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Heterogeneity and endotypes in type 1 diabetes mellitus

NATURE REVIEWS ENDOCRINOLOGY (2023)

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Review Public, Environmental & Occupational Health

The phenotype of type 1 diabetes in sub-Saharan Africa

Jean Claude Katte et al.

Summary: The phenotype of type 1 diabetes in Africa, especially sub-Saharan Africa, is poorly understood. Previous studies have suggested differences in phenotype from the classical form of the disease described in western literature. Accurate diagnosis is challenging due to atypical diabetes forms and limited resources. The age of onset seems to be later in sub-Saharan Africa.

FRONTIERS IN PUBLIC HEALTH (2023)

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Article Endocrinology & Metabolism

Phenotypes Associated With Zones Defined by Area Under the Curve Glucose and C-peptide in a Population With Islet Autoantibodies

Jay M. Sosenko et al.

Summary: Metabolic zones were formed based on AUCGLU and AUCPEP to explore the heterogeneity of type 1 diabetes. The zones were highly correlated with islet autoantibodies, and the predictive ability of glucose for risk depended on the level of C-peptide. Glucose secretion and insulin resistance made different contributions to glucose heterogeneity and diabetes risk.

DIABETES CARE (2023)

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Article Endocrinology & Metabolism

Milder loss of insulin-containing islets in individuals with type 1 diabetes and type 2 diabetes-associated TCF7L2 genetic variants

Maria J. Redondo et al.

Summary: This study found that TCF7L2 genetic variants are significantly associated with a higher percentage of residual insulin-containing cells in individuals with type 1 diabetes. This suggests the existence of a subtype of type 1 diabetes that is associated with genetic factors predisposing to type 2 diabetes, and these individuals exhibit less severe beta cell loss.

DIABETOLOGIA (2023)

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Article Medicine, General & Internal

Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes A Randomized Clinical Trial

Gregory P. Forlenza et al.

Summary: Verapamil can partially preserve pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes, as evidenced by improved stimulated C-peptide secretion at 52 weeks compared with placebo.

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (2023)

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Article Rheumatology

Unmet need in rheumatology: reports from the Advances in Targeted Therapies meeting, 2022

Kevin L. Winthrop et al.

Summary: This article summarizes the unmet clinical and scientific needs in the field of rheumatology. It highlights the importance of clinical trial design innovation and the need to better understand the natural history of rheumatic diseases. The article also identifies the specific unmet needs in different rheumatological disease-specific groups and emphasizes the importance of developing therapies and therapeutic strategies for treatment-refractory disease.

ANNALS OF THE RHEUMATIC DISEASES (2023)

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Article Endocrinology & Metabolism

Islet Autoimmunity Is Highly Prevalent and Associated With Diminished β-Cell Function in Patients With Type 2 Diabetes in the GRADE Study

Barbara Brooks-Worrell et al.

Summary: The prevalence of islet autoimmunity in patients with type 2 diabetes is higher than previously reported. T-cell-mediated autoimmunity is associated with reduced beta-cell function and poorer glycemic control.

DIABETES (2022)

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Article Endocrinology & Metabolism

2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022

Summary: The American Diabetes Association's Standards of Medical Care in Diabetes provide clinical practice recommendations, treatment goals, and tools for evaluating the quality of care in diabetes management.

DIABETES CARE (2022)

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Article Endocrinology & Metabolism

Heterogeneity of Type 1 Diabetes at Diagnosis Supports Existence of Age-Related Endotypes

Anna Parviainen et al.

Summary: Our study analyzed the characteristics of 6,015 children and adolescents diagnosed with type 1 diabetes between 2003 and 2019. The findings suggest that there are different underlying mechanisms in type 1 diabetes based on the age at diagnosis. Children diagnosed at a younger age showed stronger genetic susceptibility, higher frequency of autoantibodies, and a higher prevalence of affected relatives, while those diagnosed at an older age presented with a higher male preponderance and more severe metabolic decompensation.

DIABETES CARE (2022)

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Article Endocrinology & Metabolism

Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the US National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases

William T. Cefalu et al.

Summary: This article summarizes the rapid innovation and advancement in diabetes research and clinical care in recent years, reflecting on the significant impact of the discovery of insulin on diabetes. It also provides an overview of the agenda and outcomes of a joint symposium, covering various areas of research such as islet biology, the heterogeneity of diabetic phenotypes, and precision medicine in diabetes.

