Abstract
Introduction
Dietary Interventions
Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β-cell function in new-onset type 1 diabetes mellitus
Gabbay MA1, Sato MN2, Finazzo C2, Duarte AJ2, Dib SA1
1Diabetes Center of Endocrinology Division, Department of Medicine, São Paulo Federal University, Sãu Paulo, Brazil; and 2LIM56-Immunology Laboratory, University of São Paulo, São Paulo, Brazil
Archives of Pediatric and Adolescent Medicine 2012;
Background
Vitamin D deficiency has been associated with T1D, and epidemiologic studies suggest that vitamin D supplementation may decrease risk of developing T1D. Two previous studies evaluated whether 1,25(OH)2D3 (calcitriol) improves β-cell function in subjects with recent-onset T1D. The current study used cholecalciferol.
Methods
The study randomized 38 subjects, age 7 to 30, enrolled within 6 months of diagnosis of T1D, and with preserved C-peptide (at least 0.2 nmol/l). Intervention consisted of cholecalciferol, 2,000 IU, or placebo, daily for 18 months.
Results
Outcome measures were assessed at 0, 6, 12, and 18 months. HbA1c, insulin use, and body mass index were similar in both groups (except for a baseline difference in HbA1c). Mean fasting and stimulated C-peptide values did not differ between groups. However, percent change from baseline of stimulated C-peptide at 12 and 18 months was asserted to be better in the cholecalciferol group. In addition, by Kaplan-Meier life table analysis, the cumulative incidence of progression to undetectable fasting or stimulated C-peptide was less in the cholecalciferol group. The authors also claimed that there was an increase in regulatory T-cells at 12 months in the cholecalciferol group.
Conclusion
The authors concluded, “Cholecalciferol used as adjunctive therapy with insulin is safe and associated with a protective immunologic effect and slow decline of residual β-cell function in patients with new-onset T1DM. Cholecalciferol may be an interesting adjuvant in T1DM prevention trials.”
Comment
The potential role of vitamin D as a preventative intervention for T1D has been suggested for some time. For the past two years, we have reported on studies using 1,25(OH)2D3 (calcitriol) in two separate studies. Unfortunately, both of those failed to show a beneficial effect. The current study has mixed results and is not readily interpreted as it does not state what was the planned primary outcome. Whereas the mean fasting and stimulated C-peptide were not different between groups at any time-point, the authors state that the percent change in stimulated C-peptide is better in the cholecalciferol group and that by life table there is slowed loss of measurable C-peptide. Looking at the figures that represent these assertions, one is not completely convinced. Nonetheless, the authors are appropriately conservative in their conclusions, which champion usingcholecalciferol as adjunctive therapy in prevention trials. Indeed, the vitamin D story deserves a robust clinical trial for prevention of T1D. It is time to stop fiddling with small groups in recent-onset trials and pose the question. As noted last year, however, given the tendency toward nearly routine supplementation with vitamin D, it is uncertain whether a controlled study of its use in prevention can actually be conducted.
