Diabetes Prevention Trial-Type Research Articles

OGTT Metrics Surpass Continuous Glucose Monitoring Data for T1D Prediction in Multiple-Autoantibody-Positive Individuals.

The value of continuous glucose monitoring (CGM) for monitoring autoantibody (AAB)-positive individuals in clinical trials for progression of type 1 diabetes (T1D) is unknown. Compare CGM with oral glucose tolerance test (OGTT)-based metrics in prediction of T1D. At academic centers, OGTT and CGM data from multiple-AAB relatives were evaluated for associations with T1D diagnosis. Participants were multiple-AAB-positive individuals in a TrialNet Pathway to Prevention (TN01) CGM ancillary study (n = 93). The intervention was CGM for 1 week at baseline, 6 months, and 12 months. Receiver operating characteristic (ROC) curves of CGM and OGTT metrics for prediction of T1D were analyzed. Five of 7 OGTT metrics and 29/48 CGM metrics but not HbA1c differed between those who subsequently did or did not develop T1D. ROC area under the curve (AUC) of individual CGM values ranged from 50% to 69% and increased when adjusted for age and AABs. However, the highest-ranking metrics were derived from OGTT: 4/7 with AUC ∼80%. Compared with adjusted multivariable models using CGM data, OGTT-derived variables, Index60 and DPTRS (Diabetes Prevention Trial-Type 1 Risk Score), had higher discriminative ability (higher ROC AUC and positive predictive value with similar negative predictive value). Every 6-month CGM measures in multiple-AAB-positive individuals are predictive of subsequent T1D, but less so than OGTT-derived variables. CGM may have feasibility advantages and be useful in some settings. However, our data suggest there is insufficient evidence to replace OGTT measures with CGM in the context of clinical trials.

1440-P: Single Islet Antigen 2 Antibody–Positive (IA2A Ab+) Children Exhibit Significant Metabolic Abnormalities and 5-Year Type 1 Diabetes (T1D) Risk

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 effect of age on longitudinal measures of beta cell function and insulin sensitivity during the progression of early stage type 1 diabetes

Aim/hypothesisThe risk of progressing from autoantibody positivity to type 1 diabetes is inversely related to age. Separately, whether age influences patterns of C-peptide loss or changes in insulin sensitivity in autoantibody-positive individuals who progress to stage 3 type 1 diabetes is unclear.MethodsBeta cell function and insulin sensitivity were determined by modelling of OGTTs performed in 658 autoantibody-positive participants followed longitudinally in the Diabetes Prevention Trial–Type 1 (DPT-1). In this secondary analysis of DPT-1 data, time trajectories of beta cell function and insulin sensitivity were analysed in participants who progressed to type 1 diabetes (progressors) to address the impact of age on patterns of metabolic progression to diabetes.ResultsAmong the entire DPT-1 cohort, the highest discriminant age for type 1 diabetes risk was 14 years, with participants aged <14 years being twice as likely to progress to type 1 diabetes as those aged ≥14 years. At study entry, beta cell glucose sensitivity was impaired to a similar extent in progressors aged <14 years and progressors aged ≥14 years. From study entry to stage 3 type 1 diabetes onset, beta cell glucose sensitivity and insulin sensitivity declined in both progressor groups. However, there were no significant differences in the yearly rate of decline in either glucose sensitivity (−13.7 [21.2] vs −11.9 [21.5] pmol min−1 m−2 [mmol/l]−1, median [IQR], p=0.52) or insulin sensitivity (−22 [37] vs −14 [40] ml min−1 m−2, median [IQR], p=0.07) between progressors aged <14 years and progressors aged ≥14 years.Conclusions/interpretationOur data indicate that during progression to stage 3 type 1 diabetes, rates of change in declining glucose and insulin sensitivity are not significantly different between progressors aged <14 years and progressors aged ≥14 years. These data suggest there is a predictable course of declining metabolic function during the progression to type 1 diabetes that is not influenced by age.Graphical abstract

Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening.

We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk. Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial-Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5-7.5), as well as in TNPTP Ab- children (n = 94). Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide-to-AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab- relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001). Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab- relatives, suggesting persistent β-cell responsiveness in nonprogressors.

The Transition From a Compensatory Increase to a Decrease in C-peptide During the Progression to Type 1 Diabetes and Its Relation to Risk.

To define the relationship between glucose and C-peptide during the progression to type 1 diabetes (T1D). We longitudinally studied glucose and C-peptide response curves (GCRCs), area under curve (AUC) for glucose, and AUC C-peptide from oral glucose tolerance tests (OGTTs), and Index60 (which integrates OGTT glucose and C-peptide values) in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 72) and TrialNet Pathway to Prevention Study (TNPTP) (n = 82) participants who had OGTTs at baseline and follow-up time points before diagnosis. Similar evolutions of GCRC configurations were evident between DPT-1 and TNPTP from baseline to 0.5 years prediagnosis. Whereas AUC glucose increased throughout from baseline to 0.5 years prediagnosis, AUC C-peptide increased from baseline until 1.5 years prediagnosis (DPT-1, P = 0.004; TNPTP, P = 0.012) and then decreased from 1.5 to 0.5 years prediagnosis (DPT-1, P = 0.017; TNPTP, P = 0.093). This change was mostly attributable to change in the late AUC C-peptide response (i.e., 60- to 120-min AUC C-peptide). Median Index60 values of DPT-1 (1.44) and TNPTP (1.05) progressors to T1D 1.5 years prediagnosis (time of transition from increasing to decreasing AUC C-peptide) were used as thresholds to identify individuals at high risk for T1D in the full cohort at baseline (5-year risk of 0.75-0.88 for those above thresholds). A transition from an increase to a decrease in AUC C-peptide ∼1.5 years prediagnosis was validated in two independent cohorts. The median Index60 value at that time point can be used as a pathophysiologic-based threshold for identifying individuals at high risk for T1D.

