We used correlations of C-peptide secretion between follow-up time points (autocorrelation) of Ab+ relatives in the TrialNet Pathway to Prevention study to assess the loss of characteristic β-cell ...function during progression to T1D. Measures of β-cell function: AUC C-peptide; C-peptide Index (30-0 min C-peptide)/(30-0 min glucose); and Index60 (composite of glucose and C-peptide during first 60 minutes of OGTT) were assessed (table 1). Spearman correlations of AUC C-peptide from baseline to pre-diagnosis (6 months before) OGTTs of progressors (Pro; Age=8.7±3.6 yrs; n=182) were lower than correlations of AUC C-peptide from baseline to last OGTTs of non-progressors (NPro; Age=9.6±3.8 yrs; n=3,137; p<0.001 for all). Among Pro, correlations of AUC C-peptide from baseline to diagnosis OGTTs were considerably lower than correlations of AUC C-peptide from baseline to pre-diagnosis OGTTs (p=<0.001 for all). In conclusion, the lower C-peptide autocorrelation from baseline to last OGTTs of Pro compared to NPro indicates that β-cell function is already appreciably altered 6 months before diagnosis. Among Pro, the substantial decline of C-peptide autocorrelation from 6 months before diagnosis to diagnosis suggests a marked loss of β-cell function in that interval. Autocorrelation offers another approach for providing insight into β-cell compromise.
Disclosure
H.M.Ismail: Consultant; Rise Therapeutics. D.D.Cuthbertson: None. J.S.Skyler: Advisory Panel; Adocia, Altheia Sciences, Arecor, Avotres Inc., Bayer Inc., COUR Pharmaceuticals, Dance Biopharm/Aerami, Diasome, Enthera, Immnomolecular Therapeutics, Kriya Therapeutics, Oramed Pharmaceuticals, Orgenesis Inc., Precigen, Inc., ViaCyte, Inc., Board Member; Applied Therapeutics Inc., Dexcom, Inc., Consultant; Novo Nordisk, Sanofi, Signos, 4Immune, Other Relationship; Imcyse, Provention Bio, Inc. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. J.Sosenko: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK129799-01A1)
We studied 5-yr T1D risk associations using a series of risk factors in an autoantibody positive population of 6,020 in the TrialNet Pathway to Prevention study (PTP) study. We used data from 25 ...subgroups developed from 5 AUC glucose (<115;115-<130;130-<145;145-<160; ≥160 mg/dl) and 5 AUC C-peptide (<3.5;3.5-<5.0;5.0-<6.5;6.50-<8.0; ≥8.0 ng/ml) categories from baseline OGTT data. Subgroup boundaries were set to provide quantitative power for proper statistical analysis (range: 138 to 487) . We assessed 5-yr T1D risk associations with risk factors among the 25 subgroups using correlation coefficients and linear regression analysis (slope: 5-yr risk/risk factor prevalence) . The table shows the strongest correlation of 5-yr T1D risk with IA-2A (r=0.96) . This was consistent in split sample analyses, as were the linear regression indices (Sample 1 vs. Sample 2: r=0.96 vs. 0.93; intercept=-0.186 vs. -0.228; slope=0.014 vs. 0.015) . Using the regression indices for a cross-sample validation (i.e., predicting 5-yr risk for one sample using its IA-2A prevalence and the other sample's regression indices) , the predicted/actual 5-yr risk was 0.27/0.26 for Sample 1 and 0.27/0.23 for Sample 2.
In summary, in PTP subgroups, 5-yr T1D risk correlated strongly with IA-2A. Further, regression indices predicted 5-yr T1D risk in cross-sample validation, suggesting a tight linkage between active β-cell decline and IA-2A.
Disclosure
H.M.Ismail: n/a. D.D.Cuthbertson: None. M.A.Atkinson: None. M.J.Redondo: Advisory Panel; Provention Bio, Inc. J.Sosenko: None. Type 1 diabetes trialnet: n/a.