DIABETES CARE (2022)

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Review Endocrinology & Metabolism

100 YEARS OF INSULIN: Pancreas pathology in type 1 diabetes: an evolving story

Sarah J. Richardson et al.

Summary: This article reviews the current knowledge of pancreatic pathology in type 1 diabetes, highlighting the pathological changes associated with the disease and their correlation with clinical stages. The main findings include beta-cell loss, insulitis, and the hyperexpression of HLA class I and class II molecules. Additionally, changes affecting extracellular matrix components, evidence of viral infections, inflammation, and ER stress are also observed. These insights contribute to the identification of novel therapeutic targets and have implications for clinical trial design.

JOURNAL OF ENDOCRINOLOGY (2022)

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Review Endocrinology & Metabolism

Modeling human T1D-associated autoimmune processes

Mohsen Khosravi-Maharlooei et al.

Summary: This review summarizes the insights provided by animal models of type 1 diabetes in understanding the role and regulation of the immune system in human disease pathogenesis. The article describes the various models developed so far and discusses their limitations and the need for improved physiological relevance.

MOLECULAR METABOLISM (2022)

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Review Endocrinology & Metabolism

The Prevalence of Islet Autoantibodies in Children and Adolescents With Type 1 Diabetes Mellitus: A Global Scoping Review

Carlo Ross et al.

Summary: This study provides a global synthesis of the prevalence of iAb in children and adolescents with type 1 diabetes from different countries and regions, revealing IA-2A as the most prevalent in new-onset diabetes and GADA as the most common in established cases. There are substantial variations in prevalence across different regions.

FRONTIERS IN ENDOCRINOLOGY (2022)

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Editorial Material Endocrinology & Metabolism

Unveiling a novel type 1 diabetes endotype: Opportunities for intervention

Paolo Fiorina et al.

DIABETES-METABOLISM RESEARCH AND REVIEWS (2022)

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Article Endocrinology & Metabolism

Evaluating T cell responses prior to the onset of type 1 diabetes

Sefina Arif et al.

Summary: This study aimed to evaluate T cell phenotypes and metabolic profiles in high-risk individuals who progressed to type 1 diabetes. The results showed a prevalent proinflammatory T cell response in these individuals, which could potentially be used for disease staging and identifying autoantibody-positive individuals.

DIABETIC MEDICINE (2022)

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Review Endocrinology & Metabolism

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Magloire Pandoua Nekoua et al.

Summary: This review highlights the role of persistent enterovirus infections in triggering islet autoimmunity and type 1 diabetes mellitus (T1DM), and discusses the potential of vaccination or antiviral therapies in preventing T1DM onset.

NATURE REVIEWS ENDOCRINOLOGY (2022)

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Article Endocrinology & Metabolism

Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes

Jorma Ilonen et al.

Summary: The study aimed to characterize the demographics and genetic associations of type 1 diabetes endotypes defined by the first appearing islet specific autoantibodies. The analysis of children diagnosed with type 1 diabetes before the age of 10 years revealed significant differences in demographic and genetic features between endotypes defined by glutamic acid decarboxylase (GADA) or insulin autoantibodies (IAA) as the first autoantibody. The results support the assumption that the first autoantibody can be deduced based on islet autoantibody combinations, and strong differences were observed in sex, age, and genetic associations between GADA-initiated and IAA-initiated autoimmunity.

PEDIATRIC DIABETES (2022)

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Review Health Care Sciences & Services

Personalized Immunotherapies for Type 1 Diabetes: Who, What, When, and How?

Claire Deligne et al.

Summary: Our understanding of the immunopathological features of type 1 diabetes has improved, and personalized treatment based on disease stage and patient characteristics could enhance therapeutic efficacy.

JOURNAL OF PERSONALIZED MEDICINE (2022)

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Article Endocrinology & Metabolism

The β-Cell in Type 1 Diabetes Pathogenesis: A Victim of Circumstances or an Instigator of Tragic Events?

Roberto Mallone et al.

Summary: Recent reports have renewed interest in the active role of beta-cells in the pathogenesis of type 1 diabetes. Some studies suggest that type 1 diabetes may primarily be a disease of beta-cells, with autoimmunity playing a secondary role. This perspective encourages the search for environmental triggers that damage beta-cells, and highlights the potential of beta-cells to amplify autoimmune vulnerability and eventually undergo self-destruction. On the other hand, beta-cells also mount protective mechanisms, which may offer novel therapeutic targets for combining immunomodulatory and beta-cell protective agents.

