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Summary The Network for Pancreatic Organ donors with Diabetes (nPOD) programme was developed in response to an unmet research need for human pancreatic tissue obtained from individuals with type 1 diabetes mellitus and people at increased risk [i.e. autoantibody (AAb)-positive] for the disease. This necessitated the establishment of a type 1 diabetes-specific AAb screening platform for organ procurement organizations (OPOs). Assay protocols for commercially available enzyme-linked immunosorbent assays (elisas) determining AAb against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA-2A) and zinc transporter-8 (ZnT8A) were modified to identify AAb-positive donors within strict time requirements associated with organ donation programmes. These rapid elisas were evaluated by the international islet AAb standardization programme (IASP) and used by OPO laboratories as an adjunct to routine serological tests evaluating donors for organ transplantation. The rapid elisas performed well in three IASPs (2011, 2013, 2015) with 98-100% specificity for all three assays, including sensitivities of 64–82% (GADA), 60–64% (IA-2A) and 62–68% (ZnT8A). Since 2009, nPOD has screened 4442 organ donors by rapid elisa; 250 (5·6%) were identified as positive for one AAb and 14 (0.3%) for multiple AAb with 20 of these cases received by nPOD for follow-up studies (14 GADA+, two IA-2A+, four multiple AAb-positive). Rapid screening for type 1 diabetes-associated AAb in organ donors is feasible, allowing for identification of non-diabetic, high-risk individuals and procurement of valuable tissues for natural history studies of this disease.

Background The development of anti-islet cell autoimmunity precedes clinical type 1 diabetes and occurs very early in life. During this early period, dietary factors strongly impact on the composition of the gut microbiome. At the same time, the gut microbiome plays a central role in the development of the infant immune system. A functional model of the association between diet, microbial communities, and the development of anti-islet cell autoimmunity can provide important new insights regarding the role of the gut microbiome in the pathogenesis of type 1 diabetes. Results A novel approach was developed to enable the analysis of the microbiome on an aggregation level between a single microbial taxon and classical ecological measures analyzing the whole microbial population. Microbial co-occurrence networks were estimated at age 6 months to identify candidates for functional microbial communities prior to islet autoantibody development. Stratification of children based on these communities revealed functional associations between diet, gut microbiome, and islet autoantibody development. Two communities were strongly associated with breast-feeding and solid food introduction, respectively. The third community revealed a subgroup of children that was dominated by Bacteroides abundances compared to two subgroups with low Bacteroides and increased Akkermansia abundances. The Bacteroides-dominated subgroup was characterized by early introduction of non-milk diet, increased risk for early autoantibody development, and by lower abundances of genes for the production of butyrate via co-fermentation of acetate. By combining our results with information from the literature, we provide a refined functional hypothesis for a protective role of butyrate in the pathogenesis of type 1 diabetes. Conclusions Based on functional traits of microbial communities estimated from co-occurrence networks, we provide evidence that alterations in the composition of mucin degrading bacteria associate with early development of anti-islet cell autoimmunity. We hypothesize that lower levels of Bacteroides in favor of increased levels of Akkermansia lead to a competitive advantage of acetogens compared to sulfate reducing bacteria, resulting in increased butyrate production via co-fermentation of acetate. This hypothesis suggests that butyrate has a protective effect on the development of anti-islet cell autoantibodies. Electronic supplementary material The online version of this article (doi:10.1186/s40168-016-0163-4) contains supplementary material, which is available to authorized users.

Remarkable progress has been made in strategies to arrest pancreatic β-cell destruction in type 1 diabetes. Although knowledge of the disease has increased, a safe therapeutic intervention to reverse or prevent it remains elusive. The interaction of genes, immune system, and environment result in a complex disease process that has delayed hopes for a cure. Several well-designed prevention and intervention studies have aspired to test potentially efficacious and safe therapies. This article updates the principles used to design prevention and intervention trials, reviews clinical trials, addresses controversial issues, and provides a framework for future efforts to interdict this condition.

Background The Network for Pancreatic Organ donors with Diabetes was established to recover and characterize pancreata and related organs from cadaveric organ donors with various risk levels for type 1 diabetes (T1D). These biospecimens are available to investigators for collaborative studies aimed at addressing questions related to TID natural history and pathogenesis.

Using salivary cortisol (SC) measurements, cortisol exposure in Addison's disease patients on hydrocortisone replacement was determined and compared with healthy controls. Cortisol pharmacokinetics was assessed in 31 patients with Addison's disease on replacement hydrocortisone doses (median daily dose 20 mg; range 5-50 mg) and 30 healthy control subjects. Saliva samples (n=16) were collected between 08:00 and 00:00 h in 1 day, using a passive drool technique. Cortisol exposure was evaluated by noncompartmental approach. In the patients, cortisol exposure was significantly higher than in controls: median inter-quartile range (IQR) peak cortisol (C(max)) 174.5 (59.3-837.0) vs. 6.50 (4.7-19.3) nmol/l, p=0.0001; area under the curve (AUC) 390.1 (177.1-928.9) vs. 21.4 (14.6-28.4) minutes*nmol/l, p=0.0001, trough cortisol level (C(min)) 0.49 (0.49-0.96) vs. 0.49 (0.49-0.49) nmol/l, p=0.02, occurring at 480.0 (0.1-660.0) vs. 405.0 (180.0-570.0) min, p=0.56. First peak cortisol was 174.5 (53.0-754.7) vs. 6.27 (3.90-8.47) nmol/l, p=0.0001 and second peak cortisol 18.90 (5.22-76.9) vs. 3.12 (1.76-4.79) nmol/l, p=0.0001. The time to first peak cortisol differed between the 2 groups, 30 (30-75) vs. 0.1 (0.1-30) minutes; p=0.0001. At doses studied, hydrocortisone replacement therapy results in cortisol pharmacokinetics being markedly different from endogenous cortisol profiles in healthy control subjects. Addison's disease patients had significantly higher SC levels compared to healthy control subjects.