Funding
NIH
Among Ab+ individuals, reports suggest glucose is atypically associated with other T1D risk factors, such as a positive association with C-peptide. Using baseline OGTT data from 6,589 Ab+ TrialNet ...Pathway to Prevention participants, we hypothesized this finding is explained by a glucose fraction unrelated to insulin secretion. Index60 (fasting C-peptide, 60-min AUC glucose and C-peptide) was used as an insulin secretion proxy in regression AUC Glucose=131.0+(8.9*Index60) to quantify two AUC glucose fractions, each present to a degree in all individuals: one dependent on insulin secretion (DEP); the other independent (INDEP). DEP equaled predicted AUC glucose; INDEP equaled actual AUC glucose - predicted AUC glucose. The phenotype of the top DEP quartile was more typical for T1D than the top INDEP quartile (Table). INDEP correlated positively with AUC C-peptide r=0.54 (p<0.001), 29% of AUC C-peptide variance. With C-peptide index (30-0 min C-peptide) / (30-0 min glucose) as the insulin secretion proxy, findings were similar. In conclusion, Ab+ individuals with high proportions of INDEP have less typical features of T1D. The INDEP AUC glucose fraction’s positive correlation with AUC C-peptide, accounting for appreciable AUC C-peptide variance, suggests that INDEP is related to insulin resistance. Those with a higher proportion of INDEP may represent an atypical subset of the at-risk population.
Disclosure
J.Sosenko: None. D.D.Cuthbertson: None. M.J.Redondo: None. H.M.Ismail: Consultant; Rise Therapeutics. E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. L.M.Jacobsen: None. B.M.Nathan: None.
The value of a pre-diagnostic surrogate endpoint for T1D prevention trials is based on detection of efficacy and association with T1D. Thus, among multiple antibody+, dysglycemic individuals with ...baseline and 6-month OGTTs, we assessed metabolic endpoints for: 1) detecting a delay in metabolic decline from baseline to 6 months between placebo and teplizumab groups in the TrialNet teplizumab T1D prevention trial (TN 10), and 2) predicting T1D by metabolic change from baseline to 6 months in the TrialNet Pathway to Prevention study (TN01). The Table shows that the 6-month change in C-peptide (Cpep) measures (AUC and 30-0 minute) differed significantly between placebo and teplizumab groups, but not the change in glucose AUC. However, prediction of T1D, indicated by receiver operating curve AUC (ROCAUC), tended to be more accurate for 6-month change of glucose AUC than for Cpep changes. Although detection of a teplizumab effect by Cpep measures was comparable to that of combined measures (Index60 and Cpep AUC/glucose AUC), the latter were more accurate predictors. In conclusion, among metabolic endpoints there was discordance between detection of a teplizumab effect and prediction accuracy of T1D. However, such discordance suggests that metabolic endpoints provide more insight into understanding effects of teplizumab and other preventive treatments than the T1D endpoint alone.
To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasu's arteritis (TAK) and giant cell arteritis (GCA).
Patients were selected from two North ...American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification.
Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA.
Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.
Even after stratification based on established risk factors, the progression to T1D is variable. Thus, we aimed to examine differences in metabolic patterns of change between NP and P to T1D, and ...identify non-metabolic factors contributing to the differences. Specifically, we analyzed OGTT and autoantibody (Aab) data from children <18 yrs participating in Diabetes Prevention Trial-Type 1 (DPT-1) or TrialNet Pathway to Prevention (PTP) , with “baseline” DPT-1 Risk Scores (DPTRS) at initial testing in the abnormal range of 6.50 to <7.50. No difference in AUC ratio (AUC C-peptide/AUC glucose) was present between P (n=85) and NP (n=161) in DPT-1 or between P (n=171) and NP (n=332) in PTP at baseline. However, during follow-up we found that by the first 6-month OGTT the AUC ratio had diverged, with lower AUC ratio in P both in DPT-1 (p=0.05) and PTP (p<0.001) , adjusting for baseline age, BMI, DPTRS, and AUC ratio. Moreover, in yearly change from baseline to last OGTT (before diagnosis in P) , AUC ratio decreased in P (p<0.001) and increased in NP (p<0.01) in DPT-1 and PTP. In assessments of factors relating to this divergence we observed that despite their metabolic similarity, at baseline P had higher harmonized IA-2A Aab positivity (70.8 vs. 49.1%, p<0.001) and titers (median 194 vs. 3, p<0.001) in PTP (not harmonized in DPT-1) . Based on this, we compared P with NP for yearly changes in IA-2A from baseline to the last visit, with adjustment for baseline values. P had a greater increase in IA-2A titer over time (p=0.025) . Furthermore, T1D progression was associated with yearly increases in IA-2A titer (HR: 1.006, 95%CI: 1.003, 1.009; p<0.001) .
