological and brain disorders, and ZFP57, a trans-acting regulator of genomic imprinting. Polymorphic CTCF and transcription factor (TF) binding sites were over-represented among hap-ASM DMRs and mQTLs, and analysis of the human data, supplemented by cross-species comparisons to macaques, indicated that CTCF and TF binding likelihood predicts the strength and direction of the allelic methylation asymmetry. These results show that hap-ASM is highly tissue specific; an important trans-acting regulator of genomic imprinting is regulated by this phenomenon; and variation in CTCF and TF binding sites is an underlying mechanism, and maps of hap-ASM and mQTLs reveal regulatory sequences underlying supra- and sub-threshold GWAS peaks in immunological and neurological disorders.


Assuntos
Metilação de DNA , Impressão Genômica , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Transativadores/genética , Alelos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Doenças do Sistema Imunitário/genética , Macaca mulatta , Macaca radiata , Doenças do Sistema Nervoso/genética , Placenta/metabolismo , Placenta/patologia , Gravidez , Especificidade da Espécie , Linfócitos T/metabolismo , Linfócitos T/patologia
8.
Nature ; 493(7434): 632-7, 2013 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-23254936

RESUMO

Mitochondrial DNA mutations transmitted maternally within the oocyte cytoplasm often cause life-threatening disorders. Here we explore the use of nuclear genome transfer between unfertilized oocytes of two donors to prevent the transmission of mitochondrial mutations. Nuclear genome transfer did not reduce developmental efficiency to the blastocyst stage, and genome integrity was maintained provided that spontaneous oocyte activation was avoided through the transfer of incompletely assembled spindle-chromosome complexes. Mitochondrial DNA transferred with the nuclear genome was initially detected at levels below 1%, decreasing in blastocysts and stem-cell lines to undetectable levels, and remained undetectable after passaging for more than one year, clonal expansion, differentiation into neurons, cardiomyocytes or ß-cells, and after cellular reprogramming. Stem cells and differentiated cells had mitochondrial respiratory chain enzyme activities and oxygen consumption rates indistinguishable from controls. These results demonstrate the potential of nuclear genome transfer to prevent the transmission of mitochondrial disorders in humans.


Assuntos
DNA Mitocondrial/genética , Técnicas de Transferência Nuclear/normas , Oócitos , Linhagem Celular , Células Cultivadas , Criopreservação , Desenvolvimento Embrionário , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Genótipo , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oócitos/citologia , Oócitos/metabolismo
9.
Nature ; 478(7367): 70-5, 2011 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-21979046

RESUMO

The exchange of the oocyte's genome with the genome of a somatic cell, followed by the derivation of pluripotent stem cells, could enable the generation of specific cells affected in degenerative human diseases. Such cells, carrying the patient's genome, might be useful for cell replacement. Here we report that the development of human oocytes after genome exchange arrests at late cleavage stages in association with transcriptional abnormalities. In contrast, if the oocyte genome is not removed and the somatic cell genome is merely added, the resultant triploid cells develop to the blastocyst stage. Stem cell lines derived from these blastocysts differentiate into cell types of all three germ layers, and a pluripotent gene expression program is established on the genome derived from the somatic cell. This result demonstrates the feasibility of reprogramming human cells using oocytes and identifies removal of the oocyte genome as the primary cause of developmental failure after genome exchange.


Assuntos
Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Oócitos/citologia , Oócitos/fisiologia , Adulto , Blastocisto/citologia , Blastocisto/metabolismo , Diferenciação Celular , Metilação de DNA , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Genoma Humano/genética , Camadas Germinativas/citologia , Camadas Germinativas/embriologia , Camadas Germinativas/metabolismo , Humanos , Doação de Oócitos , Oócitos/crescimento & desenvolvimento , Cultura Primária de Células , Transcrição Gênica , Triploidia , Adulto Jovem
10.
Pediatr Diabetes ; 16(3): 227-33, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25082184