OBJECTIVE The aim of this study was to evaluate HbA1c as an alternative criterion for impaired glucose tolerance (IGT) or type 1 diabetes (T1D) in high-risk subjects RESEARCH DESIGN AND METHODS Subjects RESULTS There were 587 subjects from DPT-1, 884 from TrialNet, 91 from TEDDY, and 420 from TRIGR. As an indicator for IGT, HbA1c sensitivity was very low across the studies (8–42%), and specificity was variable (64–95%). With HbA1c ≥6.5% threshold used for T1D diagnosis, the sensitivity was very low and specificity was high (sensitivity and specificity: DPT-1 24 and 98%, TrialNet 28 and 99%, TEDDY 34 and 98%, and TRIGR 33 and 99%, respectively). The positive predictive value of HbA1c ≥6.5% for the development of T1D was variable (50–94%) across the four studies. CONCLUSIONS HbA1c ≥6.5% is a specific but not sensitive early indicator for T1D in high-risk subjects

> Dawn portrays shadows and fleeting openings in the heavy fog. First awake, inquisitive eyes attempt to pierce the grayness, searching out a stepping stone secure enough to settle on next. “There it is, a beam showing a path.” Anxious dreams of the night begin to fade. He prepares to move forward, cautiously choosing the direction. Adjacent, others stir. Where is the path they saw so clearly only a short while before? Now, only nothingness surrounds them. The imperative that first drove them to start the journey appears less urgent. Stuck in place, feet encased in heavy mud, their despair spreads to others. “Surely this direction is wrong. There must be an easier path,” they cry. There is no end to be seen, and we have been traveling many, many years. > > —A parable by Carla J. Greenbaum For almost 50 years, type 1 diabetes has been described as an autoimmune disease characterized by the T-cell–mediated destruction of β-cells, which begins long before clinical diagnosis. Clinical trials accepting this premise and aimed at modulating the immune system before or after onset of clinical disease have failed to prevent or cure type 1 diabetes. Nonetheless, clinical trials have provided useful knowledge. Whereas some studies have demonstrated no effect on disease progression, a small number of therapies have transiently delayed the decline of β-cell function in recently diagnosed patients. In an effort to move toward new therapies for type 1 diabetes, we must continue to seek out the “openings in the heavy fog” of our parable. A review of recently completed clinical trials provides knowledge to guide the rational design of future trials. In that spirit, this Perspectives in Diabetes article focuses on critical lessons learned from: 1 ) clinical trials with negative results, 2 ) pilot studies, and 3 ) clinical trials demonstrating transient effects on …

Diabetic ketoacidosis (DKA) is an acute, still common, and preventable complication of type 1 diabetes (T1D) associated with increased health care costs, morbidity, and mortality (1,2). Clinical recommendations advise self-monitoring of ketones in people with T1D during hyperglycemia and illness to allow for early diagnosis of ketonemia or ketonuria and to reduce the risk of DKA (3,4). The potential benefits of self-monitoring of ketones can only be realized if ketone monitoring and management are conducted as advised. The purpose of this study was to characterize ketone monitoring behaviors in both children and adults with T1D who completed an online questionnaire during October and November 2015 as part of the T1D Exchange Clinic Registry. Participants were asked a number of questions about ketone …

To assess parental decision making and experiences in an autologous umbilical cord blood infusion study in young children with type 1 diabetes (T1D).Surveys were completed with 22 parents of children with T1D who received infusion and 22 parents who declined infusion.Parents who stored umbilical cord blood were middle-aged, highly-educated, Caucasian, married, and privately insured. Parents of children who did not receive infusion declined because they did not want to deplete their cord blood supply. Parents of children who decided to have their children participate in the infusion study were similar on approaches to storing cord blood and attitudes about research as compared to parents who declined to have their children participate in the infusion. Parents of children who received infusion were positive about their experiences and held expectations that infusion would lead to a T1D cure.The manner in which cord blood is stored needs to be considered so that participation in future studies does not risk depletion of the cord blood supply. In addition, it appears that the process of storing umbilical cord blood leads to restricted demographic characteristics of eligible participants, which may impact recruitment in clinical trials. These results are relevant to designing future cord blood studies in T1D and other non-malignant diseases.

OBJECTIVE To evaluate the long-term intervention effects of oral insulin on the development of type 1 diabetes and to assess the rate of progression to type 1 diabetes before and after oral insulin treatment was stopped in the Diabetes Prevention Trial–Type 1 (DPT-1). RESEARCH DESIGN AND METHODS The follow-up included subjects who participated in the early intervention of oral insulin (1994–2003) to prevent or delay type 1 diabetes. A telephone survey was conducted in 2009 to determine whether diabetes had been diagnosed and, if not, an oral glucose tolerance test (OGTT), hemoglobin A1c (HbA1c), and autoantibody levels were obtained on all subjects who agreed to participate. RESULTS Of 372 subjects randomized, 97 developed type 1 diabetes before follow-up; 75% of the remaining 275 subjects were contacted. In the interim, 77 subjects had been diagnosed with type 1 diabetes and 54 of the remainder have had an OGTT; 10 of these were diagnosed with type 1 diabetes, subsequently. Among individuals meeting the original criteria for insulin autoantibodies (IAAs) (≥80 nU/mL), the overall benefit of oral insulin remained significant (P = 0.05). However, the hazard rate in this group increased (from 6.4% [95% CI 4.5–9.1] to 10.0% [7.1–14.1]) after cessation of therapy, which approximated the rate of individuals treated with placebo (10.2% [7.1–14.6]). CONCLUSIONS Overall, the oral insulin treatment effect in individuals with confirmed IAA ≥80 nU/mL appeared to be maintained with additional follow-up; however, once therapy stopped, the rate of developing diabetes in the oral insulin group increased to a rate similar to that in the placebo group.

Objective: To examine the relationship between high-risk human leukocyte antigen (HLA) genotypes for type 1 diabetes and birth size in combination with prenatal characteristics in different countries. Study Design: Four high-risk HLA genotypes were enrolled in the Environmental determinants of Diabetes in the Young study newborn babies from the general population in Finland, Germany, Sweden and the United States. Stepwise regression analyses were used to adjust for country, parental physical characteristics and environmental factors during pregnancy. Result: Regression analyses did not reveal differences in birth size between the four type 1 diabetes high-risk HLA genotypes. Compared with DQ 4/8 in each country, (1) DQ 2/2 children were heavier in the United States (P=0.028) mostly explained however, by parental weight; (2) DQ 2/8 (P=0.023) and DQ 8/8 (P=0.046) children were longer in Sweden independent of parents height and as well as (3) in the United States for DQ 2/8 (P=0.023), but again dependent on parental height. Conclusion: Children born with type 1 diabetes high-risk HLA genotypes have comparable birth size. Longitudinal follow-up of these children should reveal whether birth size differences between countries contribute to the risk for islet autoimmunity and type 1 diabetes.

