238 results on '"Gottlieb PA"'
Search Results
2. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: Metabolic and immunologic features at baseline identify a subgroup of responders
- Author
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Herold, KC, Gitelman, SE, Ehlers, MR, Gottlieb, PA, Greenbaum, CJ, Hagopian, W, Boyle, KD, Keyes-Elstein, L, Aggarwal, S, Phippard, D, Sayre, PH, McNamara, J, and Bluestone, JA
- Subjects
Endocrinology & Metabolism ,Clinical Sciences ,Medical Physiology - Published
- 2014
3. Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: A randomized controlled trial
- Author
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Herold, KC, Gitelman, SE, Willi, SM, Gottlieb, PA, Waldron-Lynch, F, Devine, L, Sherr, J, Rosenthal, SM, Adi, S, Jalaludin, MY, Michels, AW, Dziura, J, and Bluestone, JA
- Subjects
Endocrinology & Metabolism ,Clinical Sciences ,Medical Physiology - Published
- 2014
4. B-lymphocyte depletion with rituximab and β-cell function: Two-year results
- Author
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Gitelman, Stephen, Pescovitz, MD, Greenbaum, CJ, Bundy, B, Becker, DJ, Gitelman, SE, Goland, R, Gottlieb, PA, Marks, JB, Moran, A, and Raskin, P
- Abstract
OBJECTIVE We previously reported that selective depletion of β-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of b-cell function in recentonset type 1 diabetesmellitus (T1DM) at 1 year. Subjects were followed further to determ
- Published
- 2014
5. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: Follow-up 1 year aftercessation of treatment
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Gitelman, Stephen, Orban, T, Bundy, B, Becker, DJ, DiMeglio, LA, Gitelman, SE, Goland, R, Gottlieb, PA, Greenbaum, CJ, Marks, JB, and Monzavi, R
- 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 followed to determine whether ther
- Published
- 2014
6. Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial
- Author
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Herold, KC, Gitelman, SE, Willi, SM, Gottlieb, PA, Waldron-Lynch, F, Devine, L, Sherr, J, Rosenthal, SM, Adi, S, Jalaludin, MY, Michels, AW, Dziura, J, and Bluestone, JA
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Trials and Supportive Activities ,Autoimmune Disease ,Diabetes ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Metabolic and endocrine ,Adolescent ,Antibodies ,Monoclonal ,Humanized ,C-Peptide ,Diabetes Mellitus ,Type 1 ,Female ,Glycated Hemoglobin ,Humans ,Insulin ,Male ,Autoimmunity ,Immune therapy ,Type 1 diabetes ,Paediatrics and Reproductive Medicine ,Public Health and Health Services ,Endocrinology & Metabolism ,Clinical sciences ,Public health - Abstract
Aims/hypothesisType 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes.MethodsIn a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients.ResultsThirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p
- Published
- 2013
7. Fall in C-peptide during first 2 years from diagnosis: Evidence of at least two distinct phases from composite type 1 diabetes trialnet data
- Author
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Gitelman, Stephen, Greenbaum, CJ, Beam, CA, Boulware, D, Gitelman, SE, Gottlieb, PA, Herold, KC, Lachin, JM, McGee, P, Palmer, JP, and Pescovitz, MD
- Abstract
Interpretation of clinical trials to alter the decline in β-cell function after diagnosis of type 1 diabetes depends on a robust understanding of the natural history of disease. Combining data from the Type 1 Diabetes TrialNet studies, we describe the natu
- Published
- 2012
8. Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample
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Bediaga, NG, Li-Wai-Suen, CSN, Haller, MJ, Gitelman, SE, Evans-Molina, C, Gottlieb, PA, Hippich, M, Ziegler, A-G, Lernmark, A, DiMeglio, LA, Wherrett, DK, Colman, PG, Harrison, LC, Wentworth, JM, Bediaga, NG, Li-Wai-Suen, CSN, Haller, MJ, Gitelman, SE, Evans-Molina, C, Gottlieb, PA, Hippich, M, Ziegler, A-G, Lernmark, A, DiMeglio, LA, Wherrett, DK, Colman, PG, Harrison, LC, and Wentworth, JM
- Abstract
AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.
- Published
- 2021
9. Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells
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Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Raskin P, Tresoldi E, Dell'Albani I, Stabilini A, Jofra T, Valle A, Gagliani N, BONDANZA , ATTILIO, RONCAROLO , MARIA GRAZIA, BATTAGLIA, MARCO MARIA, Orban, T, Bundy, B, Becker, Dj, Dimeglio, La, Gitelman, Se, Goland, R, Gottlieb, Pa, Greenbaum, Cj, Marks, Jb, Monzavi, R, Moran, A, Raskin, P, Tresoldi, E, Dell'Albani, I, Stabilini, A, Jofra, T, Valle, A, Gagliani, N, Bondanza, Attilio, Roncarolo, MARIA GRAZIA, and Battaglia, MARCO MARIA
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Cell ,Mice, SCID ,C-C chemokine receptor type 6 ,Biology ,T-Lymphocytes, Regulatory ,Immunophenotyping ,Cell therapy ,Mice ,Mice, Inbred NOD ,In vivo ,medicine ,Animals ,Humans ,Cells, Cultured ,Cell Proliferation ,Sirolimus ,Interleukin-2 Receptor alpha Subunit ,FOXP3 ,Forkhead Transcription Factors ,Hematology ,Phenotype ,Molecular biology ,In vitro ,Cell biology ,medicine.anatomical_structure ,Online-Only Articles ,CD4 Antigens ,Leukocytes, Mononuclear ,Cytokines ,Th17 Cells ,Female ,Ex vivo - Abstract
"\"\\\"\\\\\\\"Background The clinical use of ex vivo-expanded T-regulatory cells for the treatment of T-cell-mediated diseases has gained increasing momentum. However, the recent demonstration that FOXP3(+) T-regulatory cells may contain interleukin-17-producing cells and that they can convert into effector cells once transferred in vivo raises significant doubts about their safety. We previously showed that rapamycin permits the ex vivo expansion of FOXP3(+) T-regulatory cells while impairing the proliferation of non-T-regulatory cells. Here we investigated the Th17-cell content and the in vivo stability of rapamycin-expanded T-regulatory cells as pertinent aspects of cell-based therapy. Design and Methods T-regulatory-enriched cells were isolated from healthy volunteers and were expanded ex vivo with rapamycin with a pre-clinical applicable protocol. T-regulatory cells cultured with and without rapamycin were compared for their regulatory activity, content of pro-inflammatory cells and stability. Results We found that CD4(+)CCR6(+)CD161(+) T cells (i.e., precursor\\\\\\\\\\\\\\\/committed Th17 cells) contaminate the T-regulatory cells cultured ex vivo in the absence of rapamycin. In addition, Th17 cells do not expand when rapamycin-treated T-regulatory cells are exposed to a \\\\\\\"Th17-favorable\\\\\\\" environment. Rapamycin-expanded T-regulatory cells maintain their in vitro regulatory phenotype even after in vivo transfer into immunodeficient NOD-SCID mice despite being exposed to the irradiation-induced pro-inflammatory environment. Importantly, no additional rapamycin treatment, either in vitro or in vivo, is required to keep their phenotype fixed. Conclusions These data demonstrate that rapamycin secures ex vivo-expanded human T-regulatory cells and provide additional justification for their clinical use in future cell therapy-based trials.\\\\\\\"\\\"\""
- Published
- 2011
10. Understanding and preventing type 1 diabetes through the unique working model of TrialNet
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Battaglia, M, Anderson, MS, Buckner, JH, Geyer, SM, Gottlieb, PA, Kay, TWH, Lernmark, A, Muller, S, Pugliese, A, Roep, BO, Greenbaum, CJ, Peakman, M, Battaglia, M, Anderson, MS, Buckner, JH, Geyer, SM, Gottlieb, PA, Kay, TWH, Lernmark, A, Muller, S, Pugliese, A, Roep, BO, Greenbaum, CJ, and Peakman, M
- Abstract
Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.
