New-onset Type 1 Diabetes Research Articles

Factors contributing to partial remission in type 1 diabetes: analysis based on the insulin dose-adjusted HbA1c in 3657 children and adolescents from Germany and Austria.

Insulin dose-adjusted hemoglobin A1c (HbA1C, IDAA1c) correlates well with stimulated C-peptide levels, but has not yet been evaluated in a large cohort of patients with Type 1 diabetes (T1D). We investigated prevalence of partial remission (PREM) defined by IDAA1c ≤9 in 3657 in children with new-onset T1D who were continuously followed over 6 years. We evaluated the predictors of PREM using the multicenter database from the DPV (Diabetes Patienten Verlaufsdokumentation) registry. PREM occurred in 71% of patients. Median duration was 9 (0-21) months. Compared to children <5 years at T1D onset, those aged 5-10 and ≥10 years had twice the chance of developing PREM (OR: 2.08, CI: 1.67-2.60; P < .001 and OR: 2.16, CI: 1.70-2.75; P < .001). Boys were more likely to develop PREM than girls (OR 1.41, CI: 1.18-1.69; P = .0002). Further predictors for PREM were: ketoacidosis, autoantibodies, and HbA1c at T1D onset. These results were confirmed by quantile regression analysis with duration of PREM as dependent variable. This research on a large cohort provides insight into epidemiologic characteristics of PREM in T1D defined by IDAA1c. As IDAA1c does not discriminate between insulin sensitivity and secretion, available data cannot resolve whether the sex-difference in PREM reflects innate higher insulin resistance in girls, or better beta-cell recovery in boys. Further research is needed to clarify the usefulness and performance of IDAA1c in clinical practice.

PETS-D (parents education through simulation-diabetes): Parents’ qualitative results

ObjectiveParents who have a child newly diagnosed with type 1 diabetes (T1D) must quickly learn daily diabetes self-management. An RCT was conducted using human patient simulation (HPS) to enhance parents learning diabetes self-management with children with new-onset T1D. The purpose of this study was to describe parents’ perspectives of using HPS to augment diabetes education. MethodsA qualitative descriptive design was used with open-ended in-depth interviews of parents (n=49) post-intervention. Qualitative directed content analysis was used. ResultsThe majority of parents were positive about learning with HPS. Although a few parents said the HPS was “hokey” or “creepy,” most reported the visual and hands-on learning was realistic and very beneficial. Seeing a seizure increased their fear although they would have panicked if they had not had that learning experience, and it helped build their diabetes self-management confidence. Recommendations included teaching others with the HPS (grandparents, siblings, babysitters, and school nurses). ConclusionHPS-enhanced education is an acceptable and viable option that was generally well-received by parents of children with new-onset T1D. Practice implicationsThe technique should be studied with parents of children with other chronic illnesses to see if the benefits found in this study are applicable to other settings.

A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes.

Type 1 diabetes (T1D) is caused by immune-mediated destruction of insulin-producing β-cells. Insufficient control of autoreactive T cells by regulatory T cells (Tregs) is believed to contribute to disease pathogenesis, but changes in Treg function are difficult to quantify because of the lack of Treg-exclusive markers in humans and the complexity of functional experiments. We established a new way to track Tregs by using a gene signature that discriminates between Tregs and conventional T cells regardless of their activation states. The resulting 31-gene panel was validated with the NanoString nCounter platform and then measured in sorted CD4(+)CD25(hi)CD127(lo) Tregs from children with T1D and age-matched control subjects. By using biomarker discovery analysis, we found that expression of a combination of six genes, including TNFRSF1B (CD120b) and FOXP3, was significantly different between Tregs from subjects with new-onset T1D and control subjects, resulting in a sensitive (mean ± SD 0.86 ± 0.14) and specific (0.78 ± 0.18) biomarker algorithm. Thus, although the proportion of Tregs in peripheral blood is similar between children with T1D and control subjects, significant changes in gene expression can be detected early in disease process. These findings provide new insight into the mechanisms underlying the failure to control autoimmunity in T1D and might lead to a biomarker test to monitor Tregs throughout disease progression.