BACKGROUND Type 1 diabetes (T1DM) results from cell-mediated autoimmune destruction of the β cells of the islets of Langerhans. Autoantibodies directed against the islets are useful clinical tools that allow the recognition and confirmation of β-cell autoimmunity. CONTENT In this review we define the term “islet autoantibody,” describe the pathogenesis of autoantibody generation, and explain the uses of islet autoantibodies in clinical medicine and in research studies that concern the interruption or prevention of T1DM. We also discuss the biology of islet autoantibodies and their rates of appearance at the time of onset of T1DM and their appearance before the development of T1DM. SUMMARY The presence of islet autoantibodies in persons with diabetes confirms an autoimmune etiology. In nondiabetic individuals, islet autoantibodies are strong predictors of the later development of T1DM.

OBJECTIVE Although type 1 diabetes autoimmunity frequently begins in childhood, little is known about the relationship between age and autoimmunity development. Our aim was to determine the timing of seroconversion to diabetes-associated autoantibody (DAA) positivity and risk in first- and second-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Study subjects were identified through the Diabetes Prevention Trial-Type 1 (DPT-1). Children 3–18 years of age (n = 42,447) were screened for DAAs; 1,454 were ICA positive (≥10 JDF units), 1,758 were GAD65 positive, and 899 were ICA512 positive at the time of initial screening. Subjects who were initially antibody negative (n = 39,212) were recalled for rescreening, and 11,813 returned for rescreening. RESULTS DAA seroconversion occurred in 469 (4%) children; 258 seroconverted to ICA, 234 to GAD65, and 99 to ICA512. The median time to seroconversion was 2 years. The 2-year risk for DAAs was highest in early childhood. For each 1-year increase in age in this cohort, the risk of any autoantibody seroconversion (HR 0.95, 95% CI 0.92–0.97) decreased by 5%, and for any two autoantibodies risk decreased by 13% (0.87, 0.82–0.93). CONCLUSIONS Risk of autoantibody seroconversion among children followed in DPT-1 is age dependent. Younger children have the highest risk for DAAs, with the majority of children seroconverting by 13 years of age (75%). This suggests that annual screenings should be started in early childhood and continued through early adolescence to identify the majority of subjects at risk for type 1 diabetes and eligible for prevention trials.

Objectives An intestinal permeability defect precedes type 1 diabetes mellitus and may be a permissive factor in its pathogenesis. Butyrate strengthens the intestinal tight junctions. We hypothesized that enteral administration of sodium butyrate (NaB) in preweaned rats would result in differences in the development of diabetes associated with decreased inflammation and pancreatic β-cell destruction. Materials and methods Using biobreeding diabetes-prone rat pups, oral NaB or saline was administered twice per day via micropipette from postnatal days 10 to 23. Rat pups were randomly assigned to 1 of 4 groups for the first experiment (control group, n = 7) and 3 different doses of butyrate groups (n = 8 for each group) and 2 groups for the second and third experiments (control n = 23; NaB at 400 mg · kg(-1) · day(-1), n = 20). Animals were studied into adulthood (up to day 140) for development of diabetes. Results The results showed that the survival rates were 28% versus 20% (butyrate vs control). No significant differences in survival were seen; however, there was a trend of delaying of onset of diabetes in the butyrate group. There were no differences of pancreatic histology score of islet inflammation between the 2 groups. Cytokine-induced neutrophil chemoattractant-1 was lower in the butyrate group at a dose of 400 mg · kg(-1) · day(-1) in the distal small intestine (P = 0.008) and in the liver (P = 0.01). There were no significant differences in the tracer flux measurements across the distal ileum and colon between the 2 animal groups. Conclusions Oral NaB given during the preweaning period did not significantly decrease the subsequent development of death from diabetes in biobreeding diabetes-prone rats.

Despite improvements in our understanding of the natural history of type 1 diabetes (T1D), an intervention capable of consistently and safely preventing or reversing the disease has yet to be developed. The inability to cure this disorder results, to a large extent, from the complex pathophysiology of T1D, continued struggles to identify its precise etiological triggers, and voids in our understanding of the immunological mechanisms that specifically target pancreatic β cells. Interestingly, rapidly improving technologies for managing T1D render discussions surrounding equipoise of vital importance, especially when considering interventions deemed of “high-risk” in terms of their safety. This chapter reviews the conceptual basis for prevention versus intervention trials in settings of T1D, past experiences for clinical trials seeking such purposes, controversial issues to disease interdiction, and seeks to provide a roadmap for future efforts seeking to cure this disorder.

P>Objective We sought to determine whether autoimmunity is the predominant cause of Addison's disease in South Africa and whether human leucocyte antigen (HLA) DQ association exists. Design We compiled a national registry of patients from primary care, referral centres and private practices. Patients A total of 144 patients, 94 of European descent, 34 Mixed Ancestry, 5 Asian and 11 Black Africans (mean age 45 center dot 9 years, range 2 center dot 7-88 years; mean duration of disease 13 center dot 1 years, range 0-50 years) and controls were matched for gender and ethnicity. All potential causes were investigated. Results Fifty one per cent of cases (74 patients) were autoimmune in aetiology. Either 21-hydroxylase autoantibodies (72 patients, 50% of entire patient group) or adrenocortical autoantibodies (35 patients, 24%) were present, while 23% of patients had both. None of the Asian (n = 5) or Black (n = 11) patients had evidence of autoimmune disease. Overall 8% of patients had tuberculosis, 4% adrenoleucodystrophy, 1% adrenocorticotrophic hormone resistance syndrome and 6% X-linked adrenal hypoplasia. In those with autoimmune disease primary hypothyroidism (47%), premature ovarian failure (8%) and type 1 diabetes (7%) were the most prevalent accompanying autoimmune conditions. HLA DQB1*0201 alleles predominated in the autoimmune group (DQB1*0201: 65%vs 43% of controls P = 0 center dot 017) with the *0201/*0302 heterozygous genotype being the most prevalent (28%vs 8%P = 0 center dot 02). Conclusions While autoimmunity accounts for at least half of patients with Addison's disease in South Africa and is associated with HLA DQB1*0201, none of the Black Africans or Asians in this cohort had adrenal autoantibodies. Moreover, 21-hydroxylase autoantibodies were detectable in a higher proportion than adrenocortical autoantibodies, especially in those patients with a long history after disease onset.

