Abstract
Introduction
O
Key Articles Reviewed
Forlenza GP, McVean J, Beck RW, Bauza C, Bailey R, Buckingham B, DiMeglio LA, Sherr JL, Clements M, Neyman A, Evans-Molina C, Sims EK, Messer LH, Ekhlaspour L, McDonough R, Van Name M, Rojas D, Beasley S, DuBose S, Kollman C, Moran A for the CLVer Study Group
Van Rampelbergh J, Achenbach P, Leslie RD, Ali MA, Dayan C, Keymeulen B, Owen KR, Kindermans M, Parmentier F, Carlier V, Ahangarani RR, Gebruers E, Bovy N, Vanderelst L, Van Mechelen M, Vandepapelière P, Boitard C
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 , Herold KC; and the Type 1 Diabetes TrialNet Study Group
Chitnis T, Kaskow BJ, Case J, Hanus K, Li Z, Varghese JF, Healy BC, Gauthier C, Saraceno TJ, Saxena S, Lokhande H, Moreira TG, Zurawski J, Roditi RE, Bergmark RW, Giovannoni F, Torti MF, Li Z, Quintana F, Clementi WA, Shailubhai K, Weiner HL, Baecher-Allan CM
Krischer JP, Liu X, Lernmark Å, Hagopian WA, Rewers MJ, She JX, Toppari J, Ziegler AG, Akolkar B; on behalf of the TEDDY Study Group
Suomi T, Starskaia I, Kalim UU, Rasool O, Jaakkola MK, Grönroos T, Välikangas T, Brorsson C, Mazzoni G, Bruggraber S, Overbergh L, Dunger D*, Peakman M, Chmura P, Brunak S, Schulte AM, Mathieu C, Knip M, Lahesmaa R, Elo LL; on behalf of the INNODIA Consortium
Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial
Forlenza GP1, McVean J2,3, Beck RW4, Bauza C4, Bailey R4, Buckingham B5, DiMeglio LA6, Sherr JL7, Clements M8, Neyman A6, Evans-Molina C6, Sims EK6, Messer LH1,9, Ekhlaspour L5,10, McDonough R8, Van Name M7, Rojas D4, Beasley S2, DuBose S4,11, Kollman C4, Moran A2 for the CLVer Study Group
1Barbara Davis Center, Anschutz Medical Campus, University of Colorado, Aurora, CO; 2University of Minnesota, Minneapolis, MN; 3now with Medtronic, Northridge, CA; 4Jaeb Center for Health Research, Tampa, FL; 5Stanford University, Stanford, CA; 6Indiana University School of Medicine, Indianapolis, IN; 7Yale School of Medicine, Yale University, New Haven, CT; 8Children's Mercy Hospital, Kansas City, MO; 9Now with Tandem Diabetes Care, San Diego, CA; 10Now with University of California, San Francisco, CA; 11Now with Emory University, Atlanta, GA
This study is also discussed in DIA-2024-2508, page S-117.
As previously reported in the 2022 ATTD Yearbook, verapamil holds promise for the preservation of β-cell function in patients with type 1 diabetes (T1D). Verapamil, an antihypertensive calcium channel blocker, decreases the expression of thioredoxin-interacting protein (TXNIP), promoting the survival of insulin-producing β cells and leading to diabetes reversal in mouse models. In a pilot study conducted in newly diagnosed adults with T1D, improved C-peptide levels were observed after 1 year of treatment with oral verapamil compared with placebo. Subsequently, a double-blind, placebo-controlled, randomized clinical trial was recently conducted in children and adolescents with T1D to determine the safety and efficacy of verapamil in preserving β-cell function 12 months after diagnosis.
Methods
The 88 participants (at least 1 islet antibody positive, > 30 kg, 7–17 years) with T1D diagnosed < 31 days were randomized (1:1:1:1) to the verapamil or the placebo group, and also to receive either intensive diabetes management with an automated insulin delivery (AID) system (Tandem Diabetes Care or Medtronic) or standard diabetes management that included the use of a continuous glucose monitor (CGM; Dexcom G6). None of the participants had contraindications to use verapamil. Verapamil was dosed according to weight and was started with 60 or 120 mg/day, with a ramp up in 2- to 4-week intervals to a maximum of 360 mg/day for participants weighing more than 50 kg. The primary outcome was area under the curve (AUC) values for stimulated mixed meal tolerance test (MMTT) C-peptide level at 52 weeks. The secondary outcomes included the peak C-peptide level, the proportion with a peak C-peptide level of ≥ 0.2 pmol/mL, hemoglobin A1c (HbA1c), mean glucose, and determination of time in range (TIR) using a CGM during the 28 days before each study visit for specific glucose concentration ranges. The follow-up study visits were conducted at 6, 13, 26, 39, and 52 weeks. An electrocardiogram was performed at screening and at the 6-, 26-, and 52-week visits.