Immune interventions to preserve β cell function in type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to destruction of pancreatic β cells, lifelong dependence on insulin, and increased morbidity and mortality from diabetes-related complications. Preservation...

Immunoproteomic Profiling of Antiviral Antibodies in New-Onset Type 1 Diabetes Using Protein Arrays.

The rapid rise in the incidence of type 1 diabetes (T1D) suggests the involvement of environmental factors including viral infections. We evaluated the association between viral infections and T1D by profiling antiviral antibodies using a high-throughput immunoproteomics approach in patients with new-onset T1D. We constructed a viral protein array comprising the complete proteomes of seven viruses associated with T1D and open reading frames from other common viruses. Antibody responses to 646 viral antigens were assessed in 42 patients with T1D and 42 age- and sex-matched healthy control subjects (mean age 12.7 years, 50% males). Prevalence of antiviral antibodies agreed with known infection rates for the corresponding virus based on epidemiological studies. Antibody responses to Epstein-Barr virus (EBV) were significantly higher in case than control subjects (odds ratio 6.6; 95% CI 2.0–25.7), whereas the other viruses showed no differences. The EBV and T1D association was significant in both sex and age subgroups (≤12 and >12 years), and there was a trend toward early EBV infections among the case subjects. These results suggest a potential role for EBV in T1D development. We believe our innovative immunoproteomics platform is useful for understanding the role of viral infections in T1D and other disorders where associations between viral infection and disease are unclear.

Screening for T1D risk to reduce DKA is not economically viable.

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.

Targeting memory T cells in type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents. Persistence of autoreactive memory T cells likely contributes to the difficulty in preventing disease progression in new-onset T1D and maintaining allogeneic islet transplants by regular immunosuppressive regimens. The majority of immune interventions that have demonstrated some success in preserving beta cell function in the new-onset period have been shown to deplete or modulate memory T cells. Based on these and other considerations, preservation of residual beta cells early after diagnosis or restoration of beta cell mass by use of stem cell or transplantation technology will require a successful strategy to control the autoreactive memory T cell compartment, which could include depletion, inhibition of homeostatic cytokines, induction of hyporesponsiveness, or a combination of these approaches.

Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes.

Rapid evaluation of therapies designed to preserve β cells in persons with type 1 diabetes (T1D) is hampered by limited availability of sensitive β-cell health biomarkers. In particular, biomarkers elucidating the presence and degree of β-cell stress are needed. We characterized β-cell secretory activity and stress in 29 new-onset T1D subjects (10.6±3.0years, 55% male) at diagnosis and then 8.2±1.2weeks later at first clinic follow-up. We did comparisons with 16 matched healthy controls. We evaluated hemoglobin A1c (HbA1c), β-cell function (random C-peptide [C] and proinsulin [PI]), β-cell stress (PI:C ratio), and the β-cell stress marker heat shock protein (HSP)90 and examined these parameters' relationships with clinical and laboratory characteristics at diagnosis. Mean diagnosis HbA1c was 11.3% (100mmol/mol) and 7.6% (60mmol/mol) at follow-up. C-peptide was low at diagnosis (P<0.001 vs controls) and increased at follow-up (P<0.001) to comparable with controls. PI did not differ from controls at diagnosis but increased at follow-up (P=0.003) signifying increased release of PI alongside improved insulin secretion. PI:C ratios and HSP90 concentrations were elevated at both time points. Younger subjects had lower C-peptide and greater PI, PI:C, and HSP90. We also examined islets isolated from prediabetic nonobese diabetic mice and found that HSP90 levels were increased ∼4-fold compared with those in islets isolated from matched CD1 controls, further substantiating HSP90 as a marker of β-cell stress in T1D. Our data indicate that β-cell stress can be assessed using PI:C and HSP90. This stress persists after T1D diagnosis. Therapeutic approaches to reduce β-cell stress in new-onset T1D should be considered.