Removal of bovine insulin from cow's milk formula and early initiation of beta-cell autoimmunity in the FINDIA pilot study
Vaarala O1, Ilonen J2,3, Ruohtula T1, Pesola J4,5, Virtanen SM6,7,8, Härkönen T9, Koski M9, Kallioinen H10, Tossavainen O10, Poussa T11, Järvenpää AL12, Komulainen J5, Lounamaa R9,13, Akerblom HK9, Knip M9,14,15
1Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland; 2Immunogenetics Laboratory, University of Turku, Turku, Finland; 3Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland; 4Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 5Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland; 6Nutrition Unit, Department of Lifestyle and Participation, National Institute for Health and Welfare, Children's Hospital, University of Helsinki, Helsinki, Finland; 7Tampere School of Public Health, University of Tampere, Tampere, Finland; 8Research Unit, Tempere University Hospital, Tempere, Finland; 9National Institute for Health and Welfare, Children's Hospital, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland; 10Valio Ltd, Helsinki, Finland; 11StatConsulting Tuija Poussa, Nokia, Finland; 12Kätilöopisto Maternity Hospital, Helsinki, Finland; 13Central Finland Central Hospital, Jyväskylä, Finland; 14Folkhälsan Research Center, Helsinki, Finland; and 15Department of Pediatrics Tampere University Hospital, Tampere, Finland
Archives of Pediatric and Adolescent Medicine 2012;
Background
Epidemiologic evidence suggests that early exposure to complex dietary proteins, such as cow's milk or wheat, may serve to increase risk for β-cell autoimmunity and T1D. It has been shown that exposure to bovine insulin in cow's-milk formula (CMF) has the capacity to induce an immune response to insulin. In this pilot study, the Finnish Dietary Intervention Trial for the Prevention of Type 1 Diabetes (FINDIA), the investigators sought to establish whether a formula free of bovine insulin might reduce diabetes autoimmunity.
Methods
Eligible infants had HLA-conferred susceptibility to T1D identified on screening. A total of 5,003 infants were screened; 1,113 were found eligible; 1,104 were randomized; and 908 provided at least one follow-up sample. Randomization was to three groups: CMF (control), whey-based hydrolyzed formula (WHF), or whey-based FINDIA formula essentially free of bovine insulin, whenever breast milk was not available during the first 6 months of life. Children were followed until age three for the development of diabetes-related autoantibodies.
Results
The group assigned to the FINDIA formula had a reduced risk of development of β-cell autoimmunity (appearance of 1 or more antibodies; odds ratio in the intention-to-treat analysis 0.39 [0.17–0.91] and in the treatment-received analysis 0.23 [0.08–0.69] in the FINDIA group when compared with the CMF group).
Conclusion
Weaning to an insulin-free formula reduced the cumulative incidence of autoantibodies by age three in children at genetic risk of T1D.
Comment
Last year we discussed the report of the Finnish TRIGR Study Group, which found that the appearance of diabetes autoantibodies was reduced in half by weaning to a casein hydrolysate formula rather than a standard CMF. The full trial to reduce insulin-dependent diabetes mellitus in the genetically at risk (TRIGR) is fully enrolled and expected to report on its primary outcome—appearance of T1D—in 2017. The FINDIA study takes the question one step deeper and specifically removes bovine insulin from infant formula. The results reported herein suggest that this indeed may be helpful. One must assume that the FINDIA group will now mount a full-scale prevention trial. The issue is whether the control group should receive casein hydrolysate formula or CMF. As mentioned last year, it would seem prudent to encourage breastfeeding for as long as reasonable. And it is hoped that further studies will attempt to clarify what dietary components are best altered in attempts at primary prevention of T1D.
Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study
Hummel S1,2, Pflüger M3, Hummel M3, Bonifacio E4, Ziegler AG1,2,3
1Institute for Diabetes Research, Helmholtz Center Munich, Munich, Germany; 2Forschergruppe Diabetes der Technischen Universität Muenchen, Munich, Germany; 3Insjtitut für Diabetesforschung der Forschegruppe Diabetes e.V. am Helmholtz Zentrum München, Munich, Germany; and 4Detsche Forshungsgemeinschaft Center for Regenerative Therapies Dresden, Technisch Universität Dresden, Dresden, Germany
Diabetes Care 2011;
Human enterovirus infections in children at increased risk for type 1 diabetes: the BABYDIET study
Simonen-Tikka ML1, Pflueger M2, Klemola P1, Savolainen-Kopra C1, Smura T1, Hummel S2, Kaijalainen S1, Nuutila K1, Natri O1, Roivainen M1, Ziegler AG2
1Intestinal Viruses Unit, National Institute for Health and Welfare, Helsinki, Finland; and 2Institute for Diabetes Research, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
Diabetologia 2011;
Background
Data from mouse models suggest that deprivation of gluten or delayed exposure to gluten reduces the risk of autoimmunity and T1D. Prospective observational studies in human beings support such claims. The BABYDIET study was designed to test—in a randomized controlled trial—whether delayed exposure to gluten reduces the risk of diabetes autoimmunity.
