The challenge of modulating β-cell autoimmunity in type 1 diabetes

Published on Jan 1, 2019in The Lancet Diabetes & Endocrinology 19.31
· DOI :10.1016/S2213-8587(18)30112-8
Mark A. Atkinson82
Estimated H-index: 82
(University of Florida),
Bart O. Roep58
Estimated H-index: 58
(City of Hope National Medical Center)
+ 2 AuthorsMark Peakman51
Estimated H-index: 51
Summary With the conceptual advance about four decades ago that type 1 diabetes represents an autoimmune disease, hope arose that immune-based therapies would soon emerge to prevent and reverse the disorder. However, despite dozens of clinical trials seeking to achieve these goals, the promise remains unfulfilled, at least in a pragmatic form. With the benefit of hindsight, several important reasons are likely to account for this disappointing outcome, including failure to appreciate disease heterogeneity, inappropriate use of rodent models of disease, inadequacies in addressing the immunological and metabolic contributions to the disease, suboptimal trial designs, and lack of a clear understanding of the pathogenesis of type 1 diabetes. In this Series paper, we convey how recent knowledge gains in these areas, combined with efforts related to disease staging and emerging mechanistic data from clinical trials, provide cautious optimism that immune-based approaches to prevent the loss of β cells in type 1 diabetes will emerge into clinical practice.
  • References (93)
  • Citations (1)
Published on Jun 1, 1999in Nature Medicine 32.62
Mark A. Atkinson82
Estimated H-index: 82
(University of Florida),
Edward H. Leiter58
Estimated H-index: 58
509 Citations Source Cite
Published on Oct 1, 2015in Diabetes Care 13.40
Diane K. Wherrett15
Estimated H-index: 15
(University of Toronto),
Jane L. Chiang9
Estimated H-index: 9
(American Diabetes Association)
+ 10 AuthorsCarla J. Greenbaum54
Estimated H-index: 54
Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course. Therefore, the efficacy of disease-modifying therapies may be different in the two populations. Understanding the developmental and regulatory pathways for type 1 diabetes–modifying therapies in children will enable industry, academia, funders, advocacy groups, and regulators to translate new science to clinical care. This consensu...
27 Citations Source Cite
Meghan L. Marré6
Estimated H-index: 6
(University of Pittsburgh),
Eddie A. James29
Estimated H-index: 29
(Benaroya Research Institute),
Jon D. Piganelli30
Estimated H-index: 30
(University of Pittsburgh)
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of insulin-producing pancreatic islet β cells. Although many elegant studies have identified β cell autoantigens that are targeted by the autoimmune response, the mechanisms by which these autoantigens are generated remain poorly understood. Normal β cell physiology includes a high demand for insulin production and secretion in response to dynamic glucose sensing. T...
35 Citations Source Cite
Published on Mar 1, 1990in Pediatrics 5.51
H. Peter Chase50
Estimated H-index: 50
Nancy Butler-Simon5
Estimated H-index: 5
+ 4 AuthorsDonough O'Brien20
Estimated H-index: 20
30 Citations
Published on Oct 1, 2015in Diabetes Care 13.40
Richard A. Insel30
Estimated H-index: 30
Jessica L. Dunne5
Estimated H-index: 5
+ 13 AuthorsAnette G. Ziegler12
Estimated H-index: 12
(Technische Universität München)
Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with...
146 Citations Source Cite
Published on Feb 6, 2013in PLOS ONE 2.77
Ghanashyam Sarikonda5
Estimated H-index: 5
(La Jolla Institute for Allergy and Immunology),
Sowbarnika Sachithanantham6
Estimated H-index: 6
(La Jolla Institute for Allergy and Immunology)
+ 19 AuthorsDarius Schneider5
Estimated H-index: 5
(La Jolla Institute for Allergy and Immunology)
A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that incl...
26 Citations Source Cite
Published on Aug 17, 2011in Science Translational Medicine 16.71
Mark A. Atkinson82
Estimated H-index: 82
Recent disappointing results of clinical trials seeking type 1 diabetes (T1D) reversal suggest the need for a reevaluation of our translational efforts. This Commentary explores the need for standards in evaluating therapeutic efficacy in preclinical models of T1D.
18 Citations Source Cite
Published on Oct 1, 1982in Acta Diabetologica 3.13
Johnny Ludvigsson59
Estimated H-index: 59
(Linköping University),
Lise G. Heding3
Estimated H-index: 3
(Linköping University)
B-cell function was studied in 20 diabetic children, with an age at onset of diabetes between 1–16 years (8.8 ± 4.0). Serum samples were taken before the first insulin injection and after 1, 3, 6, 9 and in a few patients after 18 months. At 3, 9, and 18 months the patients were also given a standardized breakfast load. Serum proinsulin, C-peptide, IRI and insulin antibodies (IgG) were determined. At onset 19 patients had measurable C-peptide (0.22 ± 0.17 pmol/ml; range 0.05–0.58). Proinsulin var...
40 Citations Source Cite
Published on Apr 1, 2014in Diabetic Medicine 3.13
P. Ambery1
Estimated H-index: 1
T. W. Donner1
Estimated H-index: 1
(Johns Hopkins University School of Medicine)
+ 3 AuthorsColin Mark Dayan42
Estimated H-index: 42
(Cardiff University)
Aims Phase III DEFEND-2 investigated whether otelixizumab (3.1 mg over 8 days) preserved C-peptide secretion in patients with new-onset Type 1 diabetes, focusing on adolescents (12–17 years). Methods One hundred and seventy-nine patients (54 adolescents) were randomized to otelixizumab or placebo. The primary endpoint was change in 2-h mixed-meal-stimulated C-peptide area under the curve at month 12. Enrolment was suspended in April 2011 following negative efficacy results from DEFEND-1. DEFEND-...
29 Citations Source Cite
Published on Mar 2, 2015in Journal of Clinical Investigation 13.25
Kevan C. Herold65
Estimated H-index: 65
(Yale University),
Sahar Usmani-Brown5
Estimated H-index: 5
+ 7 AuthorsJerry P. Palmer61
Estimated H-index: 61
(University of Washington)
Role of the funding source: Funding from the NIH was used for support of the participating clinical centers and the coordinating center. The funding source did not participate in the collection or the analysis of the data. BACKGROUND. The β cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured. METHODS. Here, we measured β cell ...
65 Citations Source Cite
Cited By1
Published on Jan 1, 2019in The Lancet Diabetes & Endocrinology 19.31
Bart O. Roep58
Estimated H-index: 58
(City of Hope National Medical Center),
Daniel C S Wheeler1
Estimated H-index: 1
(King's College London),
Mark Peakman51
Estimated H-index: 51
Summary Precision medicine has emerged as a mantra for therapeutic approaches to complex diseases. The defining concept relies on a detailed insight into disease pathogenesis and therapeutic mechanism. Although the type 1 diabetes field has gained new insights into disease endotypes and indications of efficacy for several therapies, none of these is yet licensed, partly because of immune suppressive side-effects beyond control of islet autoimmunity. New strategies designed to regulate the immune...
2 Citations Source Cite