RESUMO

OBJECTIVE: Monogenic diabetes (MD) is rare and can often be confused with type 1 diabetes (T1D) in a pediatric cohort. We sought to determine clinical criteria that could optimally identify candidates for genetic testing of two common forms of MD that alter therapy: glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1α). RESEARCH DESIGN AND METHODS: We performed a retrospective chart review of 939 patients with a presumed diagnosis of T1D, 6 months-20 yr of age, and identified four clinical criteria that were unusual for T1D and could warrant further evaluation for MD: (i) negative pancreatic autoantibodies, (ii) evidence of prolonged endogenous insulin production, or (iii) strong family history of diabetes in multiple generations. One hundred and twenty-one patients were identified as having one or more of these high-risk clinical criteria and were offered screening for mutations in GCK and HNF1α; 58 consented for genetic testing. RESULTS: Of 58 patients with presumed T1D who underwent genetic testing, four were found to have GCK and one had HNF1α. No patients with only one high-risk feature were found to have MD. Of 10 patients who had two or more high risk criteria, five had MD (50%). CONCLUSION: A high frequency of MD from mutations in GCK/HNF1α may be identified among pediatric diabetic patients originally considered to have T1D by performing genetic testing on those patients with multiple clinical risk factors for MD.


Assuntos
Diabetes Mellitus/genética , Glucoquinase/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Adolescente , Criança , Pré-Escolar , Diabetes Mellitus/diagnóstico , Diabetes Mellitus Tipo 1/diagnóstico , Humanos , Lactente , Estudos Retrospectivos , Adulto Jovem
11.
Lancet ; 381(9881): 1905-15, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23562090

RESUMO

BACKGROUND: Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved ß-cell function in recent-onset type 1 diabetes. METHODS: We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. FINDINGS: Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. INTERPRETATION: Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. FUNDING: National Institutes of Health and Juvenile Diabetes Research Foundation.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Adolescente , Adulto , Análise de Variância , Anticorpos Monoclonais Humanizados , Peptídeo C/efeitos dos fármacos , Criança , Método Duplo-Cego , Feminino , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Interleucina-1/antagonistas & inibidores , Masculino , Resultado do Tratamento , Adulto Jovem
12.
Ethn Health ; 18(1): 83-96, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22762449

RESUMO

OBJECTIVES: Adherence to diabetes self care is poor for Hispanic American and African-American patients. This study examined the change in adherence over time and in response to a telemedicine intervention for elderly diabetes patients in these groups compared to white diabetes patients. We also examined whether adherence mediated the effect of the intervention on glycemic control (A1c). DESIGN: The Informatics for Diabetes Education and Telemedicine project randomized medically underserved Medicare patients (n=1665) to telemedicine case management (televideo educator visits, individualized goal-setting/problem solving) or usual care. Hispanic and African-American educators delivered the intervention in Spanish if needed. MAIN OUTCOME MEASURES: Annual assessment included A1c and self-reported adherence (Summary of Diabetes Self-Care Activities scale). A simple model (only time and group terms) and a model with covariates (e.g., age) were examined for baseline and 5 years of follow-up. SAS PROC Mixed was used with non-linear terms to examine mediating effects of adherence on A1c, by performing tests of the mediating path coefficients. RESULTS: Over time, self-reported adherence improved for the treatment group compared to usual care (p<0.001). There was no significant interaction with racial/ethnic group membership, i.e., all groups improved. However, minority subjects were consistently less adherent than whites. Also, greater comorbidity and diabetes symptoms predicted poorer adherence, greater duration of diabetes and more years of education predicted better adherence. Adherence was a significant mediator of A1c (p<0.001). CONCLUSIONS: A unique, tailored telemedicine intervention was effective in achieving improved adherence to diabetes self care. However, African-American and Hispanic American participants were less adherent than white participants at all time points despite an individualized and accessible intervention. The finding that adherence did mediate glycemic control suggests that unique interventions for minority groups may be needed to overcome this disparity.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Diabetes Mellitus Tipo 2/etnologia , Hispânico ou Latino/estatística & dados numéricos , Cooperação do Paciente/etnologia , Autocuidado/estatística & dados numéricos , População Branca/estatística & dados numéricos , Negro ou Afro-Americano/educação , Idoso , Glicemia/análise , Administração de Caso/organização & administração , Diabetes Mellitus Tipo 2/terapia , Escolaridade , Feminino , Hispânico ou Latino/educação , Humanos , Masculino , Medicare/estatística & dados numéricos , New York , Cooperação do Paciente/estatística & dados numéricos , Educação de Pacientes como Assunto/métodos , Apoio Social , Telemedicina/métodos , Estados Unidos , População Branca/educação
13.
Diabetes Care ; 46(5): 1005-1013, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36920087

