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OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were [...]

OBJECTIVE We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type I diabetes mellitus (T1DM) at 1 year. [...]

OBJECTIVE--We assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS--TrialNet Natural History Study participants [...]

OBJECTIVE--The aim of this study was to evaluate [HBA.sub.1c] as an alternative criterion for impaired glucose tolerance (IGT) or type 1 diabetes (T1D) in high-risk subjects RESEARCH DESIGN AND METHODS--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. [...]

OBJECTIVE--Previous studies have noted a specific association between type 1 diabetes and insufficient levels of vitamin D, as well as polymorphisms within genes related to vitamin D pathways. Here, we examined whether serum levels or genotypes of the vitamin D-binding protein (VDBP), a molecule key to the biologic actions of vitamin D, specifically associate with the disorder. RESEARCH DESIGN AND METHODS--A retrospective, cross-sectional analysis of VDBP levels used samples from 472 individuals of similar age and sex distribution, including 153 control subjects, 203 patients with type 1 diabetes, and 116 first-degree relatives of type 1 diabetic patients. Single nucleotide polymorphism (SNP) typing for VDBP polymorphisms (SNP rs4588 and rs7041) was performed on this cohort to determine potential genetic correlations. In addition, SNP analysis of a second sample set of banked DNA samples from 1,502 type 1 diabetic patients and 1,880 control subjects also was used to determine genotype frequencies. RESULTS--Serum VDBP levels were highest in healthy control subjects (median 423.5 [micro]g/mL [range 193.5-4,345.0; interquartile range 354.1-586]), intermediate in first-degree relatives (402.9 [micro]g/mL [204.7-4,850.0; 329.6-492.49, and lowest in type 1 diabetic patients (385.3 [micro]g/mL [99.3-1,305.0; 328.3-473.0]; P = 0.003 vs. control subjects). VDBP levels did not associate with serum vitamin D levels, age, or disease duration. However, VDBP levels were, overall, lower in male subjects (374.7 [micro]g/mL [188.9-1,602.0; 326.9449.9]) than female subjects (433.4 [micro]g/mL [99.3-4,850.0; 359.4567.8]; P < 0.0001). It is noteworthy that no differences in genotype frequencies of the VDBP polymorphisms were associated with serum VDBP levels or between type 1 diabetic patients and control subjects. CONCLUSIONS--Serum VDBP levels are decreased in those with type 1 diabetes. These studies suggest that multiple components in the metabolic pathway of vitamin D may be altered in type 1 diabetes and, collectively, have the potential to influence disease pathogenesls. Diabetes 60:2566-2570, 2011, Various pathways and characteristics of vitamin D metabolism, such as vitamin D analogs and olymorphisms in the vitamin D receptor, as well genes encoding specific vitamin D enzymes, recently have [...]

OBJECTIVE--Understanding the relationship between age and islet autoantibody (Ab) seroconversion can establish the optimal screening interval(s) to assess risk for type 1 diabetes, identify subjects who can participate in prevention trials, and determine associated costs. This study assessed the rates of seroconversion to glutamic acid decarboxylase positive ([GAD65.sup.+]), insulin positive ([mIAA.sup.+]), and insulinoma-associated protein 2 positive ([ICA512.sup.+]) in a large cohort of relatives of type 1 diabetes probands undergoing Ab rescreening in the TrialNet Natural History Study. RESEARCH DESIGN AND METHODS--Of 32,845 children aged RESULTS--There were 205 children who seroconverted to [GAD65.sup.+], 155 who seroconverted to [mIAA.sup.+], and 53 who seroconverted to [ICA512.sup.+] over 5.8 years of follow-up. The risk of mIAA (hazard ratio 0.89 [95% CI 0.85-0.92]) and GAD65 (0.96 [0.93-0.99]) seroconversion significantly decreased with increasing age (i.e., for each 1-year increase in age, the risk of seroconversion decreased by 11% [P < 0.0001] for mIAA and 4% [P = 0.04] for GAD65) across all ages. The cumulative Ab seroconversion was 2% for those CONCLUSIONS--The risk of development of islet Abs declines with increasing age in type 1 diabetes relatives. These data support annual screening for children, The incidence of type 1 diabetes varies by geography with 1 in 300 affected worldwide. Generally, pancreatic islet autoantibodies (Abs) precede type 1 diabetes and can identify those at increased [...]