2. Durable Efficacy of Alefacept in New-Onset Type 1 Diabetes: Evidence for Lasting Modulation of Effector and Regulatory T Cells (231-OR)

Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by autoreactive effector T cells. We hypothesized that a combination of targeted depletion and modulation of effector T cell activity by alefacept would result in prolonged preservation of endogenous insulin secretion in patients with newly diagnosed T1D. In a multicenter, randomized, double-blind, placebo-controlled trial we compared alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) with placebo in patients with new-onset T1D. Endpoints assessed at 24 months included meal-stimulated C-peptide area under the curve (AUC), insulin use, hypoglycemic events, and immunologic responses.

Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus — A randomized clinical trial

It is unknown if cholecalciferol is able to modify defects in regulatory T cells (Tregs) in type 1 diabetes (T1D). In this randomized, double-blind, placebo controlled trial 30 young patients with new-onset T1D were assigned to cholecalciferol (70IU/kgbodyweight/day) or placebo for 12months. Tregs were determined by FACS-analysis and functional tests were assessed with ex vivo suppression co-cultures at months 0, 3, 6 and 12. Suppressive capacity of Tregs increased (p<0.001) with cholecalciferol from baseline (−1.59±25.6%) to 3 (30.5±39.4%), 6 (44.6±23.8%) and 12months (37.2±25.0%) and change of suppression capacity from baseline to 12months was significantly higher (p<0.05) with cholecalciferol (22.2±47.2%) than placebo (−16.6±21.1%). Serum calcium and parathormone stayed within normal range.This is the first study, which showed that cholecalciferol improved suppressor function of Tregs in patients with T1D and vitamin D could serve as one possible agent in the development of immunomodulatory combination therapies for T1D.

Elevations in Circulating Methylated and Unmethylated Preproinsulin DNA in New-Onset Type 1 Diabetes.

Elevated ratios of circulating unmethylated to methylated preproinsulin (INS) DNA have been suggested to reflect β-cell death in type 1 diabetes (T1D). We tested the hypothesis that absolute levels (rather than ratios) of unmethylated and methylated INS DNA differ between subjects with new-onset T1D and control subjects and assessed longitudinal changes in these parameters. We used droplet digital PCR to measure levels of unmethylated and methylated INS DNA in serum from subjects at T1D onset and at 8 weeks and 1 year post-onset. Compared with control subjects, levels of both unmethylated and methylated INS DNA were elevated at T1D onset. At 8 weeks post-onset, methylated INS DNA remained elevated, but unmethylated INS DNA fell. At 1 year postonset, both unmethylated and methylated INS DNA returned to control levels. Subjects with obesity, type 2 diabetes, and autoimmune hepatitis exhibited lower levels of unmethylated and methylated INS compared with subjects with T1D at onset and no differences compared with control subjects. Our study shows that elevations in both unmethylated and methylated INS DNA occurs in new-onset T1D and that levels of these DNA species change during T1D evolution. Our work emphasizes the need to consider absolute levels of differentially methylated DNA species as potential biomarkers of disease.

Reversal of New-Onset Type 1 Diabetes With an Agonistic TLR4/MD-2 Monoclonal Antibody

Type 1 diabetes (T1D) is currently an incurable disease, characterized by a silent prodromal phase followed by an acute clinical phase, reflecting progressive autoimmune destruction of insulin-producing pancreatic β-cells. Autoreactive T cells play a major role in β-cell destruction, but innate immune cell cytokines and costimulatory molecules critically affect T-cell functional status. We show that an agonistic monoclonal antibody to TLR4/MD-2 (TLR4-Ab) reverses new-onset diabetes in a high percentage of NOD mice. TLR4-Ab induces antigen-presenting cell (APC) tolerance in vitro and in vivo, resulting in an altered cytokine profile, decreased costimulatory molecule expression, and decreased T-cell proliferation in APC:T-cell assays. TLR4-Ab treatment increases T-regulatory cell (Treg) numbers in both the periphery and the pancreatic islet, predominantly expanding the Helios(+)Nrp-1(+)Foxp3(+) Treg subset. TLR4-Ab treatment in the absence of B cells in NOD.scid mice prevents subsequent T cell-mediated disease, further suggesting a major role for APC tolerization in disease protection. Specific stimulation of the innate immune system through TLR4/MD-2, therefore, can restore tolerance in the aberrant adaptive immune system and reverse new-onset T1D, suggesting a novel immunological approach to treatment of T1D in humans.