Autoantibodies to islet antigen-2 (IA-2A) and glutamic acid decarboxylase (GADA) are markers for diagnosis, screening, and measuring outcomes in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consortia studies. A harmonization program was established to increase comparability of results within and among these studies.Large volumes of six working calibrators were prepared from pooled sera with GADA 4.8-493 World Health Organization (WHO) units/ml and IA-2A 2-235 WHO units/ml. Harmonized assay protocols for IA-2A and GADA using (35)S-methionine-labelled in vitro transcribed and translated antigens were developed based on methods in use in three NIDDK laboratories. Antibody thresholds were defined using sera from patients with recent onset type 1 diabetes and healthy controls. To evaluate the impact of the harmonized assay protocol on concordance of IA-2A and GADA results, two laboratories retested stored TEDDY study sera using the harmonized assays.The harmonized assays gave comparable but not identical results in the three laboratories. For IA-2A, using a common threshold of 5 DK units/ml, 549 of 550 control and patient samples were concordantly scored as positive or negative, specificity was greater than 99% with sensitivity 64% in all laboratories. For GADA, using thresholds equivalent to the 97th percentile of 974 control samples in each laboratory, 1051 (97.9%) of 1074 samples were concordant. On the retested TEDDY samples, discordance decreased from 4 to 1.8% for IA-2A (n = 604 samples; P = 0.02) and from 15.4 to 2.7% for GADA (n = 515 samples; P0.0001).Harmonization of GADA and IA-2A is feasible using large volume working calibrators and common protocols and is an effective approach to ensure consistency in autoantibody measurements.

Type 1 diabetes (T1D) is considered a disorder whose pathogenesis is autoimmune in origin, a notion drawn in large part from studies of human pancreata performed as far back as the 1960s. While studies of the genetics, epidemiology, and peripheral immunity in T1D have been subject to widespread analysis over the ensuing decades, efforts to understand the disorder through analysis of human pancreata have been far more limited. We have reviewed the published literature pertaining to the pathology of the human pancreas throughout all stages in the natural history of T1D. This effort uncovered a series of findings that challenge many dogmas ascribed to T1D and revealed data suggesting the marked heterogeneity in terms of its pathology. An improved understanding and appreciation for pancreatic pathology in T1D could lead to improved disease classification, an understanding of why the disorder occurs, and better therapies for disease prevention and management.

OBJECTIVE This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-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.

BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte–mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)

Development of efficient and safe intervention strategies for preserving and/or restoring endogenous insulin production in type 1 diabetes has encountered a wide range of challenges, including lack of standardized trial protocols and of consensus on appropriate efficacy endpoints. For the greatest part, difficulties resided in choosing the most suitable assay(s) and parameter(s) to assess the beta-cell function. It is now an accepted approach to evaluate endogenous insulin secretion by measuring C-peptide levels (with highly sensitive and normalized measurement methods) in response to a physiologic stimulus (liquid mixed-meal) under standardized conditions. Preventive interventions mandate the identification of well-defined, reliable and validated mechanistic or immunological markers of efficacy that would correlate with (and predict) the clinical outcome. This has not been consistently achieved to date. However, it has been generally agreed that for preventive studies performed very early in the disease course (in subjects without signs of autoimmunity against beta-cells) development of two or more islet related autoantibodies could be employed as biomarkers of disease and thereafter, diagnostic criteria of diabetes serve as suitable endpoints.This report summarizes the conclusions of the D-Cure workshop of international experts held in Barcelona in April 2007 and the current recommendations and updates in the field.

OBJECTIVE There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes. RESEARCH DESIGN AND METHODS Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial–Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA+). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA+). RESULTS In both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes. CONCLUSIONS The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.

The past quarter century has seen a rapid increase in our knowledge about the natural history of autoimmune type 1 diabetes. However, we stand unable to achieve our ultimate goal of preventing or reversing this disease. This viewpoint discusses controversies in current management of type 1 diabetes, the challenges in translating promising studies from mouse models of the disease to humans, hurdles faced in designing optimal prevention and intervention studies, and potential strategies to overcome these obstacles. “....Two roads diverged in a wood, and I-I took the one less traveled by, And that has made all the difference.” -The Road Not Taken Robert Frost, 1920

Objective: To assess the experiences of participants and parents of children in the oral insulin study of the Diabetes Prevention Trial – Type 1. Method: Before trial results were publicized, surveys were completed by 124 participants and 219 parents of children in the oral trial. Results: Although most of those surveyed were positive about the trial, survey results suggest that participant perspective (adult, child, parent, and gender), study procedures, and beliefs about placebo vs. active drug assignment have important implications for planning future clinical trials. Parents and children reported greater distress, worry, and difficulty making the decision to join the trial compared with adult participants. Mothers and female participants were particularly interested in additional psychosocial support during the study. Random assignment was viewed negatively by both parents and children, and close observation for diabetes onset was viewed as the most favorable aspect of the study. Adherence to study procedures declined over time and behaviors outside the study protocol to prevent/delay diabetes onset were common, particularly among those who believed the participant was taking a placebo. Children and respondents who believed that the participant was taking the active drug expressed confidence in oral insulin’s ability to delay or prevent type 1 diabetes. Conclusions: Although most participants were positive about the trial and many expressed optimism about the intervention’s potential for success, future trials need to address negative reactions to random assignment, the unique concerns of children and their parents, declining adherence, and behaviors – external to the trial – designed to delay or prevent diabetes.

Previous studies have identified a correlation, either positive or negative, between specific stool bacteria strains and certain autoimmune diseases. These conflicting data may relate to sample collection. The aim of this work was to evaluate the influence of the collection parameters of time and temperature on bacterial community composition. Samples were taken from healthy children and immediately divided in 5 sub-samples. One sample was frozen immediately at -80 ° C, while the other aliquots were frozen 12, 24, 48, and 72h later DNA extracted from each sample was used to amplify the 16S rRNA with barcoded primers. The amplified products were pooled and partial 16S rRNA sequences were obtained by pyrosequencing. Person-to-person variability in community diversity was high. A list of those taxa that comprise at least 1% of the community was made for each individual. None of these were present in high numbers in all individuals. The Bacteroides were present in the highest abundance in three of four subjects. A total of 23,701 16S rRNA sequences were obtained with an average of 1,185 reads per sample with an average length of 200 bases. Although pyrosequencing of amplified 16S rRNA identified changes in community composition over time (~10%), little diversity change was observed at 12 hours (3.06%) with gradual changes occurring after 24 (8.61%), 48 (9.72%), and 72 h (10.14%), post collection.