RESUMO

OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining ß-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS: A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS: Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Humanos , Abatacepte/uso terapêutico , Abatacepte/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Imunossupressores , Linfócitos T Reguladores , Glucose/uso terapêutico
14.
Lancet ; 378(9789): 412-9, 2011 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-21719096

RESUMO

BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes. METHODS: In this multicentre, double-blind, randomised controlled trial, patients aged 6-45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375. FINDINGS: 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1-112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47-15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept vs 15 [43%] on placebo) or neutropenia (seven [9%] vs five [14%]). INTERPRETATION: Co-stimulation modulation with abatacept slowed reduction in ß-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in ß-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. FUNDING: US National Institutes of Health.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Abatacepte , Adolescente , Adulto , Autoimunidade , Criança , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Imunossupressores/efeitos adversos , Células Secretoras de Insulina/fisiologia , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Linfócitos T/imunologia , Adulto Jovem
15.
Lancet ; 378(9788): 319-27, 2011 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-21714999

RESUMO

BACKGROUND: Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes. METHODS: Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 µg GAD-alum, two injections of 20 µg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399. FINDINGS: 145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups. INTERPRETATION: Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. FUNDING: US National Institutes of Health.


Assuntos
Doenças Autoimunes/terapia , Diabetes Mellitus Tipo 1/terapia , Glutamato Descarboxilase/uso terapêutico , Imunoterapia Ativa , Adolescente , Antígenos/imunologia , Antígenos/uso terapêutico , Doenças Autoimunes/imunologia , Canadá , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Método Duplo-Cego , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto Jovem
16.
N Engl J Med ; 361(22): 2143-52, 2009 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-19940299

RESUMO

BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos B/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Murinos , Área Sob a Curva , Linfócitos B/fisiologia , Peptídeo C/sangue , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/análise , Humanos , Imunoglobulina M/sangue , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Células Secretoras de Insulina/fisiologia , Masculino , Rituximab , Adulto Jovem
17.
Pediatr Diabetes ; 13(5): 376-83, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22332798

RESUMO

OBJECTIVE: To investigate insulin sensitivity and secretion indices and determinants of glycemic control in youth with recent-onset type 2 diabetes (T2DM) at randomization in the TODAY study, the largest study of youth with T2DM to date. METHODS: We examined estimates of insulin sensitivity [1/fasting insulin (1/I(F)), fasting glucose/insulin (G(F) /I(F)), 1/fasting C-peptide (1/C(F)), G(F) /C(F)], ß-cell function [insulinogenic index (ΔI30/ΔG30), and ΔC30/ΔG30], and disposition index (DI) in the TODAY cohort of 704 youth (14.0 ± 2.0 yr; diabetes duration 7.8 ± 5.8 months; 64.9% female; 41.1% Hispanic, 31.5% Black, 19.6% White, 6.1% American Indian, and 1.7% Asian) according to hemoglobin A1c (HbA1c) quartiles at study randomization. The randomization visit followed a run-in period (median 71 d) during which glycemic control (HbA1c ≤ 8% for at least 2 months) was achieved with metformin alone. These measures were also examined in relation to screening HbA1c levels before run-in. RESULTS: Insulin secretion indices declined with increasing HbA1c quartiles, at randomization (ΔC30/ΔG30: 0.11 ± 0.09, 0.10 ± 0.19, 0.07 ± 0.06, and 0.03 ± 0.03 ng/mL per mg/dL, p < 0.0001; DI: 0.03 ± 0.03, 0.03 ± 0.05, 0.02 ± 0.02, and 0.01 ± 0.01 mg/dL(-1) , p < 0.0001) and at screening, with no significant difference in insulin sensitivity. There were no significant differences in estimates of insulin sensitivity or secretion between genders or across the different racial groups. At randomization and screening, HbA1c correlated with DI (r = -0.3, p < 0.001), with ΔC30/ΔG30, but not with insulin sensitivity estimates. CONCLUSIONS: In youth with recent-onset T2DM treated with metformin, glycemic control, as measured by HbA1c, appears to be associated with residual ß-cell function and not insulin sensitivity.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina , Insulina/metabolismo , Adolescente , Criança , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Secreção de Insulina , Masculino , Metformina/uso terapêutico , Distribuição Aleatória
18.
Proc Natl Acad Sci U S A ; 106(37): 15768-73, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19720998