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA(g7), in an unfavorable position or register. Because of the similarities between IA(g7) and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset.

Proinsulin and MAP3865c homologous epitopes are a target of antibody response in new-onset type 1 diabetes children from continental Italy.

Mycobacterium avium subspecies paratuberculosis (MAP) asymptomatic infection is speculated to play a role in type 1 diabetes (T1D) among Sardinian subjects. Data obtained analyzing a pediatric population from mainland Italy lends support to the hypothesis, which envisions MAP as an environmental factor at play in T1D pathogenesis. Aiming to investigate the likelihood of cross-recognition between linear determinants shared by self (proinsulin) and non-self (MAP) proteins, 59 children with new onset T1D and 60 healthy controls (HCs) from continental Italy were enrolled in the study. Serum samples were subjected to indirect enzyme-linked immunosorbent assay (ELISA) for the presence of antibodies (Abs) toward four homologues MAP/proinsulin epitopes. The rate of MAP infection (42.4% in T1D children and 5% in HCs; p < 0.0001) was estimated searching for Abs against MAP specific protein MptD. The homologous MAP2404c70-85 and proinsulin (PI)46-61 peptides were recognized by 42.4 and 39% of new-onset T1D children and only in 5% of HCs (AUC = 0.76, AUC = 0.7, p < 0.0001); whereas the prevalence of Abs against MAP 1,4-α-gbp157-173 and PI64-80 peptides was 45.7 and 49.1% in new-onset T1D children, respectively, compared with 3.3% of HCs (AUC = 0.74 and p < 0.0001 in both). Pre-incubation of MAP Ab-positive sera with proinsulin peptides was able to block the binding to the correspondent MAP epitopes, thus showing that Abs against these homologous peptides are cross-reactive. MAP/Proinsulin Ab mediated cross-recognition, most likely via molecular mimicry, maybe a factor in accelerating and/or initiating T1D in MAP-infected children. Indeed, it is known that anti-proinsulin and anti-Insulin autoantibodies are the earliest to appear.

Loss of anergic B cells in prediabetic and new-onset type 1 diabetic patients.

Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen–reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD+, IgM− B-cell (BND) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire BND compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles.

Posttranslational Modification of HLA-DQ Binding Islet Autoantigens in Type 1 Diabetes

Posttranslational modification (PTM) of islet autoantigens can cause lack of central tolerance in type 1 diabetes (T1D). Tissue transglutaminase (tTG), involved in PTM of gluten antigens in celiac disease, creates negatively charged peptides favored by T1D-predisposing HLA-DQ molecules, offering an attractive candidate modifying islet autoantigens in T1D. The highly predisposing HLA-DQ8cis/trans molecules share preferences for negatively charged peptides, as well as distinct peptide-binding characteristics that distinguish their peptide-binding repertoire. We screened islet autoantigens with the tTG substrate motif for candidate-modified epitopes binding to HLA-DQ8cis/trans and identified 31 candidate islet epitopes. Deamidation was confirmed for 28 peptides (90%). Two of these epitopes preferentially bound to HLA-DQ8cis and six to HLA-DQ8trans upon deamidation, whereas all other peptides bound equally to HLA-DQ8cis/trans. HLA-DQ8cis-restricted T cells from a new-onset T1D patient could only be generated against a deamidated proinsulin peptide, but cross-reacted with native proinsulin peptide upon restimulation. The rate of T-cell autoreactivity in recent-onset T1D patients extended from 42% to native insulin to 68% adding responses to modified proinsulin, versus 20% and 37% respectively, in healthy donors. Most patients responded by interferon-γ, whereas most healthy donors produced interleukin-10 only. Thus, T-cell autoreactivity exists to modified islet epitopes that differs in quality and quantity between patients and healthy donors.