OBJECTIVE Interest continues to grow regarding the therapeutic potential for umbilical cord blood therapies to modulate autoimmune disease. We conducted an open-label phase I study using autologous umbilical cord blood infusion to ameliorate type 1 diabetes. RESEARCH DESIGN AND METHODS Fifteen patients diagnosed with type 1 diabetes and for whom autologous umbilical cord blood was stored underwent a single intravenous infusion of autologous cells and completed 1 year of postinfusion follow-up. Intensive insulin regimens were used to optimize glycemic control. Metabolic and immunologic assessments were performed before infusion and at established time periods thereafter. RESULTS Median (interquartile range [IQR]) age at infusion was 5.25 (3.1–7.3) years, with a median postdiagnosis time to infusion of 17.7 (10.9–26.5) weeks. No infusion-related adverse events were observed. Metabolic indexes 1 year postinfusion were peak C-peptide median 0.50 ng/ml (IQR 0.26–1.30), P = 0.002; A1C 7.0% (IQR 6.5–7.7), P = 0.97; and insulin dose 0.67 units · kg−1 · day−1 (IQR 0.55–0.77), P = 0.009. One year postinfusion, no changes were observed in autoantibody titers, regulatory T-cell numbers, CD4-to-CD8 ratio, or other T-cell phenotypes. CONCLUSIONS Autologous umbilical cord blood transfusion in children with type 1 diabetes is safe but has yet to demonstrate efficacy in preserving C-peptide. Larger randomized studies as well as 2-year postinfusion follow-up of this cohort are needed to determine whether autologous cord blood–based approaches can be used to slow the decline of endogenous insulin production in children with type 1 diabetes.

Increased life expectancy in cystic fibrosis (CF) is accompanied by an increasing incidence of CF related diabetes (CFRD). Altered immune reactivity occurs in CF, which we hypothesize, is exacerbated by hyperglycemia. Cystic fibrosis transmembrane conductance regulator deficient (CFTR-/-) mice were rendered hyperglycemic by streptozotocin (STZ) to test this hypothesis. CFTR-/-, C57BL/6J, and FVB/NJ mice received either STZ or lactated ringers (LR) (n=5-10). Four weeks later, splenocytes were harvested, mitogen stimulated, and analyzed for cytokine production (IL-2, IL-4, and IL-10) along with stimulation indices (SI). SI of STZ-treated CFTR-/- were elevated compared to LR-treated mice, although both were greater than C57BL/6J and FVB/NJ (p

Summary Previous studies have shown that human alpha-1 antitrypsin (hAAT) gene delivery prevents type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Furthermore, hAAT protein administration prolongs acceptance of islet allografts. Therefore, we evaluated the use of purified hAAT protein therapy to prevent T1D in NOD mice. Female NOD, non-obese resistant (NOR), Balb/c and C57BL/6 mice were injected intraperitoneally with vehicle alone or vehicle containing hAAT, human albumin or mouse albumin (or mg/injection/mouse; 2×/week). Preparations of clinical-grade hAAT included API®, Aralast®, Prolastin® and Zemaira®. Surprisingly, hAAT administration was associated with a high rate of fatal anaphylaxis. In studies seeking T1D prevention at 4 weeks of age, 100% mice died after six injections of hAAT. When administrated at 8–10 weeks of age, most (80–100%) NOD mice died following the fourth injection of hAAT, while 0% of Balb/c and C57BL/6 mice and 10% of NOR mice died. Interestingly, repeated injections of human albumin, but not mouse albumin, also induced sudden death in NOD mice. Antibodies to hAAT were induced 2–3 weeks after hAAT administration and death was prevented by treatment with anti-platelet-activating factor along with anti-histamine. In studies of disease reversal in NOD mice, using the four pharmaceutical grade formulations of hAAT, anaphylactic deaths were observed with all hAAT preparations. The propensity for fatal anaphylaxis following antigenic administration appears to be NOD- but not hAAT-specific. The susceptibility of NOD mice to hypersensitivity provides a significant limitation for testing of hAAT. Development of strategies to avoid this unwanted response is required to use this promising therapeutic agent for T1D.

Objective The physical, emotional, and economic costs of type 1 diabetes (T1D) mandate continued efforts to develop effective strategies to prevent or reverse the disease. Herein, we describe the scientific and therapeutic rationale underlying efforts utilizing umbilical cord blood (UCB) as a therapy for ameliorating the progression of this autoimmune disease. Materials and Methods We recently embarked on a pilot study to document the safety and potential efficacy of autologous UCB infusion in subjects with T1D. Under this protocol, patients recently diagnosed with the disease and for whom autologous cord blood is stored, undergo infusion. Studies are performed before infusion and every 3 to 6 months postinfusion for immunologic and metabolic assessment. To date, 15 autologous infusions have been performed. Results Preliminary observations suggest that autologous cord blood transfusion is safe and provides some slowing of the loss of endogenous insulin production in children with T1D. Mechanistic studies demonstrate that umbilical cord blood contains highly functional populations of regulatory T cells (Treg) and that increased Treg populations may be found in the peripheral blood of subjects more than 6 months after cord blood infusion. We provide the rationale for cord blood–based therapies, a summary of our initial protocol, and plans for future studies designed to explore the potential of cord blood–derived regulatory T cells to treat T1D. Conclusions Prolonged follow-up and additional mechanistic efforts are urgently needed to determine if umbilical cord blood–derived stem cells can be used as part of safe and effective therapies for T1D.

OBJECTIVE—Antilymphocyte serum can reverse overt type 1 diabetes in NOD mice; yet, the therapeutic parameters and immunological mechanisms underlying the ability for this agent to modulate autoimmune responses against β-cells are unclear, forming the rationale for this investigation. RESEARCH DESIGN AND METHODS—A form of antilymphocyte serum, rabbit anti-mouse thymocyte globulin (mATG), was utilized in a variety of in vivo and in vitro settings, each for the purpose of defining the physiological, immunological, and metabolic activities of this agent, with particular focus on actions influencing development of type 1 diabetes. RESULTS—We observed that mATG attenuates type 1 diabetes development in an age-dependent fashion, only proving efficacious at disease onset or in the late pre-diabetic phase (12 weeks of age). When provided at 12 weeks of age, mATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age-dependent fashion, the frequency and the functional activity of CD4+CD25+ regulatory T-cells. Adoptive transfer/cotransfer studies of type 1 diabetes also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in vivo. CONCLUSIONS—These findings indicate that an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of antithymocyte globulin and suggest that time-dependent windows for the ability to delay or reverse type 1 diabetes exist based on the capacity to enhance the functional activity of regulatory T-cells.