OBJECTIVE--A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice--the prototypic model for human type 1 diabetes. RESEARCH DESIGN AND METHODS--Morning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6 to 14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests. RESULTS--During prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity. CONCLUSIONS--There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease. Diabetes 60:2086-2091, 2011, Type 1 diabetes is an autoimmune disease resulting from the destruction of pancreatic insulin-producing β-cells. The NOD mouse is the most commonly used rodent model of the disease. Studies in [...]

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 [...]

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 [...]

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 l diabetes. RESEARCH DESIGN AND METHODS--A [...]

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 [...]

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 [...]

Type 1 diabetes is by characterized the autoimmune destruction of β-cells, resulting in a loss of insulin production and glucose control (1,2). In both humans and the nonobese diabetic (NOD) [...], OBJECTIVE--The autoimmune destruction of β-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes. RESEARCH DESIGN AND METHODS--Effects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or β-cell area. RESULTS--Here, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic β-cell area, attenuation of pancreatic inflammation) benefits. CONCLUSIONS--In addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.

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.sup.+] [CD25.sup.+] 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., Type 1 diabetes is a disorder of insulin deficiency resulting from the autoimmune destruction of β-cells (1). Monoclonal antibodies directed against a variety of lymphocyte subsets or their products (e.g., [...]

OBJECTIVE--To assess participant and parent experiences in the parenteral insulin arm of the Diabetes Prevention Trial for Type 1 Diabetes (DPT-1). RESEARCH DESIGN AND METHODS--Before trial results were publicized, surveys [...]

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 α-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 CD[4.sup.+]CD[25.sup.+] T-cells were identified: CD[4.sup.+]CD[25.sup.+]FOXP[3.sup.+] as well us CD[4.sup.+]FOXP[3.sup.-] T-cells expressing low levels of CD25 (CD[4.sup.+]CD[25.sup.LOW]FOXP[3.sup.-]). In all study groups, the frequency of CD[4.sup.+]CD[25.sup.+]FOXP[3.sup.+] cells was age independent, whereas CD[4.sup.+]CD[25.sup.LOW]FOXP[3.sup.-] cell frequencies strongly associated with age. In terms of additional markers for delineating cells of Treg lineage, FOXP[3.sup.+] cells were CD[127.sup.-] to CD[127.sup.LOW] whereas CD[25.sup.+] 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 CD[4.sup.+]CD[25.sup.+]FOXP[3.sup.+] 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., Although it is widely believed that type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic β-cells (1), a major void exists in our understanding of the defects in [...]

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 (CFT[R.sup.-/-]), 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 CFT[R.sup.-/-] mice 4 weeks after STZ administration (288.4 ± 97.4, 168.4 ± 35.9, and 188.0 ± 42.3 mg/dl for CFT[R.sup.-/-], C57BL/ 6J, and FVB/NJ, respectively; P < 0.05). After intraperitoneal glucose administration, elevated blood glucose levels were also observed in STZ-administered CFT[R.sup.-/-] mice. STZ reduced islets among all strains; however, only CFT[R.sup.-/-] 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 CFT[R.sup.-/-] mice demonstrated similar fasting and stimulated glucose responses in comparison to nonseusitized animals. These studies suggest metabolic derangements in CFRD originate from an islet dysfunction inherent to the CFT[R.sup.-/-] state., Cystic fibrosis is a systemic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Some of the manifestations of this disease are caused by defective [...]

OBJECTIVE--This study describes maternal depression associated with newborn genetic screening for type 1 diabetes after risk notification. RESEARCH DESIGN AND METHODS--Mothers of at-risk infants (n = 192), identified through newborn [...]