Results
Of the 88 participants enrolled, 47 were randomly assigned to the verapamil group and 41 to the placebo group. Intensive diabetes management with an AID system was provided to 22 participants (47%) in the verapamil group and 20 participants (49%) in the placebo group, and standard diabetes care to 25 (53%) and 21 (51%), respectively. Median drug adherence (pill counts) was more than 90% in both groups. In the verapamil group, the mean fasting C-peptide AUC was 0.66 pmol/mL at baseline versus 0.65 pmol/mL at the end of the trial compared with placebo (baseline value 0.60 pmol/mL vs 0.44 pmol/mL at the end) (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01–0.27 pmol/mL]; P = 0.04). The C-peptide levels were 30% higher with verapamil than with placebo.
The mean C-peptide AUC declined in the placebo group after week 13 compared to after 26 weeks for the verapamil group. MMTT C-peptide at 52 weeks showed a mean level of 0.83 pmol/mL in the verapamil group compared with 0.55 pmol/mL for the placebo group. The peak C-peptide level was > 0.2 pmol/mL in 95% of the participants in the verapamil group compared with 71% in the placebo group. Assignment to intensive diabetes management versus standard diabetes management did not influence the primary outcome. The HbA1c value decreased in the verapamil group from 10.3% at baseline to 6.6% at 52 weeks, and in the placebo group from 10.2% at baseline to 6.9% at 52 weeks. TIR (70 mg/dL to 180 mg/dL) at 52 weeks was 74% in the verapamil group compared with 70% in the placebo group.
Overall, 39 participants in the verapamil group (83%) experienced 134 adverse events and 30 participants (73%) in the placebo group experienced 91 adverse events. Three participants in each group experienced other serious adverse events that were not considered as related to the treatment. In the verapamil-treated group, three participants experienced electrocardiogram abnormalities (prolonged PR interval in one participant, second-degree heart block and prolonged PR interval in one participant, and first-degree heart block in one participant), and one participant experienced hypotension.
Conclusions
Once-daily oral verapamil administered to children and adolescents with new-onset T1D was safe and led to improved β-cell function after 1 year of treatment.
Comments
Forlenza and colleagues suggest that in view of the safety profile of verapamil compared with immunomodulatory agents, a simple once-daily oral administration of low-cost verapamil therapy should be considered for patients with newly diagnosed T1D. The 1-year improvement in C-peptide secretion achieved with verapamil is comparable to the improvement shown with efficacious immunomodulatory agents (antithymocyte globulin, teplizumab, abatacept, golimumab, rituximab) studied in newly diagnosed T1D patients.
Although it appears that C-peptide secretion is preserved in those treated with verapamil, the clinical translation to improved diabetes care may be lost with no differences in CGM TIR, HbA1c levels, or insulin dosage between the groups after 1 year. Overall, these findings should be taken with cautious optimism. However, as the authors note, larger longitudinal studies are needed to determine C-peptide preservation duration and possible long-term glycemic benefits after the resolution of the T1D honeymoon period. More research is required to determine the potential mechanisms of action and define which patients might respond best to therapy given the heterogeneity of T1D.