Methods
In this study, 150 infants with a first-degree relative with T1D and an HLA genotype consistent with T1D risk were randomized either to first gluten exposure at age 6 months (control group) or 12 months (late-exposure group) and were followed every 3 months until age 3 years and yearly thereafter. They were evaluated for safety and appearance of diabetes autoantibodies. In the second paper, 104 of the infants provided stool samples that were analyzed for human enteroviruses (HEV).
Results
In total, 70% of subjects followed the protocol, 30% did not. In terms of safety, during the first three years, weight and height were similar in children in the control and late exposure groups, as was the probability of developing transglutaminase C antibodies (TGCAs). Eleven children in the control group and 13 children in the late-exposure group developed diabetes autoantibodies (3-year risk: 12% vs. 13%; p=0.6). Seven children developed diabetes, including four in the late-exposure group. No significant differences were observed when children were analyzed as per protocol on the basis of the reported first gluten exposure of the children. Moreover (in the second paper), no correlation was found between the presence of HEV in the first year of life and the development of diabetes autoantibodies. There was no association between HEV infections and dietary intervention.
Conclusion
These articles demonstrate that delaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity in genetically at-risk children. Moreover, there was no evidence that HEV infections were involved.
Comment
There have been several proposals of environmental factors that might precipitate diabetes autoimmunity. As noted in discussing an earlier article above, the contents of formula used for weaning has been implicated, with suggestions that avoidance of cow's milk and/or avoidance of bovine insulin (in cow's milk) may reduce the likelihood of diabetes autoimmunity. The BABYDIETarticles demonstrate that delay of exposure to gluten does not alter diabetes autoimmunity. This is in contrast to implications from observational studies, yet again emphasizing the importance of randomized controlled clinical trials in answering important questions.
Novel Interventions
Administration of CD4+CD25highCD127- regulatory T cells preserves β-cell function in type 1 diabetes in children
Marek-Trzonkowska N1, Mysliwiec M2, Dobyszuk A1, Grabowska M1, Techmanska I2, Juscinska J3, Wujtewicz MA4, Witkowski P5, Mlynarski W6, Balcerska A2, Mysliwska J7, Trzonkowski P1,8
1Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Gdansk, Poland; 2Department of Pediatrics, Hematology, Oncology, and Endocrinology, Medical University of Gdansk, Gdansk, Poland; 3Blood Bank of the Pomerania Region, Gdansk Unit, Gdansk, Poland; 4Department of Anesthesiology and Critical Care, Medical University of Gdansk, Gdansk, Poland; 5Department of Surgery, Section of Transplantation, University of Chicago, Chicago, Illinois; 6Department of Pediatrics, Oncology, Hematology, and Diabetology, Medical University of Lodz, Lodz, Poland; 7Department of Immunology, Medical University of Gdansk, Gdansk, Poland; and 8Tricity Academic Experimental Facility, Medical University of Gdansk, Gdansk, Poland
Diabetes Care 2012;
Background
In T1D, it has been shown that there is either a deficiency and/or impairment of function (suppressive activity) of regulatory T-cells (Tregs). Thus, it is reasonable to propose interventions designed to enhance either Treg number or improve Treg function. One such approach would be expansion of Tregs ex vivo and subsequent reinfusion into a research subject.
Methods
The study enrolled 10 children (ages 8–16) with recent-onset T1D within two months of diagnosis. Peripheral blood was collected, cells sorted to isolate CD3+CD4+CD25highCD127- cells, a phenotype consistent with Tregs. These were expanded ex vivo under good manufacturing process (GMP) conditions. The expanded cells were reinfused into the subjects. Subjects were compared to a nonrandomized, nontreated comparison group.