- Published
- 2017
11. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial
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Gitelman, SE, Gottlieb, PA, Felner, EI, Willi, SM, Fisher, LK, Moran, A, Gottschalk, M, Moore, WV, Pinckney, A, Keyes-Elstein, L, Harris, KM, Kanaparthi, S, Phippard, D, Ding, L, Bluestone, JA, Ehlers, MR, and Team, ITNSTARTS
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Type 1 diabetes ,Thymoglobulin ,Beta cells ,Tcells ,Tregs ,C-peptide ,START trial ,ATG - Published
- 2016
12. Low-Dose Otelixizumab Anti-CD3 Monoclonal Antibody DEFEND-1 Study: Results of the Randomized Phase III Study in Recent-Onset Human Type 1 Diabetes
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Aronson R, Gottlieb PA, Christiansen JS, Donner TW, Bode BW, Pozzilli P., BOSI , EMANUELE, Aronson, R, Gottlieb, Pa, Christiansen, J, Donner, Tw, Bosi, Emanuele, Bode, Bw, and Pozzilli, P.
- Published
- 2014
13. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo controlled, phase 2 trial
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Gitelman, SE, Gottlieb, PA, Rigby, MR, Felner, EI, Willi, SM, Fisher, LK, Moran, A, Gottschalk, M, Moore, WV, Pinckney, A, Keyes-Elstein, L, Aggarwal, S, Phippard, D, Sayre, PH, Ding, L, Bluestone, JA, and Ehlers, MR
- Published
- 2014
14. Dysregulated Toll-like receptor-induced interleukin-1β and interleukin-6 responses in subjects at risk for the development of type 1 diabetes.
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Alkanani AK, Rewers M, Dong F, Waugh K, Gottlieb PA, Zipris D, Alkanani, Aimon K, Rewers, Marian, Dong, Fran, Waugh, Kathleen, Gottlieb, Peter A, and Zipris, Danny
- Abstract
We tested the hypothesis that altered Toll-like receptor (TLR) signaling may be involved in early stages of type 1 diabetes (T1D). To do so, we analyzed TLR-induced interleukin (IL)-1β and IL-6 responses in freshly isolated peripheral blood mononuclear cells (PBMNCs) from seropositive compared with seronegative subjects. Similar frequencies of myeloid dendritic cells (mDCs), plasmacytoid DCs (pDCs), and monocytes were observed in seropositive and seronegative subjects. Subjects with autoantibodies had increased proportions of monocytes expressing IL-1β ex vivo. Activating PBMNCs with TLR3, TLR4, or TLR7/8 agonists in vitro led to increased percentages of IL-1β-expressing monocytes and mDCs from seropositive versus seronegative subjects. TLR ligation also resulted in a diminished IL-6 response in seropositive individuals as lower frequencies of IL-6-expressing monocytes and mDCs were induced. The dysregulated TLR-induced IL-1β and IL-6 pathways were more readily detectable in children aged <11 years and from 11 to <21 years, respectively, and did not involve altered HbA(1c) or the presence of one or more autoantibodies. Finally, subjects with autoantibodies had lower amounts of serum chemokine (C-X-C motif) ligand 10 compared with autoantibody-negative subjects. Our data may imply that alterations in innate immune pathways are detectable in genetically susceptible individuals and could be linked with the early course of T1D. [ABSTRACT FROM AUTHOR]
- Published
- 2012
15. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data.
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Greenbaum CJ, Beam CA, Boulware D, Gitelman SE, Gottlieb PA, Herold KC, Lachin JM, McGee P, Palmer JP, Pescovitz MD, Krause-Steinrauf H, Skyler JS, Sosenko JM, Type 1 Diabetes TrialNet Study Group, Greenbaum, Carla J, Beam, Craig A, Boulware, David, Gitelman, Stephen E, Gottlieb, Peter A, and Herold, Kevan C
- Abstract
Interpretation of clinical trials to alter the decline in β-cell function after diagnosis of type 1 diabetes depends on a robust understanding of the natural history of disease. Combining data from the Type 1 Diabetes TrialNet studies, we describe the natural history of β-cell function from shortly after diagnosis through 2 years post study randomization, assess the degree of variability between patients, and investigate factors that may be related to C-peptide preservation or loss. We found that 93% of individuals have detectable C-peptide 2 years from diagnosis. In 11% of subjects, there was no significant fall from baseline by 2 years. There was a biphasic decline in C-peptide; the C-peptide slope was -0.0245 pmol/mL/month (95% CI -0.0271 to -0.0215) through the first 12 months and -0.0079 (-0.0113 to -0.0050) from 12 to 24 months (P < 0.001). This pattern of fall in C-peptide over time has implications for understanding trial results in which effects of therapy are most pronounced early and raises the possibility that there are time-dependent differences in pathophysiology. The robust data on the C-peptide obtained under clinical trial conditions should be used in planning and interpretation of clinical trials. [ABSTRACT FROM AUTHOR]
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- 2012
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16. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review.
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Moran A, Becker D, Casella SJ, Gottlieb PA, Kirkman MS, Marshall BC, Slovis B, CFRD Consensus Conference Committee, Moran, Antoinette, Becker, Dorothy, Casella, Samuel J, Gottlieb, Peter A, Kirkman, M Sue, Marshall, Bruce C, and Slovis, Bonnie
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- 2010
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17. Failure to preserve beta-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new- onset type 1 diabetes.
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Gottlieb PA, Quinlan S, Krause-Steinrauf H, Greenbaum CJ, Wilson DM, Rodriguez H, Schatz DA, Moran AM, Lachin JM, Skyler JS, Type 1 Diabetes TrialNet MMF/DZB Study Group, Gottlieb, Peter A, Quinlan, Scott, Krause-Steinrauf, Heidi, Greenbaum, Carla J, Wilson, Darrell M, Rodriguez, Henry, Schatz, Desmond A, Moran, Antoinette M, and Lachin, John M
- Abstract
Objective: This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing beta-cells in subjects with new-onset type 1 diabetes.Research Design and Methods: A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test.Results: One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly.Conclusions: Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process. [ABSTRACT FROM AUTHOR]- Published
- 2010
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18. Medical progress: autoimmune polyendocrine syndromes.
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Eisenbarth GS and Gottlieb PA
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- 2004
19. Temporal development of T cell receptor repertoires during childhood in health and disease
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Mitchell, AM, primary, Baschal, EE, additional, McDaniel, KA, additional, Simmons, KM, additional, Pyle, L, additional, Waugh, K, additional, Steck, AK, additional, Yu, L, additional, Gottlieb, PA, additional, Rewers, MJ, additional, Nakayama, M, additional, and Michels, AW, additional
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20. Inflammatory markers and diabetic retinopathy in type 1 diabetes.