In conclusion, when NP and P have a similar degree of metabolic abnormality, IA-2A titers are greater in P. Moreover, as AUC ratio declines in P and improves in NP, IA-2A titers increase more in P than in NP. These findings suggest that IA-2A is a sensitive indicator of active β-cell pathology.
Disclosure
E.K.Sims: Other Relationship; Medscape, Patent. D.D.Cuthbertson: None. L.M.Jacobsen: None. H.M.Ismail: n/a. B.M.Nathan: None. M.J.Redondo: Advisory Panel; Provention Bio, Inc. J.Sosenko: None.
The ODI is a measure of β-cell function accounting for insulin sensitivity. ODI has primarily been studied in adults and shown to be inversely predictive of type 2 diabetes (T2D) ; however, little is ...known about ODI’s prediction of T1D. We thus used data from Ab+ Trialnet Pathway to Prevention (PTP) and Diabetes Prevention Trial Type 1 (DPT-1) cohorts (relatives of T1D patients) to study this. Data were analyzed from 33PTP participants: age (mean±SD) 15.8±12.1 yrs; BMI 21.1±13.1 kg/m2; 50.1% female, and 2from DPT-1: age 14.8±10.0 yrs; BMI 21.8±6.1 kg/m2; 51.2% female. Insulin measures at baseline included insulin sensitivity (1/Fasting Insulin) ; 1/FI) , β-cell function C-peptide index: (30 min C-pep-0 min C-pep) / (30 min glucose-0 min glucose) , and ODI (1/FI) x (C-peptide Index) . Spearman correlations of C-peptide Index vs. 1/FI were r=-0.47 (p<0.001) in PTP, and r=-0.22 (p=0.001) in DPT-1. The figure shows cumulative incidence curves according to ODI quartiles (Q) for progression to T1D in both PTP and DPT-1. The diagnosis of T1D was inversely related to ODI, with Q4 vs. Q1 hazard ratios and 95% CIs of 0.13 (0.10, 0.16) , p=0.006 for PTP and of 0.13 (0.06, 0.29) , p=0.002 for DPT-1.
In conclusion, ODI is inversely predictive of T1D among Ab+ individuals. Thus, as with predicting T2D, insulin sensitivity should be taken into account when β-cell function is used to predict T1D in Ab+ populations.
Disclosure
H.M.Ismail: n/a. D.D.Cuthbertson: None. M.J.Redondo: Advisory Panel; Provention Bio, Inc. L.M.Jacobsen: None. M.A.Atkinson: None. J.Sosenko: None. Diabetes prevention trial type 1: n/a. Type 1 diabetes trialnet: n/a.