Objectives: To assess the ability of reactive hyperemia–peripheral artery tonometry (RH-PAT) to serve as a surrogate marker of endothelial dysfunction in children with type 1 diabetes (T1D). Research Design and Methods: Forty-four children with T1D [age 14.6 ± 2.7 yr; duration of diabetes 6.01 ± 4 yr; range of diabetes duration 1–16 yr; and hemoglobin A1c (HbA1c) 8.34 ± 1.2%] and 20 children without diabetes (age 14.1 ± 1.5 yr) underwent RH-PAT endothelial function testing after an overnight fast. Height, weight, body mass index (BMI), blood pressure (BP), fasting lipid profile, and glucose level were determined in each child. Children with T1D underwent a second RH-PAT study 4 wk after their initial study to determine the intrapatient variability of the technique. Results: Children with T1D had endothelial dysfunction as evidenced by lower mean RH-PAT scores (1.63 ± 0.5) when compared with children without diabetes (mean RH-PAT score 1.95 ± 0.3) (p = 0.01). Repeat RH-PAT scores were predicted by initial RH-PAT scores (p = 0.0025). Mean intrapatient standard deviation of RH-PAT score was 0.261 and mean coefficient of variation was 14.8. Variations in RH-PAT score were not explained by differences in glucose, HbA1c, BMI, systolic BP, diastolic BP, or lipids. Conclusions: Although larger validation studies are required, RH-PAT is a promising non-invasive technique to assess endothelial function in children with T1D. Non-invasive measures of endothelial dysfunction may provide the additional risk stratification data needed to justify more aggressive primary prevention of cardiovascular disease in children with T1D.

PURPOSE OF REVIEW Type 1 diabetes (T1D) is characterized by autoimmune-mediated destruction of pancreatic beta cells culminating in absolute insulin deficiency. Despite enhanced knowledge of the natural history of type 1 diabetes we have yet to develop an intervention to consistently and safely prevent or reverse type 1 diabetes. This review explores the lessons learned from recent type 1 diabetes interventional studies, sets out controversial issues and seeks to provide a roadmap for future interventions. RECENT FINDINGS The type 1 diabetes intervention studies of the 1980s demonstrated potential for preserving c-peptide, but were abandoned due to unacceptable side-effect profiles of the agents being used. Pilot studies of new immunosuppressive and immunomodulatory agents with improved side-effect profiles have recently demonstrated promise in preserving c-peptide in new-onset type 1 diabetes patients. Several of these agents, including insulin, anti-CD3, mycophenolate mofetil, daclizumab and anti-CD20, are currently being tested in multicenter intervention trials. SUMMARY The inability to cure type 1 diabetes underscores the complex pathophysiology of the disease, and our poor knowledge of the precise etiological triggers and immunological mechanisms which culminate in the disease. While ongoing efforts to test individual agents with potential to ameliorate diabetes are needed, combination therapies employing multiple safe agents are likely to be the future of type 1 diabetes intervention studies.

Regulatory T-cells (Tregs) play a critical role in maintaining dominant peripheral tolerance. Previous characterizations of Tregs in type 1 diabetes have used antibodies against CD4 and alpha-chain of the interleukin-2 receptor complex (CD25). This report extends those investigations by the addition of a more lineage-specific marker for Tregs, transcription factor forkhead box P3 (FOXP3), in subjects with type 1 diabetes, their first-degree relatives, and healthy control subjects. With inclusion of this marker, two predominant populations of CD4(+)CD25(+) T-cells were identified: CD4(+)CD25(+)FOXP3(+) as well as CD4(+)FOXP3(-) T-cells expressing low levels of CD25 (CD4(+)CD25(LOW)FOXP3(-)). In all study groups, the frequency of CD4(+)CD25(+)FOXP3(+) cells was age independent, whereas CD4(+)CD25(LOW)FOXP3(-) cell frequencies strongly associated with age. In terms of additional markers for delineating cells of Treg lineage, FOXP3(+) cells were CD127(-) to CD127(LOW) whereas CD25(+) cells were less restricted in their expression of this marker, with CD127 expressed across a continuum of levels. Importantly, no differences were observed in the frequency of CD4(+)CD25(+)FOXP3(+) T-cells in individuals with or at varying degrees of risk for type 1 diabetes. These investigations suggest that altered peripheral blood frequencies of Tregs, as defined by the expression of FOXP3, are not specifically associated with type 1 diabetes and continue to highlight age as an important variable in analysis of immune regulation.

The aim of the present study was to compare characteristics and diabetes management in children and adolescents with and without at least one parent with type 1 diabetes (T1D).In all, 12 890 participants aged18 years at enrollment in the T1D Exchange Registry were included in the present study. Statistical comparisons between those with and without parental T1D were conducted using a univariate generalized linear mixed model.Of the study participants, 1056 (8.2%) registrants had at least one parent with T1D. Those with parental T1D were slightly, albeit significantly, younger (6.3 vs 6.9 years; P 0.001) and less likely to have diabetic ketoacidosis (DKA) at diagnosis (24% vs 41%; P 0.001) than those without parental T1D. There were no differences between groups in HbA1c, use of continuous glucose monitoring or insulin pump therapy, or the development of severe hypoglycemia or DKA. In addition, there were no differences found when comparing characteristics or diabetes management in those with a mother versus those with a father with T1D.Children and adolescents with parental T1D tend to be diagnosed earlier. Diabetes management, glycemic control, and acute complications are similar in those with and without parental T1D.