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Izoura KE, Chase HP, Jackson WE, Coll JR, Osberg IM, Gottlieb PA, Rewers MJ, Garg SK, Izuora, Kenneth E, Chase, H Peter, Jackson, William E, Coll, Joseph R, Osberg, Iris M, Gottlieb, Peter A, Rewers, Marian J, and Garg, Satish K
- Published
- 2005
21. Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex
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Gottlieb Paul D, Sims Robert J, Brown Mark A, and Tucker Philip W
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Disrupting the balance of histone lysine methylation alters the expression of genes involved in tumorigenesis including proto-oncogenes and cell cycle regulators. Methylation of lysine residues is commonly catalyzed by a family of proteins that contain the SET domain. Here, we report the identification and characterization of the SET domain-containing protein, Smyd2. Results Smyd2 mRNA is most highly expressed in heart and brain tissue, as demonstrated by northern analysis and in situ hybridization. Over-expressed Smyd2 localizes to the cytoplasm and the nucleus in 293T cells. Although accumulating evidence suggests that methylation of histone 3, lysine 36 (H3K36) is associated with actively transcribed genes, we show that the SET domain of Smyd2 mediates H3K36 dimethylation and that Smyd2 represses transcription from an SV40-luciferase reporter. Smyd2 associates specifically with the Sin3A histone deacetylase complex, which was recently linked to H3K36 methylation within the coding regions of active genes in yeast. Finally, we report that exogenous expression of Smyd2 suppresses cell proliferation. Conclusion We propose that Sin3A-mediated deacetylation within the coding regions of active genes is directly linked to the histone methyltransferase activity of Smyd2. Moreover, Smyd2 appears to restrain cell proliferation, likely through direct modulation of chromatin structure.
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- 2006
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22. No relation between cystic fibrosis-related diabetes and type 1 diabetes autoimmunity.
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Gottlieb PA, Yu L, Babu S, Wenzlau J, Bellin M, Frohnert BI, Moran A, Gottlieb, Peter A, Yu, Liping, Babu, Sunanda, Wenzlau, Janet, Bellin, Melena, Frohnert, Brigitte I, and Moran, Antoinette
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- 2012
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23. Editorial.
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Gottlieb PA
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- 2010
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24. Islet-antigen reactive B cells display a unique phenotype and BCR repertoire in autoantibody positive and recent-onset type 1 diabetes patients.
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Nicholas CA, Tensun FA, Evans SA, Toole KP, Broncucia H, Hesselberth JR, Gottlieb PA, Wells KL, and Smith MJ
- Abstract
Autoreactive B cells play an important but ill-defined role in autoimmune type 1 diabetes (T1D). To better understand their contribution, we performed single cell gene and BCR-seq analysis on pancreatic islet antigen-reactive (IAR) B cells from the peripheral blood of nondiabetic (ND), autoantibody positive prediabetic (AAB), and recent-onset T1D individuals. We found that the frequency of IAR B cells was increased in AAB and T1D. IAR B cells from these donors had altered expression of B cell signaling, pro-inflammatory, infection, and antigen processing and presentation genes. Both AAB and T1D donors demonstrated a significant increase in certain heavy and light chain V genes, and these V genes were enriched in islet-reactivity. Public clones of IAR B cells were restricted almost entirely to AAB and T1D donors. IAR B cells were clonally expanded in the autoimmune donors, particularly the AAB group. Notably, a substantial fraction of IAR B cells in AAB and T1D donors appeared to be polyreactive, which was corroborated by analysis of recombinant monoclonal antibodies. These results expand our understanding of autoreactive B cell activation during T1D and identify unique BCR repertoire changes that may serve as biomarkers for increased disease risk., Competing Interests: Competing interests: The authors declare no competing financial interests.
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- 2024
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25. Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.
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Jacobsen LM, Cuthbertson D, Bundy BN, Atkinson MA, Moore W, Haller MJ, Russell WE, Gitelman SE, Herold KC, Redondo MJ, Sims EK, Wherrett DK, Moran A, Pugliese A, Gottlieb PA, Sosenko JM, and Ismail HM
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- Humans, Female, Male, Adolescent, Treatment Outcome, Randomized Controlled Trials as Topic, Child, Adult, Area Under Curve, Diabetes Mellitus, Type 1 therapy, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 immunology, C-Peptide blood, C-Peptide metabolism, Immunotherapy methods
- Abstract
Objective: Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy., Research Design and Methods: We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial., Results: Among trials meeting their primary end point, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (P = 0.030 and P < 0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. The use of C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R2 for 12-month C-peptide AUC adjusted for age and baseline value was 0.80, P < 0.001), and this finding supported the concept of smaller trial sizes down to 54 participants., Conclusions: Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early-phase clinical trials., (© 2024 by the American Diabetes Association.)
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- 2024
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26. Genetic Associations with C-peptide Levels before Type 1 Diabetes Diagnosis in At-Risk Relatives.
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Triolo TM, Parikh HM, Tosur M, Ferrat L, You L, Gottlieb PA, Oram RA, Onengut-Gumuscu S, Krischer JP, Rich SS, Steck AK, and Redondo MJ
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Objective: We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) are associated with C-peptide preservation before type 1 diabetes diagnosis., Methods: We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known SNPs and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis., Results: Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (β=-0.06, P<0.0001) and multivariate (β=-0.03, P=0.005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (β=-0.11, P=0.002) and multivariate (β=-0.06, P=0.018) analyses., Conclusions: The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC prior to diagnosis of type 1 diabetes, with implications for the design of prevention trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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27. An Insulin-Chromogranin A Hybrid Peptide Activates DR11-Restricted T Cells in Human Type 1 Diabetes.
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Callebaut A, Guyer P, Baker RL, Gallegos JB, Hohenstein AC, Gottlieb PA, Mathieu C, Overbergh L, Haskins K, and James EA
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- Humans, Animals, Mice, T-Lymphocytes, Proinsulin, C-Peptide, Chromogranin A, Peptides, Insulin, Regular, Human, Epitopes, Peptide Fragments, Insulin, Diabetes Mellitus, Type 1
- Abstract
Hybrid insulin peptides (HIPs) formed through covalent cross-linking of proinsulin fragments to secretory granule peptides are detectable within murine and human islets. The 2.5HIP (C-peptide-chromogranin A [CgA] HIP), recognized by the diabetogenic BDC-2.5 clone, is a major autoantigen in the nonobese diabetic mouse. However, the relevance of this epitope in human disease is currently unclear. A recent study probed T-cell reactivity toward HIPs in patients with type 1 diabetes, documenting responses in one-third of the patients and isolating several HIP-reactive T-cell clones. In this study, we isolated a novel T-cell clone and showed that it responds vigorously to the human equivalent of the 2.5HIP (designated HIP9). Although the responding patient carried the risk-associated DRB1*04:01/DQ8 haplotype, the response was restricted by DRB1*11:03 (DR11). HLA class II tetramer staining revealed higher frequencies of HIP9-reactive T cells in individuals with diabetes than in control participants. Furthermore, in DR11+ participants carrying the DRB4 allele, HIP9-reactive T-cell frequencies were higher than observed frequencies for the immunodominant proinsulin 9-28 epitope. Finally, there was a negative correlation between HIP9-reactive T-cell frequency and age at diagnosis. These results provide direct evidence that this C-peptide-CgA HIP is relevant in human type 1 diabetes and suggest a mechanism by which nonrisk HLA haplotypes may contribute to the development of β-cell autoimmunity., (© 2024 by the American Diabetes Association.)
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- 2024
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28. Lower Prevalence of Diabetic Ketoacidosis at Diagnosis in Research Participants Monitored for Hyperglycemia.