Funding
NIH
Current T1D staging defines multiple Ab+ as the start of T1D (Stage 1 or 2 depending on presence of dysglycemia). However, single Ab+ individuals are considered low-risk and are typically not ...considered for inclusion in prevention trials. We hypothesized that single IA2A+ children exhibit metabolic compromise with appreciable Stage 3 (clinical diabetes) risk. To test this, we evaluated 2163 confirmed single Ab+ children (IA2A, glutamic acid decarboxylase GADA, or insulin IAA) with available OGTT data in the TrialNet natural history study. With and without age and BMI adjustment (Table), IA2A+ children had higher area under the curve (AUC) glucose, lower AUC C-peptide, and higher diabetes risk indices (Diabetes Prevention Trial Type 1 Risk Score DPTRS and Index60). Cox regression demonstrated that IA2A+ children were most likely to have progressed to Stage 3 (50.9% vs. 12.0% or 9.6% over 5 years). Of single Ab+ children who did not progress to Stage 3, GADA+ most frequently progressed to multiple Ab+ (34.0% over 5 years). In conclusion, amongst single Ab+ children, IA2A+ children have greater metabolic dysfunction and rates of progression to Stage 3. These findings suggest that single IA2A+ children exhibit substantial T1D risk, should also be considered as having Stage 1 T1D, and be considered for eligibility in prevention studies.
Disclosure
E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. D.D.Cuthbertson: None. E.Bosi: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. M.J.Redondo: None. B.M.Nathan: None. H.M.Ismail: Consultant; Rise Therapeutics. L.M.Jacobsen: None. J.Sosenko: None.
The current staging system for T1D development is used for participant selection in prevention trials. This system is based on multiple Ab+ and the presence or absence of dysglycemia, but does not ...address C-peptide measures or single Ab+ individuals. Since a limited number of Ab+ individuals are available for trials, we used TrialNet Pathway to Prevention (TNPTP) study data to assess whether a composite glucose and C-peptide measure, Index60, could identify single Ab+ individuals (designated as Stage 0) with comparable risk to those in Stages 1 or 2 for progression to Stage 3. Table 1A compares normoglycemic Stage 0 individuals with Index60 values above the median (>-0.045) of the full TNPTP cohort (n=6107) vs. those at Stage 1 with Index60 below the median (< -0.045). Table 1B compares those at Stage 0 with dysglycemia and higher Index60 vs. those at Stage 2 with lower Index60. In both comparisons, Index60 stratification identified Stage 0 individuals with metabolic features characteristic of T1D (e.g., lower C-peptide with higher glucose) and comparable 5-year risk to Stage 1 or Stage 2 individuals. Thus, by considering individuals with 1 Ab and C-peptide measures, the current staging system could be improved for risk discernment and to identify appropriate eligibility for prevention trials.
Disclosure
E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. D.D.Cuthbertson: None. E.Bosi: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. M.J.Redondo: None. B.M.Nathan: None. H.M.Ismail: Consultant; Rise Therapeutics. L.M.Jacobsen: None. J.Sosenko: None.
Aims/hypothesis
Our aim was to study the association between serum 25-hydroxyvitamin D (25OHD) concentration and islet autoimmunity and type 1 diabetes in children with an increased genetic risk of ...type 1 diabetes.
Methods
Serum samples for 25OHD measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children in 15 countries. Case children (
n
= 244) were defined as having positivity for at least two out of four diabetes-associated autoantibodies measured at any one sample. For each case child, two control children were selected matched for country and date of birth (±1 year) (
n
= 488). Of the case children, 144 developed type 1 diabetes. Serum 25OHD was measured repeatedly in infancy and childhood and was compared according to age at the first seroconversion (at 6, 12 and 18 months prior to and at seroconversion) and calendar age (0, 6, 12 and 18 months).
Results
In children with islet autoimmunity, mean serum 25OHD concentration was lower 18 months prior to the age of first seroconversion of the case children compared with the control children (57.7 vs 64.8 nmol/l,
p
= 0.007). In children with type 1 diabetes (
n
= 144), mean serum 25OHD concentration was lower 18 months prior to the age of the first seroconversion (58.0 vs 65.0 nmol/l,
p
= 0.018) and at the calendar age of 12 months (70.1 vs 75.9 nmol/l,
p
= 0.031) than in their control counterparts. Analyses were adjusted for month of sample collection, human leucocyte antigen genotype, maternal type 1 diabetes and sex.
Conclusions/interpretation
The results suggest that early postnatal vitamin D may confer protection against the development of type 1 diabetes.
Trial registration
ClinicalTrials.gov
NCT00179777
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