Background Parental support and care-coordination are vital for youth with type 1 diabetes (T1D) in achieving positive health outcomes. Yet, studies are rarely designed to identify factors that influence parent/youth collaboration or how their perspectives about diabetes may vary. Methods Photovoice was used to explore how adolescent and parental perspectives on T1D compare to identify factors that may influence care collaboration. A follow-up study was conducted where parents/caregivers of adolescents with T1D were prompted to take and explain five photos capturing what diabetes meant to them. Selection criteria included having a child 12–19 years with a diagnosis of T1D (≥2 years since onset). Thirty-three parents/caregivers participated (24 mothers, six fathers, two grandmothers, and one grandfather of 19 sons/14 daughters; mean age 15 years [±2.1]; mean disease duration 6 years [±3.3]). Content analysis was used to compare parent/caregiver photos with those captured by adolescents in a previous study with 40 youth participants (20 males/20 females; mean age 15 years [±1.9]; mean disease duration 6 years [±3.9]) through a method of constant comparison. Socioeconomic status was measured by household income and parental education. Glycemic control was captured by HbA1c. Mann-Whitney U testing was used to compare representations across demographic variables (202 youth photos, 153 parental photos). Results Over half of adolescents and parents took at least one photo of: (1) diabetes supplies (2) food (3) coping mechanisms/resilience and (4) disease encroachment. Parents and adolescents similarly framed food-related issues as a major source of frustration in diabetes care. However, narratives about diabetes supplies differed: adolescents framed supplies as a negative aspect of diabetes whereas parents tended to celebrate supplies as improving life. Also, images of disease encroachment differed: adolescents took photos of their bodies to depict how diabetes trespasses on their lives whereas parents took pictures of clocks to denote sleep disruption or exhaustion from constant care demands. Conclusions Food-related issues and varying views on supplies may trigger diabetes-specific conflicts. Contrasting viewpoints about the most cumbersome aspects of diabetes may provide insight into differential paths for interventions aimed at offsetting the burdens of T1D for adolescents and parents.

Previous studies of pancreases obtained at autopsy or by radiography note reduced pancreas weight (PW) and size, respectively, in type 1 diabetes; this finding is widely considered to be the result of chronic insulinopenia. This literature is, however, limited with respect to the influence of age, sex, anthropometric factors and disease duration on these observations. Moreover, data are sparse for young children, a group of particular interest for type 1 diabetes. We hypothesised that the pancreas-to-body weight ratio would normalise confounding inter-subject factors, thereby permitting better characterisation of PW in type 1 diabetes. Transplant-grade pancreases were recovered from 216 organ donors with type 1 diabetes (n = 90), type 2 diabetes (n = 40) and no diabetes (n = 86). Whole-organ and head, body and tail weights were determined. The relative PW (RPW; PW [g] / body weight [kg]) was calculated and tested for normalisation of potential differences due to age, sex and BMI. PW significantly correlated with body weight in control donors (R 2 = 0.76, p

Children at high risk for developing type 1 diabetes (T1D) can be identified on the basis of human leukocyte antigen (HLA) genotype and the subsequent development of islet cell autoantibodies. Several studies have documented reduced incidence of diabetic ketoacidosis (DKA) in new-onset T1D when high-risk children are identified at an early age. Many have questioned whether general population screening for T1D risk should be standard of practice. We sought to perform a purely economic, cost-benefit analysis to determine if a screening program to reduce the incidence of DKA at diagnosis in children less than 5 yr is cost effective.We compared the cost of population screening with the benefit of preventing DKA. The cost of screening included one-time HLA typing on the entire population followed by islet cell autoantibody testing in high-risk children every 6 months until age 5 yr. The potential benefits of screening included reductions in parental lost income, medical expenses, morbidity, and mortality.Screening for T1D risk for the sole purpose of reducing the cost of DKA at onset of T1D was not economically viable unless HLA testing and autoantibody testing could be performed for less than $1 and $0.03, respectively.Current screening costs far outweigh the economic benefits of preventing new-onset DKA in children under 5 yr of age.

The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with T1D in the genome-wide association scan meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY participants carrying high-risk HLA genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (P < 0.05), whereof four were significant after adjustment for multiple testing (P < 0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27–1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14–1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19–1.61]), and rs1004446 in INS (HR 0.77 [0.66–0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70–3.44]). Although genes in the HLA region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease.

The cause of cystic fibrosis–related diabetes (CFRD) remains unknown, but cystic fibrosis transmembrane conductance regulator (CFTR) mutations contribute directly to multiple aspects of the cystic fibrosis phenotype. We hypothesized that susceptibility to islet dysfunction in cystic fibrosis is determined by the lack of functional CFTR. To address this, glycemia was assessed in CFTR null (CFTR−/−), C57BL/6J, and FVB/NJ mice after streptozotocin (STZ)-induced β-cell injury. Fasting blood glucose levels were similar among age-matched non–STZ-administered animals, but they were significantly higher in CFTR−/− mice 4 weeks after STZ administration (288.4 ± 97.4, 168.4 ± 35.9, and 188.0 ± 42.3 mg/dl for CFTR−/−, C57BL/6J, and FVB/NJ, respectively; P < 0.05). After intraperitoneal glucose administration, elevated blood glucose levels were also observed in STZ-administered CFTR−/− mice. STZ reduced islets among all strains; however, only CFTR−/− mice demonstrated a negative correlation between islet number and fasting blood glucose (P = 0.02). To determine whether a second alteration associated with cystic fibrosis (i.e., airway inflammation) could impact glucose control, animals were challenged with Aspergillus fumigatus. The A. fumigatus–sensitized CFTR−/− mice demonstrated similar fasting and stimulated glucose responses in comparison to nonsensitized animals. These studies suggest metabolic derangements in CFRD originate from an islet dysfunction inherent to the CFTR−/− state.

This article reviews our current understanding of the etiology, presentation, and management of type 1 diabetes. The discussion includes a review of the natural history of diabetes, the complex relationship between genetic and environmental risk for type 1 diabetes, and current methods for prediction of type 1 diabetes. The article also reviews the current management of children who have new-onset type 1 diabetes, age-appropriate management goals, and diabetes complications. Finally, the article discusses the future of diabetes screening programs and the progress toward the ultimate goal of curing type 1 diabetes.