Results
There was an increase in the percentage of circulating FoxP3+ Tregs. This was accompanied by a decrease in HbA1c, insulin dose, and glucose level. C-peptide levels were sustained to a greater degree in the subjects treated with Tregs. There were no significant adverse events.
Conclusion
The authors concluded that the study demonstrated that the administration of Tregs is safe and tolerable in children with recent-onset T1D. There also were apparent benefits.
Comment
This represents the first report of autologous Treg therapy in T1D. Remarkably, these were polyclonal Tregs, not antigen-specific Tregs. Nonetheless, there was a hint of therapeutic efficacy, without adverse events. In 2004, it was shown that administration of expanded antigen-specific Tregs suppresses autoimmune diabetes in mice. The current study used polyclonal, rather than antigen-specific, Tregs and still showed potential efficacy. Thus, this study serves as a clarion call for further investigation of both polyclonal and antigen-specific Tregs, coupled with careful mechanistic studies designed to help elucidate exactly which therapeutic approach might induce immune tolerance and stabilize T1D.
Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function
Long SA1, Rieck M1, Sanda S2, Bollyky JB2, Samuels PL1, Goland R3, Ahmann A4, Rabinovitch A5, Aggarwal S6, Phippard D5, Turka LA6,7, Ehlers MR8, Bianchine PJ9, Boyle KD10, Adah SA9, Bluestone JA11, Buckner JH1, Greenbaum CJ2; for Diabetes TrialNet and the Immune Tolerance Network
1Translational Immunology Program, Benaroya Research Institute, Seattle, WA; 2Diabetes Program, Benaroya Research Institute, Seattle, WA; 3Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY; 4Harold Schnitzer Diabetes Health Center, Oregon Health and Science University, Portland, OR; 5Hanford Research, University of South Dakota, Sioux Falls, SD; 6Tolerance Assays and Data Analysis Group, Immune Tolerance Network, Bethesda, MD; 7Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; 8Clinical Trials Group, Immune Tolerance Network, San Francisco, CA; 9Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, MD; 10Rho Federal Systems Division, Inc., Chapel Hill, NC; and 11Diabetes Center and Department of Medicine, University of California San Francisco, San Francisco, CA
Diabetes 2012;
Background
IL-2 stimulates Tregs. The combination of IL-2 plus rapamycin was effective in the treatment of autoimmune diabetes in NOD mice. Therefore, a phase 1 safety study was performed in subjects with type 1 diabetes that also evaluated the immunological effects of this combination.
Methods
Subjects with T1D for 4 to 48 months and preserved C-peptide were enrolled. Nine subjects participated. IL-2 was given for one month and rapamycin was given for three months. β-cell function was measured and a variety of immunologic outcomes were assessed.
Results
In terms of β-cell function, there was a 43% decrease in C-peptide at three months, accompanied by an increased insulin requirement but stable HbA1c levels. Interestingly, by six months, there was some recovery of β-cell function. There was an expansion in Tregs at one month that was not sustained. Moreover, the in vitro Treg response to IL-2 (usually diminished in T1D and was so at baseline) was enhanced at one month, and remained so after one year. There was no impact of the therapy on activation of effector T cells. However, there was an increase in eosinophilia and in NK cells.
Conclusion
IL-2 seems both to expand Tregs and enhance Treg function, the latter sustained over time. Combination therapy with rapamycin may have adverse effects, at least transiently, on β-cell function. Further studies are required to determine whether such transient adverse effects on β-cell function would be seen with IL-2 alone.
Comment
This is a rather intriguing set of findings that highlight both the difficulty of translating findings in animal models into clinical trials, as well as the difficulty of sorting out effects of individual components when combination therapy is used. Based on the beneficial effects of IL-2 on enhancing Treg number and function in both animal models and other diseases in human beings, one suspects—but one cannot prove—that the unfortunate transient worsening of β-cell function likely could be attributed to the combination of IL-2 and rapamycin. Another issue highlighted in this trial was the meticulous exploration of immunological effects of the intervention, allowing the authors not to dismiss the potential utility of IL-2 because of the initial worsening of β-cell function. Thus, even this very small, nonrandomized trial offered important insights.
Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes
Faustman DL1, Wang L1, Okubo Y1, Burger D1, Ban L1, Man G1, Zheng H2, Schoenfeld D2, Pompei R3, Avruch J3, Nathan DM3
1The Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA; 2Department of Biostatistics, Massachusetts General Hospital, Boston, MA; and 3Diabetes Unit, Massachusetts General Hospital, Boston, MA
PLoS One 2012;
Background
Bacillus Calmette-Guerin (BCG) vaccine has been shown to reverse diabetes in rodents. The authors assert that the BCG effect is through the stimulation of tumor necrosis factor (TNF), working through abrogation of autoimmune cells and improvement of β-cell function.
Methods
Six subjects with long-standing T1D were randomized to receive either two doses of BCG or placebo. They were compared to a cohort of subjects with T1D and with healthy controls, in terms of a number of immunologic parameters, autoantibodies, and β-cell function using an ultrasensitive C-peptide assay.
Results
The authors claim that the BCG subjects, and one of the control subjects who developed acute Epstein-Barr virus (EBV) infection, showed increases in dead insulin-autoreactive T cells and induction of Tregs. They also claim that there was transient increase in C-peptide levels not seen in the nonrandomized cohort of subjects with T1D.
Conclusion
The authors conclude “that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes.”
Comment
This paper is extremely hard to interpret. There were only six subjects randomized, and one of the three subjects in the placebo group developed EBV infection, which the authors assert resulted in similar effects to those claimed in the BCG-treated group. Moreover, there was no statistical comparison between the two randomized groups, but rather serial observations were compared to subjects in a separate cohort. Further, there were not uniform changes seen in the three treated subjects. In addition, although the protocol indicated that TNF levels would be measured, these are not reported in spite of the authors' contention that their observations were mediated by increases in TNF. The authors fail to cite a trial with etanercept, an anti-TNF drug, that showed potential beneficial effect on β-cell function (1). Importantly, although they report an increase in C-peptide levels using an ultrasensitive assay, there are no data that the trivial increases in C-peptide have any biological importance. If the authors are serious about wanting to evaluate BCG as an intervention, it is incumbent upon them to do an adequately powered randomized controlled clinical trial.
Update on Interventions in 2011
Improved preservation of residual beta cell function by atorvastatin in patients with recent onset type 1 diabetes and high CRP levels (DIATOR trial)
Strom A1, Kolb H2, Martin S3, Herder C1, Simon MC1, Koenig W4, Heise T5, Heinemann L5, Roden M1,6, Schloot NC1,6; DIATOR Study Group
1Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; 2Immunobiology Research Group, University Hospital, University of Düsseldorf, Düsseldorf, Germany; 3West-German Centre of Diabetes and Health, Verbund Katholischer Kliniken Düsseldorf, Düsseldorf, Germany; 4Department of Internal Medicine II - Cardiology, University of Ulm Medical Center, Ulm, Germany; 5Profil Institute for Metabolic Research, Neuss, Germany; and 6Department of Metabolic Diseases, University Hospital, Düsseldorf, Germany
PLoS One 2012;
Background
A recent randomized, placebo-controlled trial (discussed in last year's review), of the effect of atorvastatin treatment on the progression of newly diagnosed T1D, suggested that C-peptide declined over time more slowly in the atorvastatin group than in the placebo group when the groups were considered independently. The aim of this secondary analysis was to identify patient subgroups that might differ in the decline of β-cell function during treatment with atorvastatin.
