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1. Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data

Author

Haller, Michael J, Long, S Alice, Blanchfield, J Lori, Schatz, Desmond A, Skyler, Jay S, Krischer, Jeffrey P, Bundy, Brian N, Geyer, Susan M, Warnock, Megan V, Miller, Jessica L, Atkinson, Mark A, Becker, Dorothy J, Baidal, David A, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Herold, Kevan C, Marks, Jennifer B, Moran, Antoinette, Rodriguez, Henry, Russell, William E, Wilson, Darrell M, Greenbaum, Carla J, Battaglia, Manuela, Becker, Dorothy, Bingley, Penelope, Bosi, Emanuele, Buckner, Jane, Clements, Mark, Colman, Peter G, DiMeglio, Linda, Evans-Molina, Carmella, Gottlieb, Peter, Herold, Kevan, Knip, Mikael, Lernmark, Ake, Moore, Wayne, Muir, Andrew, Palmer, Jerry, Peakman, Mark, Philipson, Louis, Raskin, Philip, Redondo, Maria, Russell, William, Sosenko, Jay M, Spain, Lisa, Wentworth, John, Wherrett, Diane, Winter, William, Ziegler, Anette, Anderson, Mark, Antinozzi, Peter, Insel, Richard, Kay, Thomas, Pugliese, Alberto, Roep, Bart, Toppari, Jorma, Leschek, Ellen, Bourcier, Katarzyna, Ridge, John, Rafkin, Lisa, Santiago, Irene, Bundy, Brian, Abbondondolo, Michael, Adams, Timothy, Asif, Ilma, Bjellquist, Jenna, Boonstra, Matthew, Burroughs, Cristina, Cleves, Mario, Cuthbertson, David, DeSalvatore, Meagan, Eberhard, Christopher, Fiske, Steve, Ford, Julie, Garmeson, Jennifer, Geyer, Susan, and Hays, Brian

Subjects
Prevention, Diabetes, Clinical Trials and Supportive Activities, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Adolescent, Adult, Antilymphocyte Serum, C-Peptide, CD4-CD8 Ratio, Child, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Flow Cytometry, Glycated Hemoglobin, Granulocyte Colony-Stimulating Factor, Humans, Immunologic Factors, Male, T-Lymphocytes, Regulatory, Young Adult, Type 1 Diabetes TrialNet ATG-GCSF Study Group, Medical and Health Sciences, Endocrinology & Metabolism
Abstract

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

Published
2019

2. Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes

Author

Haller, Michael J, Schatz, Desmond A, Skyler, Jay S, Krischer, Jeffrey P, Bundy, Brian N, Miller, Jessica L, Atkinson, Mark A, Becker, Dorothy J, Baidal, David, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Herold, Kevan C, Marks, Jennifer B, Moran, Antoinette, Rodriguez, Henry, Russell, William, Wilson, Darrell M, Greenbaum, Carla J, Greenbaum, C, Atkinson, M, Baidal, D, Battaglia, M, Becker, D, Bingley, P, Bosi, E, Buckner, J, Clements, M, Colman, P, DiMeglio, L, Evans-Molina, C, Gitelman, S, Goland, R, Gottlieb, P, Herold, K, Knip, M, Krischer, J, Lernmark, A, Moore, W, Moran, A, Muir, A, Palmer, J, Peakman, M, Philipson, L, Raskin, P, Redondo, M, Rodriguez, H, Russell, W, Spain, L, Schatz, DA, Sosenko, J, Wherrett, D, Wilson, D, Winter, W, Ziegler, A, Anderson, M, Antinozzi, P, Benoist, C, Blum, J, Bourcier, K, Chase, P, Clare-Salzler, M, Clynes, R, Cowie, C, Eisenbarth, G, Fathman, CG, Grave, G, Harrison, L, Hering, B, Insel, R, Jordan, S, Kaufman, F, Kay, T, Kenyon, N, Klines, R, Lachin, J, Leschek, E, Mahon, J, Marks, JB, Monzavi, R, Nanto-Salonen, K, Nepom, G, Orban, T, Parkman, R, Pescovitz, M, Peyman, J, Pugliese, A, Ridge, J, Roep, B, Roncarolo, M, Savage, P, Simell, O, Sherwin, R, Siegelman, M, Skyler, JS, Steck, A, Thomas, J, Trucco, M, and Wagner, J