DIABETES (2022)

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Article Endocrinology & Metabolism

A Novel Intron-Encoded Neuropilin-1 Isoform in Pancreatic Islets Associated With Very Young Age of Onset of Type 1 Diabetes

Michael J. MacDonald et al.

Summary: Net synthesis of pancreatic beta-cells peaks before 2 years of age and beta-cell mass is set within the first 5 years of life. In-frame translational readthrough of the NRP1 gene generates a truncated neuropilin-1 protein, which lacks downstream sequence necessary for binding VEGF and stimulates beta-cell replication. Decreased insulin cells and a genetic marker in NRP1 intron 9 are associated with early onset of type 1 diabetes.

DIABETES (2022)

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Article Multidisciplinary Sciences

A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes

Khyati Girdhar et al.

Summary: This article investigates the potential role of Parabacteroides distasonis in the pathogenesis of type 1 diabetes (T1D). The study found that a peptide sequence from P. distasonis can activate T cells from T1D patients and nonobese diabetic mice. Colonization of the mouse colon with P. distasonis accelerates the development of T1D and elicits an immune response.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2022)

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Article Endocrinology & Metabolism

Two-age islet-autoantibody screening for childhood type 1 diabetes: a prospective cohort study

Mohamed Ghalwash et al.

Summary: This study identifies efficient strategies for early islet autoantibody screening in children, with optimal ages for two measurements being 2 years and 6 years, providing high sensitivity and positive predictive value for diagnosing clinical type 1 diabetes.

LANCET DIABETES & ENDOCRINOLOGY (2022)

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Editorial Material Endocrinology & Metabolism

On the road to universal screening for risk of type 1 diabetes Comment

Maria J. Redondo

LANCET DIABETES & ENDOCRINOLOGY (2022)

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Review Endocrinology & Metabolism

Type 1 diabetes in diverse ancestries and the use of genetic risk scores

Maria J. Redondo et al.

Summary: This review provides an overview of the development and application of genetic risk scores (GRS) in type 1 diabetes, highlighting the differences in type 1 diabetes genetics among populations of diverse genetic ancestries.

LANCET DIABETES & ENDOCRINOLOGY (2022)

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Article Immunology

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects

Antti-Pekka Laine et al.

Summary: Non-HLA loci play a crucial role in the genetic susceptibility to type 1 diabetes, affecting immune-cell and pancreatic beta-cell functions. This study replicated previous associations and identified new loci associated with disease progression and the appearance of autoantibodies.

FRONTIERS IN IMMUNOLOGY (2022)

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Article Medicine, General & Internal

A classification and regression tree analysis identifies subgroups of childhood type 1 diabetes

Peter Achenbach et al.

Summary: This study identified subgroups of young patients with diabetes using the multivariable classification and regression tree analysis method. These subgroups showed significant differences in clinical and biochemical characteristics and had potential pathogenetic and therapeutic relevance.

EBIOMEDICINE (2022)

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Article Endocrinology & Metabolism

Predictors of the Initiation of Islet Autoimmunity and Progression to Multiple Autoantibodies and Clinical Diabetes: The TEDDY Study

Jeffrey P. Krischer et al.

Summary: The objective of this study was to distinguish predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children. The results showed that different predictors were associated with the different types of first appearing autoantibodies. Factors such as male sex, Finnish residence, having a sibling with type 1 diabetes, specific genes, were associated with seroconversion. The predictors of progression to diabetes differed from the predictors of progression to multiple autoantibodies.

DIABETES CARE (2022)

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Letter Endocrinology & Metabolism

Images From the Exeter Archival Diabetes Biobank Now Accessible via Pancreatlas

Noel G. Morgan et al.

DIABETES CARE (2022)

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Review Endocrinology & Metabolism

The role of GABA in islet function

D. Walker Hagan et al.

Summary: GABA, a neurotransmitter produced in the islet, influences the activity of islet cells through multiple receptors and interacts with cellular metabolism. Loss or reduction of GABA in diabetic individuals may contribute to disease pathogenesis and dysfunction of islet cells.

FRONTIERS IN ENDOCRINOLOGY (2022)

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Article Endocrinology & Metabolism

Heterogeneity of Type 1 Diabetes at Diagnosis Supports Existence of Age-Related Endotypes

Anna Parviainen et al.

Summary: The study found significant age-related differences in characteristics of children and adolescents diagnosed with type 1 diabetes. Children diagnosed at age <7 years had more autoimmune-related characteristics, while those diagnosed at age >= 13 years had higher male preponderance, longer duration of symptoms, and more severe metabolic decompensation.