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Sooy MGQ, Pyle L, Alonso GT, Broncucia HC, Rewers A, Gottlieb PA, Simmons KMW, Rewers MJ, and Steck AK
- Abstract
Context: In Colorado children, the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) has been increasing over time., Objective: Evaluate the prevalence of and factors involved in DKA at T1D diagnosis among participants followed in monitoring research studies before diagnosis compared to patients from the community., Setting and Participants: Patients < 18 years diagnosed with T1D between 2005 and 2021 at the Barbara Davis Center for Diabetes., Outcome: Prevalence of and factors associated with DKA at diagnosis among participants in preclinical monitoring studies compared to those diagnosed in the community., Results: Of 5049 subjects, 164 were active study participants, 42 inactive study participants, and 4843 were community patients. Active study participants, compared to community patients, had lower HbA1c (7.3% vs 11.9%]; P < 0.001) and less frequently experienced DKA (4.9% vs 48.5%; P < 0.001), including severe DKA (1.2% vs 16.2%; P < 0.001). Inactive study participants had intermediate levels for both prevalence and severity of DKA. DKA prevalence increased in community patients, from 44.0% to 55%, with less evidence for a temporal trend in study participants. DKA prevalence was highest in children <2 years (13% in active study participants vs 83% in community patients). In community patients, younger age (P = 0.0038), public insurance (P < 0.0001), rural residence (P < 0.0076), higher HbA1c (P < 0.0001), and ethnicity minority status (P < 0.0001) were associated with DKA at diagnosis., Conclusions: While DKA prevalence increases in community patients over time, it stayed <5% in active research participants, who have a 10 times lower prevalence of DKA at diagnosis, including in minorities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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29. C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis.
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Taylor PN, Collins KS, Lam A, Karpen SR, Greeno B, Walker F, Lozano A, Atabakhsh E, Ahmed ST, Marinac M, Latres E, Senior PA, Rigby M, Gottlieb PA, and Dayan CM
- Subjects
- Adult, Child, Humans, C-Peptide therapeutic use, Cross-Sectional Studies, Glycated Hemoglobin, Hypoglycemic Agents therapeutic use, Insulin therapeutic use, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 complications
- Abstract
Background: Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent β-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of β-cell function and metabolic outcomes in new-onset type 1 diabetes., Methods: 21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA
1c , insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c , total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test., Findings: 6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c . For HbA1c , IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods., Interpretation: Interventions that preserve β-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials., Funding: JDRF and Diabetes UK., Competing Interests: Declaration of interests PNT declares personal consulting fees from Immunovant and leadership roles in the Society for Endocrinology and British Thyroid Association. CMD declares lecturing or has been involved as an advisor for: Novo Nordisk, Sanofi-Genzyme, Janssen, Servier, Lilly, AstraZeneca, Provention Bio, UCB, MSD, Vielo Bio, Avotres, Worg, and Novartis. He holds patents jointly with Midatech, and Provention Bio and Sanofi. PAG declares consulting fees from Provention Bio and Viacyte and co-founded ImmunoMolecular Therapeutics for which he holds shares and serves as Chief Medical Officer and is a board member. He has received research support from the National Institutes of Health, Helmsley Charitable Trust, the Juvenile Diabetes Research Foundation, Nova Pharmaceuticals, Intrexon T1D Partners, Novartis, Imcyse, and Provention Bio. ALa received salary funding from JDRF in partnership with Diabetes UK. EL is a former Regeneron Pharmaceuticals employee and owns stock in the company. PAS holds the Charles A Allard Chair in Diabetes Research. He is a co-investigator in Diabetes Action Canada, and the board chair of Diabetes Canada. He has received consulting fees or honoraria from Abbott, Bayer, Eli Lilly, Insulet, Novo Nordisk, and Vertex. ALo, BG, EA, FW, and KSC are employees of the Critical Path Institute, a non-profit organisation supported by the US Food and Drug Administration of the Department of Health and Human Services. The Critical Path Institute is 55% funded by the Food and Drug Administration of the Department of Health and Human Services, totalling US $17 612 250, and 45% funded by non-government sources, totalling $14 203 111. The contents are those of the authors and do not necessarily represent the official views of, nor are an endorsement by, the Food and Drug Administration of the Department of Health and Human Services or the US Government. The Type 1 Diabetes Consortium at the Critical Path Institute receives funding from the following organisations: JDRF, Helmsley Charitable Trust, Novo Nordisk, Provention Bio, Sanofi, and Diamyd Medical. EA is a former employee of Abcam and owns stock in the company. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2023
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30. Utility and precision evidence of technology in the treatment of type 1 diabetes: a systematic review.
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Jacobsen LM, Sherr JL, Considine E, Chen A, Peeling SM, Hulsmans M, Charleer S, Urazbayeva M, Tosur M, Alamarie S, Redondo MJ, Hood KK, Gottlieb PA, Gillard P, Wong JJ, Hirsch IB, Pratley RE, Laffel LM, and Mathieu C
- Abstract
Background: The greatest change in the treatment of people living with type 1 diabetes in the last decade has been the explosion of technology assisting in all aspects of diabetes therapy, from glucose monitoring to insulin delivery and decision making. As such, the aim of our systematic review was to assess the utility of these technologies as well as identify any precision medicine-directed findings to personalize care., Methods: Screening of 835 peer-reviewed articles was followed by systematic review of 70 of them (focusing on randomized trials and extension studies with ≥50 participants from the past 10 years)., Results: We find that novel technologies, ranging from continuous glucose monitoring systems, insulin pumps and decision support tools to the most advanced hybrid closed loop systems, improve important measures like HbA1c, time in range, and glycemic variability, while reducing hypoglycemia risk. Several studies included person-reported outcomes, allowing assessment of the burden or benefit of the technology in the lives of those with type 1 diabetes, demonstrating positive results or, at a minimum, no increase in self-care burden compared with standard care. Important limitations of the trials to date are their small size, the scarcity of pre-planned or powered analyses in sub-populations such as children, racial/ethnic minorities, people with advanced complications, and variations in baseline glycemic levels. In addition, confounders including education with device initiation, concomitant behavioral modifications, and frequent contact with the healthcare team are rarely described in enough detail to assess their impact., Conclusions: Our review highlights the potential of technology in the treatment of people living with type 1 diabetes and provides suggestions for optimization of outcomes and areas of further study for precision medicine-directed technology use in type 1 diabetes., (© 2023. Springer Nature Limited.)
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- 2023
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31. Teplizumab: A Disease-Modifying Therapy for Type 1 Diabetes That Preserves β-Cell Function.
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Herold KC, Gitelman SE, Gottlieb PA, Knecht LA, Raymond R, and Ramos EL
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- Adult, Child, Humans, C-Peptide, Insulin, Regular, Human, Antibodies, Monoclonal, Humanized therapeutic use, Insulin therapeutic use, Diabetes Mellitus, Type 1 drug therapy
- Abstract
Objective: In November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1 diabetes on the basis of data from the pivotal study TN-10., Research Design and Methods: To provide confirmatory evidence of the effects of teplizumab on preserving endogenous insulin production, an integrated analysis of C-peptide data from 609 patients (n = 375 patients receiving teplizumab and n = 234 control patients) from five clinical trials in stage 3 type 1 diabetes was conducted., Results: The primary outcome of the integrated analysis, change from baseline in stimulated C-peptide, was significantly improved at years 1 (average increase 0.08 nmol/L; P < 0.0001) and 2 (average increase 0.12 nmol/L; P < 0.0001) after one or two courses of teplizumab. An analysis of exogenous insulin use was also conducted, showing overall reductions of 0.08 (P = 0.0001) and 0.10 units/kg/day (P < 0.0001) at years 1 and 2, respectively. An integrated safety analysis of five clinical trials that enrolled 1,018 patients with stage 2 or 3 type 1 diabetes (∼1,500 patient-years of follow-up for teplizumab-treated patients) was conducted., Conclusions: These data confirm consistency in the preservation of β-cell function, as measured by C-peptide, across multiple clinical trials. This analysis showed that the most common adverse events included lymphopenia, rash, and headache, a majority of which occurred during and after the first few weeks of teplizumab administration and generally resolved without intervention, consistent with a safety profile characterized by self-limited adverse events after one or two courses of teplizumab treatment., (© 2023 by the American Diabetes Association.)