Subjects
Pediatric, Diabetes, Clinical Trials and Supportive Activities, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Adolescent, Adult, Antilymphocyte Serum, C-Peptide, Child, Cytoprotection, Diabetes Mellitus, Type 1, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Glycated Hemoglobin, Granulocyte Colony-Stimulating Factor, Humans, Insulin-Secreting Cells, Male, Pilot Projects, Polyethylene Glycols, Recombinant Proteins, Young Adult, Type 1 Diabetes TrialNet ATG-GCSF Study Group
Abstract

ObjectiveA pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration

Published
2018

3. Excess BMI in Childhood: A Modifiable Risk Factor for Type 1 Diabetes Development

Author

Ferrara, Christine Therese, Geyer, Susan Michelle, Liu, Yuk-Fun, Evans-Molina, Carmella, Libman, Ingrid M, Besser, Rachel, Becker, Dorothy J, Rodriguez, Henry, Moran, Antoinette, Gitelman, Stephen E, Redondo, Maria J, and Group, the Type 1 Diabetes TrialNet Study

Subjects
Biomedical and Clinical Sciences, Public Health, Clinical Sciences, Health Sciences, Nutrition and Dietetics, Diabetes, Autoimmune Disease, Prevention, Clinical Research, Pediatric, Metabolic and endocrine, Adolescent, Age Factors, Body Mass Index, Child, Child, Preschool, Diabetes Mellitus, Type 1, Female, Humans, Male, Multivariate Analysis, Pediatric Obesity, Risk Factors, Sex Factors, Type 1 Diabetes TrialNet Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveWe aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth.Research design and methodsWe studied 1,117 children in the TrialNet Pathway to Prevention cohort (autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index. Recursive partitioning and multivariate analyses yielded sex- and age-specific ceBMI thresholds for greatest type 1 diabetes risk.ResultsHigher ceBMI conferred significantly greater risk of progressing to type 1 diabetes. The increased diabetes risk occurred at lower ceBMI values in children

Published
2017

5. Adolescents with clinical type 1 diabetes display reduced red blood cell glucose transporter isoform 1 (GLUT1)

Author

Garg, Meena, Thamotharan, Manikkavasagar, Becker, Dorothy J, and Devaskar, Sherin U

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Diabetes, Pediatric Research Initiative, Clinical Research, Autoimmune Disease, Metabolic and endocrine, Adolescent, Biomarkers, Blood Glucose, Blood-Brain Barrier, Cognition Disorders, Diabetes Mellitus, Type 1, Down-Regulation, Enzyme-Linked Immunosorbent Assay, Erythrocytes, Glucose Clamp Technique, Glucose Transporter Type 1, Glycated Hemoglobin, Humans, Hyperglycemia, Hypoglycemia, Hypoglycemic Agents, Insulin, Models, Biological, Prospective Studies, BBB, hyperinsulinemic clamp, hypoglycemic clamp, RBC glucose transporter 1, T1D, Hyperinsulinemic clamp, Hypoglycemic clamp, Paediatrics and Reproductive Medicine, Endocrinology & Metabolism, Clinical sciences, Paediatrics
Abstract

Type 1 diabetic (T1D) adolescent children on insulin therapy suffer episodes of both hyper- and hypoglycemic episodes. Glucose transporter isoform GLUT1 expressed in blood-brain barrier (BBB) and red blood cells (RBC) compensates for perturbed circulating glucose toward protecting the supply to brain and RBCs. We hypothesized that RBC-GLUT1 concentration, as a surrogate for BBB-GLUT1, is altered in T1D children. To test this hypothesis, we measured RBC-GLUT1 by enzyme-linked immunosorbent assay (ELISA) in T1D children (n = 72; mean age 15.3 ± 0.2 yr) and control children (CON; n = 11; mean age 15.6 ± 0.9 yr) after 12 h of euglycemia and during a hyperinsulinemic-hypoglycemic clamp with a nadir blood glucose of ~3.3 mmol/L for 90 min (clamp I) or ~3 mmol/L for 45 min (clamp II). Reduced baseline RBC-GLUT1 was observed in T1D (2.4 ± 0.17 ng/ng membrane protein); vs. CON (4.2 ± 0.61 ng/ng protein) (p < 0.0001). Additionally, baseline RBC-GLUT1 in T1D negatively correlated with hemoglobin A1c (HbA1c) (R = -0.23, p

Published
2014

6. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials

Author

Moran, Antoinette, Bundy, Brian, Becker, Dorothy J, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Greenbaum, Carla J, Herold, Kevan C, Marks, Jennifer B, Raskin, Philip, Sanda, Srinath, Schatz, Desmond, Wherrett, Diane K, Wilson, Darrell M, Krischer, Jeffrey P, Skyler, Jay S, Group, for the Type 1 Diabetes TrialNet Canakinumab Study, Pickersgill, Linda, de Koning, Eelco, Ziegler, Anette-G, Böehm, Bernhard, Badenhoop, Klaus, Schloot, Nanette, Bak, Jens Friis, Pozzilli, Paolo, Mauricio, Didac, Donath, Marc Y, Castaño, Luis, Wägner, Ana, Lervang, Hans Henrik, Perrild, Hans, Mandrup-Poulsen, Thomas, and Group, for the AIDA Study