DIABETES CARE (2022)

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Article Endocrinology & Metabolism

Index60 as an additional diagnostic criterion for type 1 diabetes

Maria J. Redondo et al.

Summary: The study compared characteristics of individuals identified in the peri-diagnostic range by different glucose and C-peptide tests. Participants with high 2-hour glucose levels had older age, higher C-peptide responses, higher percentage of overweight/obesity, and lower multiple autoantibody positivity compared to those with high Index60 levels or both. Progression to diabetes was observed in participants with high glucose levels and/or high Index60 levels.

DIABETOLOGIA (2021)

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Article Endocrinology & Metabolism

Adult-Onset Type 1 Diabetes: Current Understanding and Challenges

R. David Leslie et al.

Summary: Recent epidemiological data indicates that over half of new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences are present between adult-onset and childhood-onset type 1 diabetes, many of which remain poorly understood.

DIABETES CARE (2021)

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Article Endocrinology & Metabolism

Low-Dose ATG/GCSF in Established Type 1 Diabetes: A Five-Year Follow-up Report

Andrea Lin et al.

Summary: The study found that low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy can maintain C-peptide levels in some patients with type 1 diabetes over the long term, but after 5 years there were no significant differences compared to the placebo group. This emphasizes the importance of long-term follow-up in ongoing and completed phase 2 trials of low-dose ATG therapy for type 1 diabetes.

DIABETES (2021)

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Article Cell Biology

Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals

Emily K. Sims et al.

Summary: A single 14-day course of teplizumab treatment in high-risk individuals showed lasting effects on delaying type 1 diabetes diagnosis and improving beta cell function. Changes in CD8(+) T cell subsets indicated that partially exhausted effector cells were associated with clinical response to immune therapy. This trial demonstrated improvements in metabolic responses and diabetes delay with immune therapy.

SCIENCE TRANSLATIONAL MEDICINE (2021)

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Article Endocrinology & Metabolism

Footprints of Immune Cells in the Pancreas in Type 1 Diabetes; to B or Not to B: Is That Still the Question?

Pia Leete et al.

Summary: Significant progress has been made in understanding the phenotypes of circulating immune cell sub-populations in human type 1 diabetes, but much less is known about the equivalent populations that infiltrate the islets to cause beta-cell loss. The phenotype and role of B-lymphocytes in the pancreas remain enigmatic, especially in relation to CD8+ T-lymphocytes. Differences in the proportion of islet-associated B-lymphocytes between different age groups suggest two endotypes of the disease, with CD8+ T-lymphocytes forming the predominant population in all groups.

FRONTIERS IN ENDOCRINOLOGY (2021)

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Article Endocrinology & Metabolism

Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes

Teresa Rodriguez-Calvo et al.

Summary: Analysis of data from clinical cohorts and human pancreatic tissue suggests that reduced prohormone processing is an early and persistent feature in type 1 diabetes. This article reviews the current knowledge on alterations in islet prohormone expression and processing in type 1 diabetes, discusses their clinical impact, and outlines key next steps for further research. Exploring prohormone processing as a potential biomarker for personalized intervention in the natural history of type 1 diabetes and as a pathogenic anchor for identifying disease-specific endotypes is important for future studies.

DIABETES (2021)

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Review Endocrinology & Metabolism

Advances in Type 1 Diabetes Prediction Using Islet Autoantibodies: Beyond a Simple Count

Michelle So et al.

Summary: Islet autoantibodies are key markers for diagnosing type 1 diabetes and identifying at-risk individuals pre-symptomatically. Prediction of disease progression based on autoantibody count has been shown to be effective, but heterogeneous. Characteristics such as molecular specifics and sequence-dependent risk profiles have emerged as predictive features. Studying these features can improve trial design aimed at predicting and preventing disease.

ENDOCRINE REVIEWS (2021)

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Article Immunology

HLA class I hyper-expression unmasks beta cells but not alpha cells to the immune system in pre-diabetes

Mehdi A. Benkahla et al.

Summary: This study found that HLA-I is highly expressed in insulin-containing islets of type 1 diabetic donors before clinical diagnosis, mainly by alpha cells and associated with intra-cellular accumulation in the Golgi. In T1D donors, there is a significant correlation between HLA-I and infiltrating CD8 T cells in islets.