Methods
The diabetes and atorvastatin (DIATOR) trial included 89 subjects with recent onset T1D, who received placebo or atorvastatin for 18 months. For the secondary analysis, patients were stratified by single baseline characteristics that were considered to possibly be modified by atorvastatin treatment.
Results
The subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment. That group also had higher median values of BMI, IL-6, IL-1RA, sICAM-1, and E-selectin.
Conclusion
Atorvastatin treatment may be effective in slowing the decline of β-cell function in a patient subgroup defined by higher levels of CRP and other inflammation-associated immune mediators.
Comment
The DIATOR study did not meet its primary outcome, but the decline in C-peptide within the atorvastatin group was different than that in the placebo group. This further analysis suggests that individuals with markers of inflammation may be the ones that benefit. This is consistent with suggestions that an anti-inflammatory agent might be useful as a component of combination therapy of T1D. As I indicated last year, this contributor would be enthusiastic to see a full-scale trial of atorvastatin in T1D, perhaps in a factorial design with an immunomodulatory agent.
GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus
Ludvigsson J1, Krisky D2, Casas R1, Battelino T3, Castaño L4, Greening J5, Kordonouri O6, Otonkoski T7, Pozzilli P8, Robert JJ9, Veeze HJ10, Palmer J11
1Linköping University, Linköping, Sweden; 2Diamyd Medical, Pittsburgh, PA; 3University Medical Center–University Children's Hospital, Faculty of Medicine, Ljubljana, Slovenia; 4Hospital de Cruces–University of Basque Country, Barakaldo, Bizkaia, Spain; 5Department of Paediatrics, Leicester Royal Infirmary, Leicester, United Kingdom; 6Diabetes Center for Children and Adolescents, Kinderkrankenhaus auf der Bult, Hannover, Germany; 7Children's Hospital, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland; 8University Campus Bio-Medico, Rome, Italy; 9Hôpital Necker–Enfants Malades, Université René Descartes Paris 5, Paris, France; 10Stichting Diabeter, Rotterdam, The Netherlands; and 11Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA
New Engl J Med 2012;
Background
Glutamic acid decarboxylase (GAD) is an important antigen in T1D. There have been mixed results with use of an aluminum hydroxide-formulated GAD (GAD-alum) vaccine in preserving β-cell function. A pilot study had modest effect (2). A Phase 2 study discussed last year had no effect (3). This report is a Phase 3 study designed to determine whether GAD vaccine preserves β-cell function in recent-onset T1D.
Methods
The study randomized 334 subjects age 10–20 years, within three months of diagnosis of T1D, to one of three treatment groups (4 doses of vaccine; 2 doses of vaccine and 2 doses of placebo; or 4 doses of placebo). The primary endpoint was β-cell function—as measured by change in stimulated C-peptide—at 15 months.
Results
The stimulated C-peptide level declined to a similar degree in all three groups, with no evidence of a treatment effect. HbA1c levels, insulin use, and adverse events did not differ between groups.
Conclusion
Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period in patients with recently diagnosed T1D.
Comment
As discussed in last year's review, GAD-alum does not seem to have an effect in recent-onset T1D. As was noted then, the animal studies with GAD were all performed as prevention of T1D. A small pilot GAD prevention study, DIAPREV-IT, is currently underway in Sweden (NCT01122446). If that study suggests potential benefit of GAD, it would be desirable to perform a full-scale GAD prevention study.