Subjects
Clinical Trials and Supportive Activities, Clinical Research, Diabetes, Autoimmune Disease, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Adolescent, Adult, Analysis of Variance, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, C-Peptide, Child, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Humans, Hypoglycemic Agents, Immunologic Factors, Insulin-Secreting Cells, Interleukin 1 Receptor Antagonist Protein, Interleukin-1, Male, Treatment Outcome, Young Adult, Type 1 Diabetes TrialNet Canakinumab Study Group, AIDA Study Group, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundInnate 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 β-cell function in recent-onset type 1 diabetes.MethodsWe 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.FindingsPatients 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.InterpretationCanakinumab 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.FundingNational Institutes of Health and Juvenile Diabetes Research Foundation.

Published
2013

13. Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk

Author

Nucci, Anita M., Virtanen, Suvi M., Cuthbertson, David, Ludvigsson, Johnny, Einberg, Ulle, Huot, Celine, Castano, Luis, Aschemeier, Bärbel, Becker, Dorothy J., Knip, Mikael, Krischer, Jeffrey P., Mandrup-Poulsen, Thomas, Arjas, Elias, Läärä, Esa, Lernmark, Åke, Schmidt, Barbara, Åkerblom, Hans K., Hyytinen, Mila, Koski, Katriina, Koski, Matti, Pajakkala, Eeva, Salonen, Marja, Shanker, Linda, Bradley, Brenda, Dosch, Hans Michael, and Dupré, John

Subjects
Male, 0301 basic medicine, Pediatric Obesity, Heredity, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Breastfeeding, Autoimmunity, Overweight, Child Development, 0302 clinical medicine, Risk Factors, Weight management, Medicine, Child, Randomized Controlled Trials as Topic, education.field_of_study, Incidence, Age Factors, Childhood growth, Beta cell autoimmunity, Prognosis, Infant Formula, Pedigree, Europe, Type 1 diabetes, Phenotype, Child, Preschool, Female, medicine.symptom, medicine.medical_specialty, Adolescent, Length, Population, 030209 endocrinology & metabolism, Risk Assessment, Article, Islets of Langerhans, 03 medical and health sciences, Internal medicine, Internal Medicine, Humans, Genetic Predisposition to Disease, education, Genetic risk, business.industry, Proportional hazards model, Insulin, Australia, Infant, Newborn, Autoantibody, Infant, Adolescent Development, Weight, medicine.disease, Bottle Feeding, Diabetes Mellitus, Type 1, 030104 developmental biology, North America, business
Abstract

Aims/hypothesis: We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes. Methods: Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10–14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05. Results: In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2–10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p < 0.001 in time-varying Cox regression), and similarly with joint modelling. Conclusions/interpretation: In children at genetic risk of type 1 diabetes, being overweight at 2–10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes. Trial registration: ClinicalTrials.gov NCT00179777 Graphical abstract: [Figure not available: see fulltext.]

Published
2021
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16. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial

Author

Orban, Tihamer, Bundy, Brian, Becker, Dorothy J, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Greenbaum, Carla J, Marks, Jennifer B, Monzavi, Roshanak, Moran, Antoinette, Raskin, Philip, Rodriguez, Henry, Russell, William E, Schatz, Desmond, Wherrett, Diane, Wilson, Darrell M, Krischer, Jeffrey P, and Skyler, Jay S

Published
2011
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17. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial

Author

Wherrett, Diane K, Bundy, Brian, Becker, Dorothy J, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Greenbaum, Carla J, Herold, Kevan C, Marks, Jennifer B, Monzavi, Roshanak, Moran, Antoinette, Orban, Tihamer, Palmer, Jerry P, Raskin, Philip, Rodriguez, Henry, Schatz, Desmond, Wilson, Darrell M, Krischer, Jeffrey P, and Skyler, Jay S

Published
2011
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22. Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk

Author

Nucci, Anita M, Virtanen, Suvi M, Cuthbertson, David, Ludvigsson, Johnny, Einberg, Ulle, Huot, Celine, Castano, Luis, Aschemeier, Bärbel, Becker, Dorothy J, Knip, Mikael, Krischer, Jeffrey P, University of Zurich, and Nucci, Anita M