First-in-Human, Double-Blind, Randomized Phase 1b Study of Peptide Immunotherapy IMCY-0098 in New-Onset Type 1 Diabetes
Van Rampelbergh J1, Achenbach P2,3, Leslie RD4, Ali MA5, Dayan C5, Keymeulen B6, Owen KR7,8, Kindermans M9, Parmentier F9, Carlier V1, Ahangarani RR1, Gebruers E1, Bovy N1, Vanderelst L1, Van Mechelen M1, Vandepapelière P1, Boitard C10,11
1Imcyse S.A., Liège, Belgium; 2Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany; 3Forschergruppe Diabetes, Technical University Munich, Klinikum Rechts Der Isar, Munich, Germany; 4Department of Immunobiology, Queen Mary University of London, London, UK; 5Diabetes Research Group, Cardiff University School of Medicine, Cardiff University, Cardiff, UK; 6Member of Belgian Diabetes Registry, Academic Hospital and Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium; 7Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK; 8Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK; 9Ariana Pharmaceuticals SA, Paris, France; 10Inserm U1016, Cochin Institute, Paris, France; 11Medical Faculty, Université de Paris, Paris, France
Both antigen and peptide immunotherapies have been proposed as safer strategies than nonspecific immunomodulatory agents in preserving β-cell function in patients with type 1 diabetes (T1D). Although oral insulin did not prevent progression to T1D in relatives with stage 2 diabetes, early clinical studies of modified insulin-derived peptides demonstrated safety but variable clinical outcomes and immunological mechanisms. An immunodominant proinsulin peptide was shown to be safe and could potentially delay C-peptide decline. Although GAD65 and GAD65-derived peptide trials have not been successful in terms of efficacy, future studies will likely explore peptide modification; optimal dose; and sites, routes, and doses of administration together with perhaps more focused patient selection and precision medicine. Mice studies have shown that IMCY-0098 (Imotope, a synthetic 15 amino acid peptide derived from the C domain of proinsulin with an MHC/HLA class II-restricted T-cell epitope sequence linked to a thiol-disulfide oxidoreductase motif) generates antigen-specific cytolytic CD4+ T cells that have effector memory phenotype, express high levels of granzyme B, and specifically eliminate antigen-presenting cells (APCs) that present this epitope. This study evaluated the safety of use of IMCY-0098 in adults with newly diagnosed T1D.
Methods
This double-blind phase 1b study was conducted in 40 young adults (18–30 years with T1D diagnosed within 6 months). All participants were HLADR3+ and/or DR4+, islet autoantibody positive (glutamic acid decarboxylase [GAD], islet antigen-2 [IA-2], and/or ZnT8), and had fasting C-peptide > 0.2 nmol/L and/or stimulated C-peptide ≥ 0.4 nmol/L. Patients were randomized (3:1) to IMCY-0098 or placebo in 2-week intervals. Those allocated to receive the intervention were administered dose A (50 μg followed by 3 doses of 25 μg), dose B (150 μg followed by 3 doses of 75 mcg), and dose C (450 μg followed by 3 doses of 225 μg). Patients were followed for 24 weeks. The primary end point was to assess safety and change in fasting C-peptide levels. The secondary end points included 2-hour mixed meal tolerance test C-peptide, hemoglobin A1c (HbA1c), glycemic profiles, and changes in insulin dose.
Results
There were no major systemic side effects. Mild adverse effects were noted in all groups (60%, 66%, 77.8%, and 68.8% in those receiving placebo and doses A, B, and C, respectively). There was no significant decline in C-peptide in any of the groups from baseline to end of study.
Conclusions
IMCY-0098 therapy in recent onset T1D was safe at all three doses tested. Because there was no decline in fasting C-peptide levels, these preliminary clinical data support the design of a phase 2 study in patients with recent-onset T1D.
Comments
Although this pilot study demonstrated that IMCY-0098 was safe, there was no significant difference in C-peptide between the intervention and placebo groups. As the authors have commented, the lack of difference between the placebo and treatment arms may have been due to the small sample size and the short duration of follow-up. Given that this was the first in-human study, the dosing also may be suboptimal. These factors need to be considered in next study designs together with potential biomarkers of response.
Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial
Russell WE1, Bundy BN2, Anderson MS3,4, Cooney LA4, Gitelman SE5, Goland RS6, Gottlieb PA7, Greenbaum CJ8, Haller MJ9, Krischer JP2, Libman IM10, Linsley PS8, Long SA8, Lord SM8, Moore DJ11, Moore WV12, Moran AM13, Muir AB14, Raskin P15, Skyler JS16, Wentworth JM17, Wherrett DK18, Wilson DM19, Ziegler AG20,21, Herold KC22, and the Type 1 Diabetes TrialNet Study Group
1Departments of Pediatrics and Cell & Developmental Biology, Vanderbilt University Medical Center, Nashville, TN; 2Health Informatics Institute, University of South Florida, Tampa, FL; 3Department of Medicine, University of California, San Francisco, San Francisco, CA; 4Immune Tolerance Network, Seattle, WA; 5Diabetes Center, University of California, San Francisco, San Francisco, CA; 6Departments of Medicine and Pediatrics, Columbia University, New York, NY; 7Barbara Davis Diabetes Center, University of Colorado, Anschutz, CO; 8Benaroya Research Institute, Seattle, WA; 9Department of Pediatrics, University of Florida, Gainesville, FL; 10University of Pittsburgh, Pittsburgh, PA; 11Departments of Pediatrics and Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN; 12Children's Mercy Hospital, Kansas City, MO; 13Department of Pediatrics, University of Minnesota, Minneapolis, MN; 14Emory University, Atlanta, GA; 15University of Texas Southwestern, Dallas, TX; 16Department of Medicine, University of Miami, Miami, FL; 17Royal Melbourne Hospital and The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; 18Hospital for Sick Children, University of Toronto, Toronto, Ont. Canada; 19Stanford University, Stanford, CA; 20Forschergruppe Diabetes, Technical University Munich at Klinikum rechts der Isar, Munich, Germany; 21Institute for Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany; 22Yale University, New Haven, CT
Data from previous studies have indicated that T cells play a critical role in β-cell destruction. Abatacept (CTLA4Ig) blocks T-cell costimulatory signals that are delivered through the CD80/86 axis and hence, T-cell activation. In an earlier prospective study conducted in the TrialNet network in newly diagnosed (stage 3) patients, abatacept was shown to delay the decline of C-peptide over a 2-year period. Consequently, a randomized, placebo-controlled trial using abatacept was conducted in participants with stage 1 (two or more islet autoantibodies plus euglycemia) type 1 diabetes (T1D) to determine whether drug treatment would prevent progression to stage 2 (islet antibodies plus dysglycemia) or stage 3 diabetes.
Methods
Multiple centers participated in this international TrialNet study (including the United States, Canada, Australia, United Kingdom, Germany, Finland, Sweden, and Italy). Eligible participants (stage 1 T1D between 6 and 45 years old) were all relatives of patients with T1D and were positive for two or more T1D autoantibodies (excluding insulin autoantibodies [IAA] because of overlapping eligibility with another ongoing prevention trial at that time using oral insulin) measured in two consecutive samples 6 months before trial start. All participants were randomized in a 1:1 ratio to abatacept or placebo. The treatment included 14 intravenous infusions of abatacept or placebo at 0, 2, and 4 weeks and, after this initial period, monthly for 12 months. The dose of abatacept was 10 mg/kg to a maximum of 1000 mg per dose. The primary end point was time from randomization to either a consecutively confirmed abnormal glucose tolerance (AGT) test result or to stage 3 T1D. Oral glucose tolerance tests (OGTT) were performed every 6 months together with immunological studies. A random glucose measurement was performed at 3 months and an OGTT undertaken with suspicion of progression to stage 3. Data on adverse events were collected.
Results
Of the 212 T1D patients who were randomized, 101 were assigned to the active treatment arm and 111 to the placebo group. There were two groups: ages < 18 years (n = 134) and > 18 years (n = 78). In the pediatric group 47% received abatacept, while 49% of the adults received it. The follow-up period for stage 2 T1D (consecutive abnormal OGTTs) was on an average, 36.9 months, and 47.6 months for the development of stage 3 T1D. The study end point was met by 81 participants (38%): 74 developed AGT, and stage 3 T1D was diagnosed in seven. The median time to the development of AGT was 89.2 and 71.6 months for the abatacept and placebo groups, respectively. Of the 74 who met the primary end point of AGT, stage 3 T1D was diagnosed in 33. The difference in time to T1D diagnosis was not statistically significantly different between the treatment groups, although there was slight improvement in β-cell function at 12 months (P = 0.03). Adverse events were similar between the two groups, except for skin and connective tissue disorders, which were more frequently observed with abatacept. Interestingly, the levels of ICOS1 Tfh (inducible T-cell costimulatory T follicular helper cell) were lower in adults compared to children at study entry. Abatacept treatment led to a decline in the frequency of activated ICOS1 Tfh cells and T-regulatory cells at months 3, 6, and 12. However, 12 months after cessation of treatment, both cell types returned to pretreatment levels in all age groups. No effect on the development of new insulin autoantibodies (IAA), glutamic acid decarboxylase autoantibodies (GADA), or islet cell antibodies (ICA) was observed. Adverse events were similar between the two groups, except for skin and connective tissue disorders, which were more frequently observed with abatacept.