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- 2023
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32. Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.
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Tobias DK, Merino J, Ahmad A, Aiken C, Benham JL, Bodhini D, Clark AL, Colclough K, Corcoy R, Cromer SJ, Duan D, Felton JL, Francis EC, Gillard P, Gingras V, Gaillard R, Haider E, Hughes A, Ikle JM, Jacobsen LM, Kahkoska AR, Kettunen JLT, Kreienkamp RJ, Lim LL, Männistö JME, Massey R, Mclennan NM, Miller RG, Morieri ML, Most J, Naylor RN, Ozkan B, Patel KA, Pilla SJ, Prystupa K, Raghavan S, Rooney MR, Schön M, Semnani-Azad Z, Sevilla-Gonzalez M, Svalastoga P, Takele WW, Tam CH, Thuesen ACB, Tosur M, Wallace AS, Wang CC, Wong JJ, Yamamoto JM, Young K, Amouyal C, Andersen MK, Bonham MP, Chen M, Cheng F, Chikowore T, Chivers SC, Clemmensen C, Dabelea D, Dawed AY, Deutsch AJ, Dickens LT, DiMeglio LA, Dudenhöffer-Pfeifer M, Evans-Molina C, Fernández-Balsells MM, Fitipaldi H, Fitzpatrick SL, Gitelman SE, Goodarzi MO, Grieger JA, Guasch-Ferré M, Habibi N, Hansen T, Huang C, Harris-Kawano A, Ismail HM, Hoag B, Johnson RK, Jones AG, Koivula RW, Leong A, Leung GKW, Libman IM, Liu K, Long SA, Lowe WL Jr, Morton RW, Motala AA, Onengut-Gumuscu S, Pankow JS, Pathirana M, Pazmino S, Perez D, Petrie JR, Powe CE, Quinteros A, Jain R, Ray D, Ried-Larsen M, Saeed Z, Santhakumar V, Kanbour S, Sarkar S, Monaco GSF, Scholtens DM, Selvin E, Sheu WH, Speake C, Stanislawski MA, Steenackers N, Steck AK, Stefan N, Støy J, Taylor R, Tye SC, Ukke GG, Urazbayeva M, Van der Schueren B, Vatier C, Wentworth JM, Hannah W, White SL, Yu G, Zhang Y, Zhou SJ, Beltrand J, Polak M, Aukrust I, de Franco E, Flanagan SE, Maloney KA, McGovern A, Molnes J, Nakabuye M, Njølstad PR, Pomares-Millan H, Provenzano M, Saint-Martin C, Zhang C, Zhu Y, Auh S, de Souza R, Fawcett AJ, Gruber C, Mekonnen EG, Mixter E, Sherifali D, Eckel RH, Nolan JJ, Philipson LH, Brown RJ, Billings LK, Boyle K, Costacou T, Dennis JM, Florez JC, Gloyn AL, Gomez MF, Gottlieb PA, Greeley SAW, Griffin K, Hattersley AT, Hirsch IB, Hivert MF, Hood KK, Josefson JL, Kwak SH, Laffel LM, Lim SS, Loos RJF, Ma RCW, Mathieu C, Mathioudakis N, Meigs JB, Misra S, Mohan V, Murphy R, Oram R, Owen KR, Ozanne SE, Pearson ER, Perng W, Pollin TI, Pop-Busui R, Pratley RE, Redman LM, Redondo MJ, Reynolds RM, Semple RK, Sherr JL, Sims EK, Sweeting A, Tuomi T, Udler MS, Vesco KK, Vilsbøll T, Wagner R, Rich SS, and Franks PW
- Subjects
- Humans, Consensus, Evidence-Based Medicine, Precision Medicine, Diabetes Mellitus diagnosis, Diabetes Mellitus genetics, Diabetes Mellitus therapy
- Abstract
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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33. Identification of an anergic BND cell-derived activated B cell population (BND2) in young-onset type 1 diabetes patients.
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Stensland ZC, Magera CA, Broncucia H, Gomez BD, Rios-Guzman NM, Wells KL, Nicholas CA, Rihanek M, Hunter MJ, Toole KP, Gottlieb PA, and Smith MJ
- Subjects
- Humans, Cross-Sectional Studies, B-Lymphocytes, T-Lymphocytes, Insulin, Diabetes Mellitus, Type 1
- Abstract
Recent evidence suggests a role for B cells in the pathogenesis of young-onset type 1 diabetes (T1D), wherein rapid progression occurs. However, little is known regarding the specificity, phenotype, and function of B cells in young-onset T1D. We performed a cross-sectional analysis comparing insulin-reactive to tetanus-reactive B cells in the blood of T1D and controls using mass cytometry. Unsupervised clustering revealed the existence of a highly activated B cell subset we term BND2 that falls within the previously defined anergic BND subset. We found a specific increase in the frequency of insulin-reactive BND2 cells in the blood of young-onset T1D donors, which was further enriched in the pancreatic lymph nodes of T1D donors. The frequency of insulin-binding BND2 cells correlated with anti-insulin autoantibody levels. We demonstrate BND2 cells are pre-plasma cells and can likely act as APCs to T cells. These findings identify an antigen-specific B cell subset that may play a role in the rapid progression of young-onset T1D., (© 2023 Stensland et al.)
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- 2023
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34. Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.
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Russell WE, Bundy BN, Anderson MS, Cooney LA, Gitelman SE, Goland RS, Gottlieb PA, Greenbaum CJ, Haller MJ, Krischer JP, Libman IM, Linsley PS, Long SA, Lord SM, Moore DJ, Moore WV, Moran AM, Muir AB, Raskin P, Skyler JS, Wentworth JM, Wherrett DK, Wilson DM, Ziegler AG, and Herold KC
- Subjects
- Humans, Abatacept therapeutic use, Abatacept pharmacology, Immunosuppressive Agents, T-Lymphocytes, Regulatory, Glucose therapeutic use, Diabetes Mellitus, Type 1 drug therapy
- Abstract
Objective: Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-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., (© 2023 by the American Diabetes Association.)
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- 2023
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35. Barriers to Screening: An Analysis of Factors Impacting Screening for Type 1 Diabetes Prevention Trials.