Subjects
Diabetes and Metabolism, 2712 Endocrinology, Diabetes and Metabolism, Endocrinology, 10036 Medical Clinic, 2724 Internal Medicine, Internal Medicine, 610 Medicine & health
Published
2021

23. Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes

Author

Pacaud, Daniele, Nucci, Anita M., Cuthbertson, David, Becker, Dorothy J., Virtanen, Suvi M., Ludvigsson, Johnny, Ilonen, Jorma, Knip, Mikael, Pacaud, Daniele, Nucci, Anita M., Cuthbertson, David, Becker, Dorothy J., Virtanen, Suvi M., Ludvigsson, Johnny, Ilonen, Jorma, and Knip, Mikael

Abstract

Aims/hypothesis The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility. Methods In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member. Results Multiple autoantibodies (>= 2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046,p < 0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722,p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator groupn = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (zscore/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70],p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity. Conclusions/interpretation The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first, Funding Agencies|University of Helsinki; Helsinki University Central Hospital; Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HD040364, HD042444, HD051997]; Special Statutory Funding Program for Type 1 diabetes Research; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); JDRF InternationalJuvenile Diabetes Research Foundation; Finnish Academy of SciencesAcademy of Finland; Commission of the European Communities (specific RTD programme `Quality of Life and management of Living Resources) [QLK1-2002-00372]; EFSD/JDRF/Novo Nordisk Focused Research Grant

Published
2021
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24. Increasing plasma glucose before the development of type 1 diabetes-the TRIGR study

Author

Ludvigsson, Johnny, Cuthbertson, David, Becker, Dorothy J., Kordonouri, Olga, Aschemeier, Bärbel, Pacaud, Daniele, Clarson, Cheril, Krischer, Jeffrey P., Knip, Mikael, Ludvigsson, Johnny, Cuthbertson, David, Becker, Dorothy J., Kordonouri, Olga, Aschemeier, Bärbel, Pacaud, Daniele, Clarson, Cheril, Krischer, Jeffrey P., and Knip, Mikael

Abstract

Objective: The beta-cell stress hypothesis suggests that increased insulin demand contributes to the development of type 1 diabetes. In the TRIGR trial we set out to assess the profile of plasma glucose and HbA1c before the diagnosis of clinical diabetes compared to nondiabetic children. Research Design and Methods: A cohort of children (N = 2159) with an affected first-degree relative and increased HLA risk were recruited 2002-2007 and followed until 2017. To study the relationship between plasma glucose/HbA1c and the development of autoantibodies or clinical disease Kaplan-Meir curves were developed. Mixed models were constructed for plasma glucose and HbA1c separately. Results: A family history of type 2 diabetes was related to an increase in plasma glucose (p < 0.001). An increase in glucose from the previous sample predicted clinical diabetes (p < 0.001) but not autoantibodies. An increase of HbA1c of 20% or 30% from the previous sample predicted the development of any autoantibody (p < 0.003 resp < 0.001) and the development of diabetes (p < 0.002 resp < 0.001. Participants without autoantibodies had lower HbA1c (mean 5.18%, STD 0.24; mean 33.08 mmol/mol, STD 2.85) than those who progressed to clinical disease (5.31%, 0.42; 34.46 mmol/mol, 4.68; p < 0.001) but higher than those who developed any autoantibody (5.10%, 0.30; 32.21 mmol/mol, 3.49; p < 0.001), or multiple autoantibodies (5.11%, 0.35; 32.26 mmol/mol, 3.92; p < 0.003). Conclusions: A pronounced increase in plasma glucose and HbA1c precedes development of clinical diabetes, while the association between plasma glucose or HbA1c and development of autoantibodies is complex. Increased insulin demand may contribute to development of type 1 diabetes., Funding Agencies|Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HD040364, HD042444, HD051997]; Special Statutory Funding Program for Type 1 Diabetes Research; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); Juvenile Diabetes Research Foundation InternationalJuvenile Diabetes Research Foundation; Academy of FinlandAcademy of FinlandEuropean Commission; Commission of the European CommunitiesEuropean Commission [QLK1-2002-00372]; EFSD/JDRF/Novo Nordisk Focused Research Grant

Published
2021
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25. Diabetic Ketoacidosis at the Time of Diagnosis of Type 1 Diabetes in Children: Insights From TRIGR

Author

Nakhla, Meranda, Cuthbertson, David, Becker, Dorothy J., Pacaud, Daniele, Ludvigsson, Johnny, Knip, Mikael, Legault, Laurent, Nakhla, Meranda, Cuthbertson, David, Becker, Dorothy J., Pacaud, Daniele, Ludvigsson, Johnny, Knip, Mikael, and Legault, Laurent