JOURNAL OF AUTOIMMUNITY (2021)

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Review Medicine, Research & Experimental

Type 1 diabetes mellitus: much progress, many opportunities

Alvin C. Powers

Summary: Type 1 diabetes is a result of autoimmune response requiring lifelong insulin therapy. Although there is considerable heterogeneity in genetics, pathology, and clinical course of T1D, there are still knowledge gaps and opportunities for improving understanding of its pathogenesis. Emerging therapies are being developed to treat or prevent T1D.

JOURNAL OF CLINICAL INVESTIGATION (2021)

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Article Multidisciplinary Sciences

Interpreting type 1 diabetes risk with genetics and single-cell epigenomics

Joshua Chiou et al.

Summary: Genome-wide association studies of type 1 diabetes identified risk variants that were enriched in specific cell types, including cells of the exocrine pancreas. The study highlights the role of the exocrine pancreas in the pathogenesis of T1D and underscores the importance of large-scale genetic studies and single-cell epigenomics in understanding complex diseases.

NATURE (2021)

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Article Endocrinology & Metabolism

Latent Autoimmune Diabetes of Adults (LADA) Is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes

Angus G. Jones et al.

Summary: LADA, diagnosed after age 35, presents clinical features similar to type 2 diabetes but with type 1 diabetes-associated islet autoantibodies. The current definition of LADA identifies a group with features intermediate between typical type 1 and type 2 diabetes, leading to difficulties in classification. Improved approaches are needed to increase test specificity and better understand the detailed pathophysiological components of late-onset autoimmune diabetes.

DIABETES CARE (2021)

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Article Endocrinology & Metabolism

Characteristics of children diagnosed with type 1 diabetes before vs after 6 years of age in the TEDDY cohort study

Jeffrey P. Krischer et al.

Summary: Children diagnosed with type 1 diabetes before the age of 6 tend to develop autoantibodies earlier and progress to diabetes more rapidly compared to those diagnosed between 6-13 years of age. The diabetes risk associated with HLA genotypes is significant in older children, while for younger children, the country of origin was a significant factor. Early onset diabetes is likely preceded by IAA autoantibodies and is more aggressive, while in older children, the progression to diabetes does not seem to be influenced by age or family history once multiple autoantibodies are present.

DIABETOLOGIA (2021)

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Article Endocrinology & Metabolism

Type 2 diabetes in prepubertal children

Marcela Astudillo et al.

Summary: The study found that T2D can develop before puberty, and children with prepubertal T2D have more severe obesity, greater insulin resistance, and more frequent dyslipidemia. These findings suggest that children with prepubertal T2D are at increased risk for associated morbidity compared with older youth.

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Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic beta-Cells

Jamie R. J. Inshaw et al.

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Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies

Maarit K. Koskinen et al.

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Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes

Manuela Battaglia et al.

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Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study

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Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents

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Single Islet Autoantibody at Diagnosis of Clinical Type 1 Diabetes is Associated With Older Age and Insulin Resistance

Maria J. Redondo et al.

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Slowed Metabolic Decline After 1 Year of Oral Insulin Treatment Among Individuals at High Risk for Type 1 Diabetes in the Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Oral Insulin Prevention Trials

Jay M. Sosenko et al.

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Characteristics of adult- compared to childhood-onset type 1 diabetes

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Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis

Pia Leete et al.

DIABETOLOGIA (2020)

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Article Endocrinology & Metabolism

Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes

Ulf Hannelius et al.

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Next steps in the identification of gene targets for type 1 diabetes

Struan F. A. Grant et al.

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A combined risk score enhances prediction of type 1 diabetes among susceptible children

Lauric A. Ferrat et al.

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Challenges in the diagnosis of diabetes type in pediatrics

Alejandro F. Siller et al.

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Raffaella Buzzetti et al.

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Maria J. Redondo et al.

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Mark A. Atkinson et al.

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Mia J. Smith et al.

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Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes

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Metformin Improves Peripheral Insulin Sensitivity in Youth With Type 1 Diabetes

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An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes

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Genetic and Environmental Interaction in Type 1 Diabetes: a Relationship Between Genetic Risk Alleles and Molecular Traits of Enterovirus Infection?

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Time-Resolved Autoantibody Profiling Facilitates Stratification of Preclinical Type 1 Diabetes in Children

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Emily K. Sims et al.

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Carla Greenbaum et al.

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Genetics of type 1 diabetes

Maria J. Redondo et al.

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C-Peptide Decline in Type 1 Diabetes Has Two Phases: An Initial Exponential Fall and a Subsequent Stable Phase

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