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Kinney M, You L, Sims EK, Wherrett D, Schatz D, Lord S, Krischer J, Russell WE, Gottlieb PA, Libman I, Buckner J, DiMeglio LA, Herold KC, and Steck AK
- Abstract
Context: Participants with stage 1 or 2 type 1 diabetes (T1D) qualify for prevention trials, but factors involved in screening for such trials are largely unknown., Objective: To identify factors associated with screening for T1D prevention trials., Methods: This study included TrialNet Pathway to Prevention participants who were eligible for a prevention trial: oral insulin (TN-07, TN-20), teplizumab (TN-10), abatacept (TN-18), and oral hydroxychloroquine (TN-22). Univariate and multivariate logistic regression models were used to examine participant, site, and study factors at the time of prevention trial accrual., Results: Screening rates for trials were: 50% for TN-07 (584 screened/1172 eligible), 9% for TN-10 (106/1249), 24% for TN-18 (313/1285), 17% for TN-20 (113/667), and 28% for TN-22 (371/1336). Younger age and male sex were associated with higher screening rates for prevention trials overall and for oral therapies. Participants with an offspring with T1D showed lower rates of screening for all trials and oral drug trials compared with participants with other first-degree relatives as probands. Site factors, including larger monitoring volume and US site vs international site, were associated with higher prevention trial screening rates., Conclusions: Clear differences exist between participants who screen for prevention trials and those who do not screen and between the research sites involved in prevention trial screening. Participant age, sex, and relationship to proband are significantly associated with prevention trial screening in addition to key site factors. Identifying these factors can facilitate strategic recruitment planning to support rapid and successful enrollment into prevention trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2023
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36. Temporal development of T cell receptor repertoires during childhood in health and disease.
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Mitchell AM, Baschal EE, McDaniel KA, Simmons KM, Pyle L, Waugh K, Steck AK, Yu L, Gottlieb PA, Rewers MJ, Nakayama M, and Michels AW
- Subjects
- Child, High-Throughput Nucleotide Sequencing methods, Humans, Infant, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell, alpha-beta genetics, Diabetes Mellitus, Type 1 genetics, Influenza, Human
- Abstract
T cell receptor (TCR) sequences are exceptionally diverse and can now be comprehensively measured with next-generation sequencing technologies. However, a thorough investigation of longitudinal TCR repertoires throughout childhood in health and during development of a common childhood disease, type 1 diabetes (T1D), has not been undertaken. Here, we deep sequenced the TCR-β chain repertoires from longitudinal peripheral blood DNA samples at 4 time points beginning early in life (median age of 1.4 years) from children who progressed to T1D (n = 29) and age/sex-matched islet autoantibody-negative controls (n = 25). From 53 million TCR-β sequences, we show that the repertoire is extraordinarily diverse early in life and narrows with age independently of disease. We demonstrate the ability to identify specific TCR sequences, including those known to recognize influenza A and, separately, those specific for insulin and its precursor, preproinsulin. Insulin-reactive TCR-β sequences were more common and frequent in number as the disease progressed in those who developed T1D compared with genetically at risk nondiabetic children, and this was not the case for influenza-reactive sequences. As an independent validation, we sequenced and analyzed TCR-β repertoires from a cohort of new-onset T1D patients (n = 143), identifying the same preproinsulin-reactive TCRs. These results demonstrate an enrichment of preproinsulin-reactive TCR sequences during the progression to T1D, highlighting the importance of using disease-relevant TCR sequences as powerful biomarkers in autoimmune disorders.
- Published
- 2022
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37. Mechano-Sensing Channel PIEZO2 Enhances Invasive Phenotype in Triple-Negative Breast Cancer.
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Katsuta E, Takabe K, Vujcic M, Gottlieb PA, Dai T, Mercado-Perez A, Beyder A, Wang Q, and Opyrchal M
- Subjects
- Cadherins genetics, Cadherins metabolism, Cell Line, Tumor, Cell Movement genetics, Epithelial-Mesenchymal Transition genetics, Humans, Ion Channels genetics, Phenotype, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Vimentin genetics, Vimentin metabolism, Triple Negative Breast Neoplasms pathology
- Abstract
Background: Mechanically gated PIEZO channels lead to an influx of cations, activation of additional Ca
2+ channels, and cell depolarization. This study aimed to investigate PIEZO2's role in breast cancer., Methods: The clinical relevance of PIEZO2 expression in breast cancer patient was analyzed in a publicly available dataset. Utilizing PIEZO2 overexpressed breast cancer cells, and in vitro and in vivo experiments were conducted., Results: High expression of PIEZO2 was correlated with a worse survival in triple-negative breast cancer (TNBC) but not in other subtypes. Increased PEIZO2 channel function was confirmed in PIEZO2 overexpressed cells after mechanical stimulation. PIEZO2 overexpressed cells showed increased motility and invasive phenotypes as well as higher expression of SNAIL and Vimentin and lower expression of E-cadherin in TNBC cells. Correspondingly, high expression of PIEZO2 was correlated with the increased expression of epithelial-mesenchymal transition (EMT)-related genes in a TNBC patient. Activated Akt signaling was observed in PIEZO2 overexpressed TNBC cells. PIEZO2 overexpressed MDA-MB-231 cells formed a significantly higher number of lung metastases after orthotopic implantation., Conclusion: PIEZO2 activation led to enhanced SNAIL stabilization through Akt activation. It enhanced Vimentin and repressed E-cadherin transcription, resulting in increased metastatic potential and poor clinical outcomes in TNBC patients.- Published
- 2022
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38. Association of High-Affinity Autoantibodies With Type 1 Diabetes High-Risk HLA Haplotypes.
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Triolo TM, Pyle L, Broncucia H, Armstrong T, Yu L, Gottlieb PA, and Steck AK
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- Adolescent, Adult, Autoantibodies, Child, Child, Preschool, Female, Glutamate Decarboxylase, HLA Antigens genetics, HLA-DR3 Antigen genetics, HLA-DR4 Antigen genetics, Haplotypes, Humans, Insulin Antibodies, Male, Young Adult, Diabetes Mellitus, Type 1 diagnosis
- Abstract
Objective: Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes., Methods: We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least 1 RBA diabetes-related Ab [glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (IAA)] and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (z-scores) for analyses., Results: Mean age at initial visit was 19.4 ± 13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA-DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (P < 0.05)., Conclusions: ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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39. Peripheral immunophenotyping of AITD subjects reveals alterations in immune cells in pediatric vs adult-onset AITD.
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Stensland ZC, Coleman BM, Rihanek M, Baxter RM, Gottlieb PA, Hsieh EWY, Sarapura VD, Simmons KM, Cambier JC, and Smith MJ
- Abstract
Autoimmune thyroid disease (AITD) is caused by aberrant activation of the immune system allowing autoreactive B and T cells to target the thyroid gland leading to disease. Although AITD is more frequently diagnosed in adults, children are also affected but rarely studied. Here, we performed phenotypic and functional characterization of peripheral blood immune cells from pediatric and adult-onset AITD patients and age-matched controls using mass cytometry. Major findings indicate that unlike adult-onset AITD patients, pediatric AITD patients exhibit a decrease in anergic B cells (B
ND ) and DN2 B cells and an increase in immature B cells compared to age-matched controls. These results indicate alterations in peripheral blood immune cells seen in pediatric-onset AITD could lead to rapid progression of disease. Hence, this study demonstrates diversity of AITD by showing differences in immune cell phenotypes and function based on age of onset, and may inform future therapies., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)- Published
- 2021
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40. Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample.