Metabolic Changes over Time
The metabolic progression to type 1 diabetes as indicated by serial oral glucose tolerance testing in the Diabetes Prevention Trial–Type 1
Sosenko JM1, Skyler JS1, Herold KC2, Palmer JP3; Type 1 Diabetes TrialNet; and Diabetes Prevention Trial–Type 1 Study Groups
1Division of Endocrinology, University of Miami Miller School of Medicine, Miami, FL; 2Department of Immunobiology, Yale University School of Medicine, New Haven, CT; and 3VA Puget Sound Health Care System, Division of Endocrinology, Metabolism and Nutrition, University of Washington, Seattle, WA
Diabetes 2012;
Summary
This paper reviews the metabolic progression to T1D in subjects at risk of the disease followed in the Diabetes Prevention Trial-Type 1 (DPT-1). Subjects had serial oral glucose tolerance tests (OGTTs) while being followed in two intervention trials. The data indicates that the metabolic progression to T1D commonly begins at least two years before diagnosis. It is characterized by increasing glucose levels with little change in overall C-peptide levels (as indicated by the AUC C-peptide and the peak C-peptide) until six months before diagnosis. Within six months of diagnosis, the levels of the overall C-peptide measures fall more markedly, and the decline accelerates even more after diagnosis. Data suggest that the more rapid decline could be related to decreased β-cell sensitivity to glucose.
Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite type 1 diabetes TrialNet data
Greenbaum CJ1, Beam CA2, Boulware D2, Gitelman SE3, Gottlieb PA4, Herold KC5, Lachin JM6, McGee P6, Palmer JP7, Pescovitz MD8, Krause-Steinrauf H6, Skyler JS9, Sosenko JM9 on behalf of the Type 1 Diabetes TrialNet Study Group
1Benaroya Research Institute, Seattle, WA; 2Department of Pediatrics, University of South Florida, Tampa, FL; 3Department of Pediatrics, University of California San Francisco, San Francisco, CA; 4Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver, Aurora, CO; 5Department of Immunobiology, Yale University School of Medicine, New Haven, CT; 6Biostatistics Center, George Washington University, Washington DC; 7Veterans Affairs Puget Sound Health Care System and Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA; 8Departments of Surgery and Microbiology and Immunology, Indiana University, Indianapolis, IN; and 9University of Miami Diabetes Research Institute, Miami, FL
Diabetes 2012;
Summary
This article looks at combined data from several trials conducted by Type 1 Diabetes TrialNet and describes the natural history of β-cell function, as measured during serial mixed meal tolerance tests (MMTTs) from shortly after diagnosis through two years post-study randomization. It assesses the degree of variability between patients and investigates factors that may be related to C-peptide preservation or loss. The article reports that 93% of individuals have detectable C-peptide two years from diagnosis. In 11% of subjects, there was no significant fall from baseline by two years. Moreover, there was a biphasic decline in C-peptide with a greater rate of decline of C-peptide during the first year than during the second year after diagnosis. The rate of decline of C-peptide was similar in individuals aged 7 to 21 and greater than in subjects older than 21 years. However, the youngest subjects (aged 7 to 12) started with lower C-peptide than older subjects aged 12 to 46 years.
Comment
These two articles provide a summary of the metabolic progression of the T1D disease process from two years prior to diagnosis of T1D to two years after the diagnosis of T1D. Making these observations during clinical trials allowed serial measurements to be made in a carefully controlled fashion, although it should be noted that the tests were different in that the subjects prior to diagnosis had OGTTs whilst those subsequent to diagnosis had MMTTs in order to avoid giving a large glucose load to individuals who might not be able to handle it. Collectively, there is a wealth of information in these articles, which give insights into the nature of the metabolic progression of the disease process. Unfortunately, other than antibody measurements, there are not similar detailed immunological measurements that could serve to clarify the immunologic processes that could explain some of the observations. For example, does an immunologic trigger precipitate the decline in stimulated C-peptide over the six months prior to diagnosis? Does something change immunologically approximately one year after diagnosis, resulting in a slower decline in β-cell function thereafter? There is still much to be learned about the natural history of T1D.
Intervention Strategies in Animal Models
The next three papers evaluate potential promising intervention strategies in animal models. Since they are in animals rather than human beings, their details will not be provided; rather they will be discussed in the author's COMMENTS.
Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation
Ablamunits V1, Henegariu O1, Hansen JB2,3, Opare-Addo L1, Preston-Hurlburt P1, Santamaria P4, Mandrup-Poulsen T2,3, Herold KC1
1Department of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT; 2Hagedorn Research Institute, Gentofte, Denmark; 3Institute of Biomedicine, University of Copenhagen, Copenhagen, Denmark; 4Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
Diabetes 2012;
Prevention of autoimmune diabetes and induction of β-cell proliferation in NOD mice by hyperbaric oxygen therapy
Faleo G1, Fotino C1, Bocca N1, Molano RD1, Zahr-Akrawi E1, Molina J1, Villate S1, Umland O1, Skyler JS1,2, Bayer AL1,3, Ricordi C1–5, Pileggi A1,2,4,5
1Diabetes Research Institute, Cell Transplant Center, University of Miami, Miami, FL; 2Department of Medicine, University of Miami, Miami, FL; 3Department of Microbiology and Immunology, University of Miami, Miami, FL; 4DeWitt Daughtry Family Department of Surgery, University of Miami, Miami, FL; and 5Department of Biomedical Engineering, University of Miami, Miami, FL
Diabetes 2012;
Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice
Takiishi T1, Korf H1, Van Belle TL1, Robert S1, Grieco FA2, Caluwaerts S3, Galleri L2, Spagnuolo I2, Steidler L3, Van Huynegem K3, Demetter P4, Wasserfall C5, Atkinson MA5, Dotta F2, Rottiers P3, Gysemans C1, Mathieu C1
1Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium; 2Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy; 3ActoGeniX NV, Zwijnaarde, Belgium; 4Department of Pathology, Université Libre de Bruxelles, Brussels, Belgium; and 5Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
Journal of Clinical Investigation 2012;
Comments
Although each year there are many studies of various forms of immune intervention in animal models, particularly the non-obese diabetic (NOD) mouse, I have chosen three articles to highlight as the interventions discussed may offer important insights and directions for clinical trials. The first article, by Ablamunits et al., shows that the combination of an immunomodulatory agent impacting adaptive immunity (anti-CD3), together with an anti-inflammatory approach impacting innate immunity (IL-1 blockade), has a synergistic effect in reversing T1D in NOD mice. This type of combination strategy is exactly what needs to be tested in human beings as single agent approaches, even when “positive” have only resulted in transient improvement in β-cell function. The second paper, by Faleo et al., studied the use of hyperbaric oxygen therapy (HOT), which was shown both to prevent T1D and induce β-cell proliferation in NOD mice. HOT is an approach that can be readily tested in clinical trials, either alone or as one component of a combination approach. The third article, by Takiishi et al., reversed diabetes in NOD mice by using the bacteria Lactococcus lactis, genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory cytokine IL-10, in combination therapy with low-dose systemic anti-CD3. This represents a novel approach that combines three strategies—an autoantigen, a beneficial cytokine, and an agent that impacts adaptive immunity. If the addition of such a genetically modified bacteria could allow a shorter course of anti-CD3 therapy, this could be an attractive approach to prevent T1D or sustain β-cell function.
Overall Commentary
The last two years have seen several immune intervention trials in T1D fail to achieve success in meeting their primary outcome measure, including studies with anti-CD3, with GAD-alum, and with IL-1 blockade, although the articles describing some of these results have yet to appear. This has resulted in a flurry of editorial and commentary articles that take a bleak approach to the field. In contrast, this author believes there are many potential interventions that hold promise, particularly if they are used as components of combination therapy. Several new strategies are approaching clinical evaluation. My bias is that we must be patient, yet proceed with diligence. Moreover, it is important that trials be carefully designed, well controlled, and adequately sized to assure valid interpretation.
Footnotes
Author Disclosure Statement
The author is chairman of the Type 1 Diabetes Advisory Board of Sanofi Diabetes; serves on advisory boards for Bristol-Myers Squibb, Viacyte and Sekris; has been an advisor to Merck, Gilead, and Takeda; and his institution has received research grants from Halozyme, Mesoblast, and Osiris.