Conclusions
In this randomized, placebo-controlled trial in a group of participants with stage 1 T1D, abatacept treatment did not result in a statistically significant delay in the progression to stage 2 or 3 T1D. However, abatacept altered immune cell subsets and led to decreased C-peptide decline.
Comments
Abatacept monotherapy for 1 year did not significantly delay the progression of diabetes from stage 1 to stage 2 or 3 in at-risk relatives. Although there was an effect on immune cell subsets and some preservation of insulin secretion, there was no effect on diabetes development from stage 1 to stage 2 or 3. It is also unsure whether the decrease in T-regulatory cells that was observed with abatacept reduced its beneficial effects. Additionally, there may be other costimulatory pathways that do not involve CD80/CD86 in the early stage of the disease and thus, are not affected by abatacept. It is also likely that the timing of administration of the active treatment may have been less than optimal (autoimmune priming may have already occurred earlier); this may also have been compounded by later follow-ups because the study was conducted during the COVID-19 pandemic. Co-stimulation blockade by abatacept might still be useful in a combinatorial therapeutic approach.
Nasal Administration of Anti-CD3 Monoclonal Antibody Modulates Effector CD8+ T Cell Function and Induces a Regulatory Response in T Cells in Human Subjects
Chitnis T1,2, Kaskow BJ1,2, Case J1,2, Hanus K1,2, Li Z1,2, Varghese JF1,2, Healy BC1,2, Gauthier C1,2, Saraceno TJ2, Saxena S1,2, Lokhande H2, Moreira TG1,2, Zurawski J2, Roditi RE3,4, Bergmark RW3,4, Giovannoni F1,2, Torti MF1,2, Li Z1,2, Quintana F1,2, Clementi WA5, Shailubhai K6, Weiner HL1,2, Baecher-Allan CM1,2
1Harvard Medical School, Boston, MA; 2Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA; 3Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School, Boston, MA; 4Department of Surgery, Brigham and Women's Hospital, Boston, MA; 5Clementi Ltd., Rosemont, PA; 6Tiziana Life Science, Doylestown, PA
Parenteral administration of a humanized anti-CD3 Mab (teplizumab) has shown positive effects in type 1 diabetes (T1D). Multiple studies in the past have shown that immune interactions at mucosal surfaces can induce tolerogenic induction of regulatory T cells. Mucosal administration of anti-CD3 mAb has been used to treat autoimmune and inflammatory diseases by inducing regulatory interleukin 10 (IL-10)–producing T cells. Foralumab is a human IgG1 anti-CD3 mAb with the Fc portion mutated, which minimizes cytokine release when given intravenously. This study investigated the safety of nasally administered foralumab in healthy human volunteers.
Methods
Twenty-seven healthy volunteers (18–65 years, 9 per group; 6 treatment and 3 placebo) received nasal foralumab or placebo at a dose of 10 μg, 50 μg, or 250 μg administered via a particle dispersion device daily for 5 days. One spray of the study drug or placebo was given in each nostril. Safety was closely monitored, and samples were obtained on day 1 (pretreatment), 7, 14, and 30 days after treatment, and were subjected to fluorescence-activated cell sorting (FACS) and scRNAseq for immune studies. Peripheral blood mononuclear cells (PMBCs) from healthy donors were used for in vitro studies in which foralumab was compared with UCHT1 anti-human CD3 mAb.
Results
Although nasal foralumab at all doses did not modulate CD3 on T-cell surfaces, the 50 μg dose showed more immune effects compared with the other doses (reduced CD8+ effector memory cells, increase in naive CD8+ and CD4+ T cells, and reduced CD8+ T-cell granzyme B and perforin expression). In vitro, foralumab induced CD8+ T-cell stimulation, reduced CD4+ T-cell proliferation, and lowered expression of interferon-γ (IFNγ), IL-17, and tumor necrosis factor-α (TNF-α). Foralumab induced immune checkpoint molecules (LAP, TIGIT, and KLRG1) on CD8+ and CD4+ T cells in a mechanism independent of CD8 T cells. Differentially expressed genes observed by scRNAseq in CD8+ and CD4+ populations promoted survival and were anti-inflammatory. In the CD8+ population, there was induction of TIGIT, TGFB1, and KIR3DL2, indicative of a regulatory phenotype. In the memory CD4+ population, there was induction of CTLA4, KLRG1, and TGFB, whereas there was an induction of TGF-B1 in naïve CD4+ T cells. In monocytes, there was induction of genes (HLA-DP, HLA-DQ) that promote a less inflammatory immune response. No side effects were observed at any dose. The otolaryngology examinations were normal, there was no Epstein-Barr virus reactivation, and no participants developed human anti-mouse antibodies.