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Bediaga NG, Li-Wai-Suen CSN, Haller MJ, Gitelman SE, Evans-Molina C, Gottlieb PA, Hippich M, Ziegler AG, Lernmark A, DiMeglio LA, Wherrett DK, Colman PG, Harrison LC, and Wentworth JM
- Subjects
- Adolescent, Area Under Curve, Blood Glucose metabolism, Body Mass Index, C-Peptide blood, Child, Child, Preschool, Diabetes Mellitus, Type 1 blood, Disease Progression, Female, Glucose Tolerance Test, Glycated Hemoglobin metabolism, Humans, Male, Proportional Hazards Models, ROC Curve, Asymptomatic Diseases, Autoantibodies blood, Diabetes Mellitus, Type 1 diagnosis, Insulin Antibodies blood, Receptor-Like Protein Tyrosine Phosphatases, Class 8 immunology, Zinc Transporter 8 immunology
- Abstract
Aims/hypothesis: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw., Methods: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da., Results: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA
1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60 , M90 and M120 , based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615., Conclusions/interpretation: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120 , its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification., (© 2021. The Author(s).)- Published
- 2021
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41. Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
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Gitelman SE, Bundy BN, Ferrannini E, Lim N, Blanchfield JL, DiMeglio LA, Felner EI, Gaglia JL, Gottlieb PA, Long SA, Mari A, Mirmira RG, Raskin P, Sanda S, Tsalikian E, Wentworth JM, Willi SM, Krischer JP, and Bluestone JA
- Subjects
- Adolescent, Adult, Biomarkers analysis, Blood Glucose analysis, Diabetes Mellitus, Type 1 pathology, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, Young Adult, Diabetes Mellitus, Type 1 drug therapy, Imatinib Mesylate therapeutic use, Protein Kinase Inhibitors therapeutic use
- Abstract
Background: Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes., Methods: We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L
-1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed)., Findings: Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI -0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events., Interpretation: A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required., Funding: Juvenile Research Diabetes Foundation., Competing Interests: Declaration of interests SEG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Caladrius, Intrexon, Janssen, Provention Bio, and Tolerion. JLG has consulted for Vertex Pharmaceuticals and Regeneron Pharmaceuticals, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PAG has served on advisory boards for Caladrius, Bristol Myers Squibb, and Lilly, received grant support from Caladrius, Novo Nordisk, and Pfizer, and is co-founder and chief medical officer for ImmunoMolecular Therapeutics. RGM has a patent application for DNA methylation in inflammatory disease. SMW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals and Medtronic, and a data and safety monitoring board for the US National Institutes of Health (NIH). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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42. Low-Dose ATG/GCSF in Established Type 1 Diabetes: A Five-Year Follow-up Report.
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Lin A, Mack JA, Bruggeman B, Jacobsen LM, Posgai AL, Wasserfall CH, Brusko TM, Atkinson MA, Gitelman SE, Gottlieb PA, Gurka MJ, Mathews CE, Schatz DA, and Haller MJ
- Subjects
- Area Under Curve, C-Peptide metabolism, Diabetes Mellitus, Type 1 metabolism, Humans, Pilot Projects, Antilymphocyte Serum therapeutic use, Diabetes Mellitus, Type 1 drug therapy, Granulocyte Colony-Stimulating Factor therapeutic use
- Abstract
Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes ( n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data ( n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo ( P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders ( n = 9) and nonresponders ( n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA
1c over 5 years (mean [95% CI] adjusted change 0.29% [-0.69%, 1.27%]), but the study was not powered for comparisons against nonresponders 1.75% (-0.57%, 4.06%) or placebo recipients 1.44% (0.21%, 2.66%). These data underscore the importance of long-term follow-up in previous and ongoing phase 2 trials of low-dose ATG in recent-onset type 1 diabetes., (© 2021 by the American Diabetes Association.)- Published
- 2021
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43. T-cell responses to hybrid insulin peptides prior to type 1 diabetes development.
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Mitchell AM, Alkanani AA, McDaniel KA, Pyle L, Waugh K, Steck AK, Nakayama M, Yu L, Gottlieb PA, Rewers MJ, and Michels AW
- Subjects
- Adolescent, Adult, Autoantibodies genetics, Autoantibodies immunology, Autoantigens immunology, Autoimmunity genetics, Autoimmunity immunology, CD4-Positive T-Lymphocytes immunology, Child, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 pathology, Disease Progression, Female, Humans, Insulin genetics, Insulin-Secreting Cells immunology, Islets of Langerhans immunology, Islets of Langerhans pathology, Male, Peptides immunology, T-Lymphocytes immunology, Young Adult, Autoantigens genetics, Diabetes Mellitus, Type 1 genetics, Insulin immunology, Interferon-gamma genetics, Peptides genetics
- Abstract
T-cell responses to posttranslationally modified self-antigens are associated with many autoimmune disorders. In type 1 diabetes, hybrid insulin peptides (HIPs) are implicated in the T-cell-mediated destruction of insulin-producing β-cells within pancreatic islets. The natural history of the disease is such that it allows for the study of T-cell reactivity prior to the onset of clinical symptoms. We hypothesized that CD4 T-cell responses to posttranslationally modified islet peptides precedes diabetes onset. In a cohort of genetically at-risk individuals, we measured longitudinal T-cell responses to native insulin and hybrid insulin peptides. Both proinflammatory (interferon-γ) and antiinflammatory (interluekin-10) cytokine responses to HIPs were more robust than those to native peptides, and the ratio of such responses oscillated between pro- and antiinflammatory over time. However, individuals who developed islet autoantibodies or progressed to clinical type 1 diabetes had predominantly inflammatory T-cell responses to HIPs. Additionally, several HIP T-cell responses correlated to worsening measurements of blood glucose, highlighting the relevance of T-cell responses to posttranslationally modified peptides prior to autoimmune disease development., Competing Interests: Competing interest statement: P.A.G. and A.W.M. are inventors on a patent, “Insulin Mimotopes and Methods of Using the Same” (US patent number 10,363,288).
- Published
- 2021
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44. Advances in Diabetes Treatment - Once-Weekly Insulin.
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Gottlieb PA and Michels AW
- Subjects
- Glucagon-Like Peptides, Humans, Insulin, Regular, Human, Diabetes Mellitus, Type 2 drug therapy, Hypoglycemic Agents administration & dosage, Insulin administration & dosage
- Published
- 2020
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45. Exenatide extended release in patients with type 1 diabetes with and without residual insulin production.
- Author
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Herold KC, Reynolds J, Dziura J, Baidal D, Gaglia J, Gitelman SE, Gottlieb PA, Marks J, Philipson LH, Pop-Busui R, and Weinstock RS
- Subjects
- Exenatide, Glycated Hemoglobin analysis, Humans, Hypoglycemic Agents therapeutic use, Insulin, Venoms therapeutic use, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 2
- Abstract
Aims: To test whether a long-acting GLP-1 receptor agonist would improve glucose control in patients with type 1 diabetes (T1D) and to determine whether the presence of residual beta cell function would affect the response. In addition, we sought to determine whether the drug would affect beta cell function., Methods: We performed a randomized placebo-controlled trial of exenatide extended release (ER) in participants with T1D with and without detectable levels of C-peptide. Seventy-nine participants were randomized to exenatide ER 2 mcg weekly, or placebo, stratified by the presence or absence of detectable C-peptide levels. The primary outcome was the difference in glycated haemoglobin (HbA1c) levels at 24 weeks. Participants were followed for another 6 months off study drug., Results: At week 24, the time of the primary outcome, the least squares (LS) mean HbA1c level was 7.76% (95% confidence interval [CI] 7.42, 8.10) in the exenatide ER group versus 8.0% (95% CI 7.64, 8.35) in the placebo group (P = 0.08). At week 12 the LS mean HbA1c levels were 7.71% (95% CI 7.37, 8.05) in the exenatide ER group versus 8.05% (95% CI 7.7, 8.4) in the placebo group (P = 0.01). The improvement at week 12 was driven mainly by those with detectable levels of C-peptide. Those treated with exenatide ER lost weight at 12 and 24 weeks compared to those treated with placebo (P <0.001 and P = 0.007). The total insulin dose was lower, but not when corrected for body weight, and was not affected by residual insulin production. Adverse events were more frequent with exenatide ER, but hypoglycaemia was not increased., Conclusion: Treatment with exenatide ER may have short-term benefits in some individuals with T1D who are overweight or who have detectable levels of C-peptide, but short-term improvements were not sustained., (© 2020 John Wiley & Sons Ltd.)