Efficacy and safety of low‐dose otelixizumab anti‐CD3 monoclonal antibody in preserving C‐peptide secretion in adolescent type 1 diabetes: DEFEND‐2, a randomized, placebo‐controlled, double‐blind, multi‐centre study

PhaseIII DEFEND-2 investigated whether otelixizumab (3.1mg over 8days) preserved C-peptide secretion in patients with new-onset Type1 diabetes, focusing on adolescents (12-17years). One hundred and seventy-nine patients (54 adolescents) were randomized to otelixizumab or placebo. The primary endpoint was change in 2-h mixed-meal-stimulated C-peptide area under the curve at month12. Enrolment was suspended in April 2011 following negative efficacy results from DEFEND-1. DEFEND-2 terminated early after 12months' efficacy and safety follow-up. Change from baseline C-peptide was not significantly different [∆=-0.09nmol/l (95%CI -0.17 to 0; P=0.051)]. No differential C-peptide effect was seen for otelixizumab in adolescents and more adverse events were reported. Efficacy and tolerability of otelixizumab was similar to DEFEND-1. The 3.1-mg dose was non-efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required. Clinical Trials Registry No: NCT00763451.

Teplizumab (Anti-CD3 mAb) Treatment Preserves C-Peptide Responses in Patients With New-Onset Type 1 Diabetes in a Randomized Controlled Trial

Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses of teplizumab, an Fc receptor–nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean −0.28 nmol/L [95% CI −0.36 to −0.20]) versus control (mean −0.46 nmol/L [95% CI −0.57 to −0.35]; P = 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA1c and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy.

Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes

Type 1 diabetes (T1D) patients have numeral and functional defects in peripheral immune cells, but the pre-diabetic period is fairly uncharacterized. Our aim was to analyze expression of immunological markers in T1D high risk children and relate it to clinical/immunological parameters. Children from ABIS (All Babies in Southeast Sweden) with ≥2 diabetes related autoantibodies were considered at high risk. Age-matched controls and new-onset T1D patients were included. Expression of genes related to immune cell function and different arms of the immune system was assessed in peripheral blood mononuclear cells using PCR array. Risk children had lower TNF and CD45, and although there were few differences between the groups, expression of many genes differed when comparing children with regard to residual insulin secretion. Hence, expression of immune related genes seemed related not only to the autoimmune process but rather to residual β-cell function, which was decreased already during the pre-diabetic phase.

Effect of Calcitriol on Bone Turnover and Osteocalcin in Recent-Onset Type 1 Diabetes

BackgroundVitamin D supplementation in childhood improves the achievement of peak bone mass. We investigated the effect of supplementation with calcitriol on bone turnover in recent-onset type 1 diabetes (T1D). Moreover, the association between osteocalcin and parameters of β-cell function and metabolic control was examined.Methodology/Principal FindingsWe conducted a post-hoc analysis of a double-blind, placebo-controlled study of calcitriol supplementation to preserve β-cell function. 27 recent-onset T1D subjects, mean age 22 years, were randomized to 0.25 µg calcitriol per day or placebo (1∶1) and followed up for one year. Changes in bone formation (osteoclacin) and resorption (beta-CrossLaps) markers, and differences between placebo and calcitriol-treated group were evaluated. At baseline, osteocalcin levels were significantly lower in female than in male patients (P<0.01) while no other metabolic parameters as HbA1c and C-peptide differed between gender. No significant correlations were found in relation to HbA1c, insulin requirement and C-peptide. At 1 year follow-up, no significant differences were observed between calcitriol and placebo groups for osteocalcin and β-CrossLaps. In the placebo group osteocalcin levels were unrelated with parameters of metabolic control, such as C-peptide, insulin requirement or HbA1c. Changes of C-peptide, insulin requirement and HbA1c were not related to osteocalcin levels.ConclusionsSupplementation with 0.25 µg calcitriol per day to patients with new-onset T1D does not affect circulating markers of bone turnover. OC levels were unrelated to β-cell function and other metabolic parameters suggesting that OC is ineffective to control pancreatic function in presence of aggressive autoimmune destruction.