Conclusions
The study findings demonstrated that nasal foralumab is safe, immunologically active in humans, and presents a new avenue for the treatment of autoimmune and central nervous system disease.
Comments
Nasal anti-CD3 acts locally at the mucosal surface as an immunomodulatory agent. This study showed that nasal application of foralumab at doses of 10–250 μg given for 5 consecutive days to healthy individuals was safe; interestingly, most of the immune effects (in this small-dose escalating study) were seen at the 50 μg dose. The finding that the immune effect with 50 μg was more immunomodulatory than at 250 μg is similar to animal studies of mucosal tolerance.
The biological effect of nasal anti-CD3 is clearly different from intravenously delivered anti-CD3 Ab. Intravenous application of anti-CD3 is associated with modulation of CD3 from the cell surface, a decrease in CD3 cells, more frequent side effects, cytokine release syndrome, and reactivation of Epstein-Barr virus (EBV). No EBV reactivation was observed with any of the doses of foralumab given intranasally. Thus, foralumab holds potential for human T1D studies as well as other chronic inflammatory and autoimmune diseases.
Predictors of the Initiation of Islet Autoimmunity and Progression to Multiple Autoantibodies and Clinical Diabetes: The TEDDY Study
Krischer JP1, Liu X1, Lernmark Å2, Hagopian WA3, Rewers MJ4, She JX5, Toppari J6,7, Ziegler AG8, Akolkar B9 on behalf of the TEDDY Study Group
1Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL; 2Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmo, Sweden; 3Pacific Northwest Diabetes Research Institute, Seattle, WA; 4Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO; 5Jinfiniti Precision Medicine, Inc., Augusta, GA; 6Department of Pediatrics, Turku University Hospital, Turku, Finland; 7Research Centre for Integrated Physiology and Pharmacology and Centre for Population Health Research, Institute of Biomedicine, University of Turku, Turku, Finland; 8Institute of Diabetes Research, Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V., Neuherberg, Germany; 9National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
The search for potential triggers of autoimmunity leading to the development of type 1 diabetes (T1D) remains elusive. No common agents have been identified. In patients in which islet-specific autoimmunity develops, progression to clinical disease depends on multiple factors, including the age of seroconversion, the number and titer of antibodies, and which autoantibodies appear first. Although class HLA II genes define susceptibility to T1D and may be involved in initiation of the disease, they appear to have less of a role in progression to clinical T1D once autoantibodies are present. This study identifies the factors before the development of the first-appearing autoantibody and then its progression to multiple autoantibody status and to clinical disease.
Methods
The study participants were part of the prospective TEDDY (Environmental Determinants of Diabetes in the Young) cohort group. High-risk newborns (N = 8502) were followed for a median of 11.2 years (IQR, 9.3–12.6 years). Children were followed quarterly for a first-appearing islet autoantibody and progression to clinical diabetes. Follow-up of children with one or more islet autoantibodies was performed quarterly while those who were autoantibody negatives were followed twice a year after 4 years of age. Predictors were examined using Cox proportional hazard models.
Results
Among the participants, 9.8% (n = 835) developed islet autoantibodies. Of these, 701 had a single autoantibody (308 with insulin autoantibodies [IAA], 370 with glutamic acid decarboxylase autoantibodies [GADA], and 23 with islet antigen-2 [IA-2]), and 134 had multiple autoantibodies at first detection. Of those who first had a single autoantibody, 49% (n = 364) developed multiple autoantibodies, and 54.6 (N = 189) of those progressed to clinical T1D. Male sex, Finnish residence, having a sibling with T1D, the HLA DR4 allele, probiotic use before the age 28 days, and single-nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA first. Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted the development of GADA first. Having a father with T1D and the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA first. Family history of T1D and the HLA DR4 allele predicted progression to multiple autoantibodies, but not to diabetes. Males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs appear to be significantly associated with progression from multiple autoantibodies to T1D.