- Published
- 2020
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46. Disruption of membrane cholesterol organization impairs the activity of PIEZO1 channel clusters.
- Author
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Ridone P, Pandzic E, Vassalli M, Cox CD, Macmillan A, Gottlieb PA, and Martinac B
- Subjects
- Humans, Cell Membrane chemistry, Cholesterol chemistry, Ion Channels physiology, Mechanotransduction, Cellular
- Abstract
The human mechanosensitive ion channel PIEZO1 is gated by membrane tension and regulates essential biological processes such as vascular development and erythrocyte volume homeostasis. Currently, little is known about PIEZO1 plasma membrane localization and organization. Using a PIEZO1-GFP fusion protein, we investigated whether cholesterol enrichment or depletion by methyl-β-cyclodextrin (MBCD) and disruption of membrane cholesterol organization by dynasore affects PIEZO1-GFP's response to mechanical force. Electrophysiological recordings in the cell-attached configuration revealed that MBCD caused a rightward shift in the PIEZO1-GFP pressure-response curve, increased channel latency in response to mechanical stimuli, and markedly slowed channel inactivation. The same effects were seen in native PIEZO1 in N2A cells. STORM superresolution imaging revealed that, at the nanoscale, PIEZO1-GFP channels in the membrane associate as clusters sensitive to membrane manipulation. Both cluster distribution and diffusion rates were affected by treatment with MBCD (5 mM). Supplementation of polyunsaturated fatty acids appeared to sensitize the PIEZO1-GFP response to applied pressure. Together, our results indicate that PIEZO1 function is directly dependent on the membrane composition and lateral organization of membrane cholesterol domains, which coordinate the activity of clustered PIEZO1 channels., (© 2020 Ridone et al.)
- Published
- 2020
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47. Endotypes in T1D: B lymphocytes and early onset.
- Author
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Smith MJ, Cambier JC, and Gottlieb PA
- Subjects
- Age of Onset, Animals, Diabetes Mellitus, Type 1 epidemiology, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 pathology, Humans, Insulin immunology, T-Lymphocytes physiology, Time Factors, B-Lymphocytes physiology, Diabetes Mellitus, Type 1 immunology, Insulin-Secreting Cells immunology, Islets of Langerhans immunology
- Abstract
Purpose of Review: Although type 1 diabetes (T1D) is characterized by destruction of the pancreatic beta cells by self-reactive T cells, it has become increasingly evident that B cells also play a major role in disease development, likely functioning as antigen-presenting cells. Here we review the biology of islet antigen-reactive B cells and their participation in autoimmune diabetes., Recent Findings: Relative to late onset, individuals who develop T1D at an early age display increased accumulation of insulin-reactive B cells in islets. This B-cell signature is also associated with rapid progression of disease and responsiveness to B-cell depletion therapy. Also suggestive of B-cell participation in disease is loss of anergy in high-affinity insulin-reactive B cells. Importantly, loss of anergy is seen in patient's healthy first-degree relatives carrying certain T1D risk alleles, suggesting a role early in disease development., Summary: Recent studies indicate that islet-reactive B cells may play a pathogenic role very early in T1D development in young patients, and suggest utility of therapies that target these cells.
- Published
- 2020
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48. Risk of Islet and Celiac Autoimmunity in Cotwins of Probands With Type 1 Diabetes.
- Author
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Triolo TM, Pyle L, Seligova S, Yu L, Gottlieb PA, and Steck AK
- Abstract
Context: Concordance for persistent islet autoimmunity (IA) and type 1 diabetes in monozygotic twins after probands are diagnosed is variable (30%-70%). Risk for development of IA in dizygotic twins is thought to be similar to nontwin siblings. Little is known in regard to the development of celiac autoimmunity (CDA) in twins of subjects with type 1 diabetes., Objective: Our aim was to investigate the development of IA and CDA in cotwins of probands with type 1 diabetes., Methods: Since 1995, the Twin Family Study has followed 336 twins (168 twin probands with type 1 diabetes and 168 cotwins) for a median of 14 years (interquartile range:10-18 years). Cotwins were followed for the development of IA, type 1 diabetes, and CDA., Results: In monozygotic cotwins, cumulative incidence by age 20 was 14% for IA and 10% for CDA. Development of IA and CDA by age 20 was 9% and 12% in dizygotic cotwins, respectively. While the numbers are small, IA by age 30 years was 26% in monozygotic and 39% in dizygotic twins. In proportional hazards models, the proband's younger age at diagnosis, but not sex or human leukocyte antigen were associated with time to IA and CDA in cotwins., Conclusion: CDA risk by age 20 in cotwins was 10% to 12%. With long-term follow-up, cumulative incidence for IA is high in dizygotic twins, similar to monozygotic twins, suggesting a role of possible early environmental factors shared by type 1 diabetes discordant cotwins., (© Endocrine Society 2020.)
- Published
- 2020
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49. Clinical trial data validate the C-peptide estimate model in type 1 diabetes.
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Wentworth JM, Bediaga NG, Gitelman SE, Evans-Molina C, Gottlieb PA, Colman PG, Haller MJ, and Harrison LC
- Subjects
- Adolescent, Adult, Antilymphocyte Serum therapeutic use, Area Under Curve, Blood Glucose analysis, C-Peptide analysis, C-Peptide metabolism, Child, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 diagnosis, Diagnostic Techniques, Endocrine, Female, Glycated Hemoglobin analysis, Granulocyte Colony-Stimulating Factor therapeutic use, Humans, Male, Meals, Outcome Assessment, Health Care, Prognosis, Treatment Outcome, Young Adult, Biomarkers, Pharmacological analysis, Biomarkers, Pharmacological metabolism, C-Peptide blood, Clinical Trials as Topic methods, Clinical Trials as Topic statistics & numerical data, Diabetes Mellitus, Type 1 drug therapy
- Published
- 2020
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50. Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes.
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Battaglia M, Ahmed S, Anderson MS, Atkinson MA, Becker D, Bingley PJ, Bosi E, Brusko TM, DiMeglio LA, Evans-Molina C, Gitelman SE, Greenbaum CJ, Gottlieb PA, Herold KC, Hessner MJ, Knip M, Jacobsen L, Krischer JP, Long SA, Lundgren M, McKinney EF, Morgan NG, Oram RA, Pastinen T, Peters MC, Petrelli A, Qian X, Redondo MJ, Roep BO, Schatz D, Skibinski D, and Peakman M
- Subjects
- Blood Glucose metabolism, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 therapy, Disease Progression, Humans, Insulin metabolism, Precision Medicine methods, Precision Medicine trends, Biological Variation, Population physiology, Diabetes Mellitus, Type 1 classification, Diabetes Mellitus, Type 1 pathology, Phenotype
- Abstract
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management., (© 2019 by the American Diabetes Association.)
- Published
- 2020
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