The extent to which autoimmunity contributes to thyroid dysfunction in Down Syndrome (DS) individuals has not been clarified. We studied 61 persons (34 males and 27 females) with DS (age 5 months to 48 years) for the presence of thyroid autoantibodies (thyroid microsomal antibodies and thyroglobulin antibodies), pancreatic islet cell autoantibodies, gastric parietal cell autoantibodies, and adrenocortical autoantibodies. Thyroid function was determined by measurement of TSH. HLA-A, B and -DR typing was performed on 52 subjects. Forty of 61 subjects (66%) had thyroid dysfunction: elevated TSH values (greater than 5 mcIU/ml) were found in 35 of 61 individuals; 3 subjects had previously documented Hashimoto thyroiditis and were on therapy for hyperthyroidism; and 2 persons had Graves disease. No age or sex variation was detected. Seventeen (28%) subjects had thyroid autoantibodies. Fifteen of the 17 had thyroid dysfunction. Twelve of 25 subjects (48%) over 10 years with thyroid dysfunction had thyroid autoantibodies compared to only 3 of 15 (20%) under the age of 10 years. However, children less than of 10 years tended to have higher TSH values. Only 1 individual who had thyroid antibodies had gastric parietal cell autoantibodies present. Islet cell and adrenocortical autoantibodies were not found in any individuals. Neither thyroid dysfunction nor thyroid autoantibodies correlated with any HLA allele. These findings suggest that thyroid dysfunction in individuals with DS of all ages is a common heterogeneous disorder which cannot be solely explained on the basis of autoimmunity. We recommend that thyroid function be followed closely whether or not thyroid autoantibodies are present.

CD4 + CD25 + T-cells appear to play a crucial role in regulating the immune response. Therefore, we evaluated the peripheral blood frequency and function of CD4 + CD25 + T-cells in 70 type 1 diabetic patients and 37 healthy individuals. Interestingly, a positive correlation was observed between increasing age and CD4 + CD25 + T-cell frequency in both subject groups. In contrast to previous studies of nonobese diabetic mice and type 1 diabetic patients, similar frequencies of CD4 + CD25 + and CD4 + CD25 +Bright T-cells were observed in healthy control subjects and type 1 diabetic patients of similar age. There was no difference between type 1 diabetic subjects of recent-onset versus those with established disease in terms of their CD4 + CD25 + or CD4 + CD25 +Bright T-cell frequency. However, type 1 diabetic patients were markedly defective in their ability to suppress the proliferation of autologous effector T-cells in vitro. This type 1 diabetes-associated defect in suppression was associated with reduced production of interleukin (IL)-2, γ-interferon, and transforming growth factor-β, whereas other cytokines including those of adaptive and innate immunity (IL-10, IL-1β, IL-6, IL-8, IL-12p70, and tumor necrosis factor-α) were similar in control subjects and type 1 diabetic patients. These data suggest that age strongly influences the frequency of CD4 + CD25 + T-cells and that function, rather than frequency, may represent the means by which these cells associate with type 1 diabetes in humans.

After completing this article, readers should be able to: 1. Outline the current concepts of the pathogenesis of type 1 diabetes (T1D) with regard to dietary triggers and genetic susceptibility. 2. Discuss the evidence, both epidemiologic and that derived from studies of animal models, that supports the association between infant feeding practices and T1D. 3. Describe the roles for intestinal immunity and permeability in supporting the hypothetical model of cow milk protein mediation of T1D autoimmunity. 4. Delineate the goals and rationale for prospective clinical trials evaluating neonatal nutrition and the development of T1D. 5. List the putative dietary modulators of T1D. Type 1 diabetes (T1D), a disease that has unacceptably high morbidity and mortality, is increasing in incidence, prompting the redoubling of efforts toward its prevention. Progress toward prevention and cure relies on elucidation of the disease’s pathogenesis, which, to date, has remained poorly defined. The defining features of T1D, insulin deficiency and hyperglycemia, result from an immune-mediated destruction of insulin-secreting beta cells in the pancreatic islets. The loss of beta cell mass is believed to be gradual for most individuals, accounting for the sometimes prolonged asymptomatic periods of autoimmunity preceding overt diabetes (Fig. 1). Indeed, the chronic autoimmune nature of the disease is well established, as is the genetic predisposition. Specific associations with molecules of the human lymphocyte antigen (HLA) define both susceptibility to and protection from T1D. However, T1D is a polygenic disorder with more than 20 loci associated with susceptibility or resistance to the disease, of which the HLA may account for less than 50% of the genetic predisposition. Genetics clearly comprises a major component of the development of T1D, but the interaction between the environment and the immune system abnormalities is believed to weigh heavily in disease development. Indeed, trends in T1D incidence, both geographic and temporal, suggest a strong …

OBJECTIVE—The aim of this study was to assess maternal diabetes prevention efforts aimed at children identified as at risk through newborn genetic screening. RESEARCH DESIGN AND METHODS—A total of 192 mothers of children identified as at risk for type 1 diabetes through newborn genetic screening were administered a structured interview 3.6 ± 0.8 years after risk notification. The interview assessed possible diabetes prevention behaviors across six domains: health surveillance, diet, physical activity, illness prevention, medications, and stress reduction. A mother’s cognitive (diabetes risk perception and perceived control), affective (anxiety), and coping responses to the child’s at-risk status were assessed. RESULTS—A total of 67% of mothers reported one or more diabetes prevention behaviors. Monitoring behaviors (e.g., watching for signs of diabetes and checking blood glucose) were the most common, reported in 59%, followed by modifications in the child’s diet in 34% and physical activity in 14%. Potentially harmful prevention behaviors (e.g., limiting contact with other children, delaying immunizations, and giving medications including insulin) were rare. Mothers who engaged in diabetes prevention behaviors reported higher diabetes risk perception, greater anxiety, and more use of certain coping styles. Infants of these mothers were more likely to have a first-degree relative with diabetes. CONCLUSIONS—In the absence of known methods of preventing type 1 diabetes, most mothers of at-risk children report diabetes prevention behaviors. Such behaviors must be more carefully assessed to ensure accurate interpretation of data obtained from natural history studies and prevention trials.

Background Over the past decade, many immune tolerance agents have shown promise in the non-obese diabetic mouse model for prevention and reversal of type 1 diabetes but have not been successful in clinical trials among recently diagnosed type 1 patients. The trials from decades ago using Cyclosporine A in significantly lower dosages than used for organ transplantation and in similar dosages that have increased T regulatory cell populations in conditions such as atopic dermatitis, demonstrated very high initial insulin-free remission rates when administered immediately after diagnosis. Over time, all newly diagnosed type 1 patients given Cyclosporine A required insulin. Human trials with immune tolerance agents suggest that in addition to an immune tolerance agent, a beta cell regeneration agent may also be necessary to induce long-lasting remission among patients with recent onset type 1 diabetes. Methods A randomized, double-blind prospective trial among recent onset type 1 diabetes patients has been designed using Cyclosporine A and a proton-pump inhibitor, which increases gastrin levels and has been shown to work through the Reg receptor to transform pancreatic duct cells into islets. © 2013 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons, Ltd.