Conclusions
The predictors for the initial occurrence of autoantibodies (IAA first vs GADA first) and for the progression to clinical T1D differ.
Comments
Because the risk factors related to the initiation of islet autoantibodies and progression to T1D differ, it is likely that T1D is not a single disease entity but rather a heterogeneous disease with clinical disease as the end point. Should specific endotypes be defined, the path for more precise approaches to interdicting the disease can be opened. Early clinical trials including enterovirus vaccine to GADA-positive individuals have recently commenced.
Gene Expression Signature Predicts Rate of Type 1 Diabetes Progression
Suomi T1,2, Starskaia I1,2,3, Kalim UU1,2, Rasool O1,2, Jaakkola MK1,2, Grönroos T1,2, Välikangas T1,2, Brorsson C4, Mazzoni G4, Bruggraber S5, Overbergh L6, Dunger D5*, Peakman M7, Chmura P4, Brunak S4, Schulte AM8, Mathieu C6, Knip M9,10,11, Lahesmaa R1,2,12, Elo LL1,2,12 on behalf of the INNODIA Consortium
1Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520, Turku, Finland; 2InFLAMES Research Flagship Center, University of Turku, Turku, Finland; 3Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland; 4Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Department of Paediatrics, University of Cambridge, Cambridge, England, UK; 6Katholieke Universiteit Leuven/Universitaire Ziekenhuizen, Leuven, Belgium; 7Immunology & Inflammation Research Therapeutic Area, Sanofi, MA; 8Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany; 9Paediatric Research Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 10Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 11Tampere Centre for Child Health Research, Tampere University Hospital, Tampere, Finland; 12Institute of Biomedicine, University of Turku, FI-20520, Turku, Finland
Type 1 diabetes mellitus (T1D) might be considered heterogeneous from disease initiation through progression to clinical disease, and then after onset with a decline in β-cell number and function. In some patients, a significant proportion of β-cells still remain at diagnosis. Interventions have been undertaken to preserve these remaining β-cells with some degree of success. Given the disease heterogeneity, accurate stratification of patients into potential responder groups is key to the development of individualized therapies. Since earlier studies have identified gene expression signatures that predict progression to disease in at-risk patients and in newly diagnosed patients, this study identified gene-expression changes occurring in the first 2 years after clinical diagnosis and correlated them with disease progression.
Methods
After whole-blood samples collected for the INNODIA study were analyzed, a final cohort was selected consisting of 94 individuals who were < 6 weeks after diagnosis (at least one T1D autoantibody positive, aged 13.2 ± 8.5 years) at baseline and 49 who were 12 months after diagnosis. Hemoglobin A1c (HbA1c), C-peptide, and glucose were measured, and a C-peptide/glucose ratio was used as a marker of disease progression. RNA was extracted from the whole-blood samples for RNA sequencing. Cell-type proportions were estimated from the RNA-seq data using computational deconvolution. The participants were classified as rapid, intermediate, or slow progressors based on the change in their C-peptide/glucose ratio between baseline and 2-year follow-up visits. The group with the largest decrease in their ratios was categorized as slow progressors. The gene expression ratios between baseline and 1-year follow-up visits were calculated, and the differences between the rapid and slow groups were tested.
Results
Statistical testing between the rapid and slow groups revealed 16 signature genes that predicted the decline in C-peptide over 2 years. The genes and pathways related to innate immunity were down-regulated during the first year after diagnosis. Increased B-cell levels and decreased neutrophil levels were associated with rapid progression. Among the 16 genes predicting disease progression, LOC644936, NCF1, PRRG4, and C4BPA were primarily expressed by neutrophils.
Conclusions
Genetic signatures in T1D can help to predict the disease's progression, which in turn could lead to the development of individualized treatment strategies.
Comments
The results of this study highlight that the heterogeneity in T1D may be related to underlying genetic heterogeneity. Although these genetic signatures could help to predict disease progression and individualize treatment, it is difficult to say whether this can be translated clinically, given that multiple genes are involved in the disease process of T1D.
Footnotes
Author Disclosure Statement
No competing financial interests exist.