Abstract

n/a, Funding Agencies|Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HD040364, HD042444, HD051997]; Special Statutory Funding Program for Type 1 Diabetes Research; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); Juvenile Diabetes Research Foundation InternationalJuvenile Diabetes Research Foundation; Commission of the European Communities (specific RTD programme "Quality of Life and Management of Living Resources) [QLK1-2002-00372]; European Foundation for the Study of Diabetes/JDRF/Novo Nordisk Focused Research Grant; Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research)Academy of Finland [250114]; Dutch Diabetes Research Foundation; Finnish Diabetes Research Foundation

Published
2021
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26. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment

Author

Orban, Tihamer, Bundy, Brian, Becker, Dorothy J., DiMeglio, Linda A., Gitelman, Stephen E., Goland, Robin, Gottlieb, Peter A., Greenbaum, Carla J., Marks, Jennifer B., Monzavi, Roshanak, Moran, Antoinette, Peakman, Mark, Raskin, Philip, Russell, William E., Schatz, Desmond, Wherrett, Diane K., Wilson, Darrell M., Krischer, Jeffrey P., and Skyler, Jay S.

Subjects
Bristol-Myers Squibb Co., Diabetes therapy, Type 1 diabetes -- Care and treatment -- Development and progression, Peptides, Pharmaceutical industry, Health
Abstract

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were [...]

Published
2014
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27. B-Lymphocyte depletion with rituximab and β-cell function: two-year results

Author

Pescovitz, Mark D., Greenbaum, Carla J., Bundy, Brian, Becker, Dorothy J., Gitelman, Stephen E., Goland, Robin, Gottlieb, Peter A., Marks, Jennifer B., Moran, Antoinette, Raskin, Philip, Rodriguez, Henry, Schatz, Desmond A., Wherrett, Diane K., Wilson, Darrell M., Krischer, Jeffrey P., and Skyler, Jay S.

Subjects
Type 1 diabetes -- Drug therapy -- Patient outcomes -- Research, B cells -- Physiological aspects -- Research, Health
Abstract

OBJECTIVE We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type I diabetes mellitus (T1DM) at 1 year. [...]

Published
2014
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31. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function

Author

Pescovitz, Mark D., Greenbaum, Carla J., Krause-Steinrauf,Heidi, Becker, Dorothy J., Gitelman, Stephen E., Goland, Robin, Gottlieb, Peter A., Marks, Jennifer B., McGee, Paula F., Moran, Antoinette M., Raskin, Philip, Rodriguez, Henry, Schatz, Desmond A., Wherrett, Diane, Wilson, Darrell M., Lachin, John M., and Skyler, Jay S.

Subjects
Antibodies -- Health aspects, Viral antibodies -- Health aspects, B cells -- Health aspects, Type 1 diabetes -- Diagnosis, Type 1 diabetes -- Drug therapy
Abstract

The study examines if selective depletion of B-lymphocytes with rituximab decreases immune-mediated destruction of beta cells and lead to preserved beta-cell function in patients with type 1 diabetes. Results show a four-dose course of rituximab partially preserves beta-cell function over a period of one year.

Published
2009

37. Autoimmune islet destruction in spontaneous type 1 diabetes is not [beta]-cell exclusive

Author

Winer, Shawn, Tsui, Hubert, Lau, Ambrose, Song, Aihua, Li, Xiaomao, Cheung, Roy K., Sampson, Anastazia, Afifiyan, Fatemeh, Elford, Alisha, Jackowski, George, Becker, Dorothy J., Santamaria, Pere, Ohashi, Pamela, and Dosch, H -Michael

Abstract

Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100[beta]. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable [beta]-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100[beta] prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8[sup.+] T-cell receptor[sup.gp] double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and [beta]-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8[sup.+]/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes., Author(s): Shawn Winer [1, 6]; Hubert Tsui [1, 6]; Ambrose Lau [1]; Aihua Song [1]; Xiaomao Li [2]; Roy K. Cheung [1]; Anastazia Sampson [1]; Fatemeh Afifiyan [1]; Alisha Elford [...]

Published
2003
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48. Targeting of Pancreatic Glia in Type 1 Diabetes

Author

Tsui, Hubert, Chan, Yin, Tang, Lan, Winer, Shawn, Cheung, Roy K., Paltser, Geoffrey, Selvanantham, Thirumahal, Elford, Alisha R., Ellis, James R., Becker, Dorothy J., Ohashi, Pamela S., and Dosch, Hans-Michael

Published
2008

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