RESUMO

Type 1 diabetes (T1D) is the result of an autoimmune destruction of pancreatic beta cells. The cellular and molecular defects that cause the disease remain unknown. Pluripotent cells generated from patients with T1D would be useful for disease modeling. We show here that induced pluripotent stem (iPS) cells can be generated from patients with T1D by reprogramming their adult fibroblasts with three transcription factors (OCT4, SOX2, KLF4). T1D-specific iPS cells, termed DiPS cells, have the hallmarks of pluripotency and can be differentiated into insulin-producing cells. These results are a step toward using DiPS cells in T1D disease modeling, as well as for cell replacement therapy.


Assuntos
Células-Tronco Adultas/patologia , Diabetes Mellitus Tipo 1/patologia , Células-Tronco Pluripotentes/patologia , Adulto , Células-Tronco Adultas/metabolismo , Células-Tronco Adultas/transplante , Desdiferenciação Celular , Diferenciação Celular , Células Cultivadas , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/terapia , Endoderma/citologia , Endoderma/metabolismo , Camadas Germinativas/citologia , Camadas Germinativas/metabolismo , Humanos , Fator 4 Semelhante a Kruppel , Masculino , Modelos Biológicos , Pâncreas/citologia , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/transplante , Fatores de Transcrição/metabolismo
19.
J Clin Transl Endocrinol ; 29: 100300, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35601597

RESUMO

Aim: ZnT8 autoantibody positivity (ZnT8+) is associated with risk for type 1 diabetes and with metabolic complications in adults. Our aim was to assess prevalence of ZnT8 + in the Treatment of T2D in Adolescents and Youth (TODAY) cohort and describe associated phenotypic outcomes. Methods: TODAY participants were 13.98 ± 2.03 years with a confirmed diagnosis of T2D, BMI percentile of 97.69 ± 3.32 (64% female), and GAD- and IA2- at baseline. ZnT8 autoantibodies were measured at baseline and end of study. Results: 3 of 687 participants (0.29%) were ZnT8 + and there was one conversion (0.15%) from ZnT8- to ZnT8 + during the study. ZnT8A + individuals had higher HbA1c, HDL and LDL cholesterol, and IL-1ß concentrations, and lower BMI, IL-6, and triglyceride concentrations compared to the TODAY cohort and ZnT8A- individuals. They also had higher insulin sensitivity with lower insulin secretion and disposition index, metabolically resembling T1D. All ZnT8 + participants experienced loss of glycemic control on randomized treatment, but exhibited lower rates of diabetic complications than other groups. Conclusion: Given the low rate of complications in ZnT8 + individuals, ZnT8 likely does not impact the clinical course of the disease in this population.

20.
Commun Biol ; 5(1): 779, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918471

RESUMO

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). To understand mechanisms of ß-cell dysfunction, we generated stem cell-derived pancreatic endocrine cells with hypomorphic mutations in HNF1A. HNF1A-deficient ß-cells display impaired basal and glucose stimulated-insulin secretion, reduced intracellular calcium levels in association with a reduction in CACNA1A expression, and accumulation of abnormal insulin granules in association with SYT13 down-regulation. Knockout of CACNA1A and SYT13 reproduce the relevant phenotypes. In HNF1A deficient ß-cells, glibenclamide, a sulfonylurea drug used in the treatment of HNF1A-MODY patients, increases intracellular calcium, and restores insulin secretion. While insulin secretion defects are constitutive in ß-cells null for HNF1A, ß-cells heterozygous for hypomorphic HNF1A (R200Q) mutations lose the ability to secrete insulin gradually; this phenotype is prevented by correction of the mutation. Our studies illuminate the molecular basis for the efficacy of treatment of HNF1A-MODY with sulfonylureas, and suggest promise for the use of cell therapies.


Assuntos
Diabetes Mellitus Tipo 2 , Insulina , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Insulina/metabolismo , Insulina Regular Humana , Células-Tronco/metabolismo , Sinaptotagminas
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