350-OR: The Oral Disposition Index (ODI) Predicts Type 1 Diabetes (T1D) in Autoantibody-Positive (Ab+) Individuals

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&amp;lt;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

1255-P: IA-2A Autoantibody Titers Predict Subsequent Divergence between Nonprogressors (NP) and Progressors (P) to Type 1 Diabetes with Similar Degree of Initial Metabolic Abnormality

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 &amp;lt;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 &amp;lt;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&amp;lt;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&amp;lt;0.001) and increased in NP (p&amp;lt;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&amp;lt;0.001) and titers (median 194 vs. 3, p&amp;lt;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&amp;lt;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.

Association of HLA-DQ Heterodimer Residues -18β and β57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial-Type 1.

OBJECTIVEThe purpose was to test the hypothesis that the HLA-DQαβ heterodimer structure is related to the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D).RESEARCH DESIGN AND METHODSNext-generation targeted sequencing was used to genotype HLA-DQA1-B1 class II genes in 670 subjects in the Diabetes Prevention Trial–Type 1 (DPT-1). Coding sequences were translated into DQ α- and β-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset.RESULTSThe opposite diabetes risks were confirmed for HLA DQA1*03:01-B1*03:02 (hazard ratio [HR] 1.36; P = 2.01 ∗ 10−3) and DQA1*03:03-B1*03:01 (HR 0.62; P = 0.037). The HOH analysis uncovered residue −18β in the signal peptide and β57 in the β-chain to form six motifs. DQ*VA was associated with faster (HR 1.49; P = 6.36 ∗ 10−4) and DQ*AD with slower (HR 0.64; P = 0.020) progression to diabetes onset. VA/VA, representing DQA1*03:01-B1*03:02 (DQ8/8), had a greater HR of 1.98 (P = 2.80 ∗ 10−3). The DQ*VA motif was associated with both islet cell antibodies (P = 0.023) and insulin autoantibodies (IAAs) (P = 3.34 ∗ 10−3), while the DQ*AD motif was associated with a decreased IAA frequency (P = 0.015). Subjects with DQ*VA and DQ*AD experienced, respectively, increasing and decreasing trends of HbA1c levels throughout the follow-up.CONCLUSIONSHLA-DQ structural motifs appear to modulate progression from islet autoimmunity to diabetes among at-risk relatives with islet autoantibodies. Residue −18β within the signal peptide may be related to levels of protein synthesis and β57 to stability of the peptide-DQab trimolecular complex.

Oral Glucose Tolerance Test Measures of First-phase Insulin Response and Their Predictive Ability for Type 1 Diabetes.

Decreased first-phase insulin response (FPIR) during intravenous glucose tolerance testing (IVGTT) is an early indicator of β-cell dysfunction and predictor of type 1 diabetes (T1D). Assess whether oral glucose tolerance test (OGTT) measures could serve as FPIR alternatives in their ability to predict T1D in autoantibody positive (Aab+) subjects. OGTT and IVGTT were performed within 30 days of each other. Eleven OGTT variables were evaluated for (1) correlation with FPIR and (2) T1D prediction. Type 1 Diabetes TrialNet "Oral Insulin for Prevention of Diabetes in Relatives at Risk for T1D" (TN-07) and Diabetes Prevention Trial-Type 1 Diabetes (DPT-1) studies clinical sites. TN-07 (n = 292; age 9.4 ± 6.1 years) and DPT-1 (n = 194; age 15.1 ± 10.0 years) Aab + relatives of T1D individuals. (1) Correlation coefficients of OGTT measures with FPIR and (2) T1D prediction at 2 years using area under receiver operating characteristic (ROCAUC) curves. Index60 showed the strongest correlation in DPT-1 (r = -0.562) but was weaker in TN-07 (r = -0.378). C-peptide index consistently showed good correlation with FPIR across studies (TN-07, r = 0.583; DPT-1, r = 0.544; P < 0.0001). Index60 and C-peptide index had the highest ROCAUCs for T1D prediction (0.778 vs 0.717 in TN-07 and 0.763 vs 0.721 in DPT-1, respectively; P = NS), followed by FPIR (0.707 in TN-07; 0.628 in DPT-1). C-peptide index was the strongest measure to correlate with FPIR in both studies. Index60 and C-peptide index had the highest predictive accuracy for T1D and were comparable. OGTTs could be considered instead of IVGTTs for subject stratification in T1D prevention trials.

Insulin immunotherapy for pretype 1 diabetes.

Loss of tolerance to insulin likely contributes to the immunopathogenesis of type 1 diabetes (T1D). Several large clinical trials and smaller mechanistic studies have failed to demonstrate the efficacy of insulin antigen therapy. The growing awareness of the heterogeneity of T1D likely affects the response to various immune therapies including insulin. Identification of biomarkers of clinical response will provide further insight into mechanisms leading to the disease and classify responders in the quest for personalized therapy. Several biomarkers have identified subpopulations in posthoc analyses that showed benefit from oral insulin even though the placebo-controlled study was as a whole unsuccessful. High insulin autoantibody titer, low first phase insulin response, and high Diabetes Prevention Trial-Type 1 Risk Score identify at-risk relatives more likely to benefit from oral insulin. Future incorporation of human leukocyte antigen and the variable number of tandem repeats polymorphism located in the insulin gene promoter (INS VNTR) is of interest for both primary and secondary prevention studies. Although primary and secondary prevention trials using oral insulin are ongoing, those completed have been largely unsuccessful. However, we believe that oral insulin should be considered in future trials as part of combination therapies as prerandomization biomarker testing is refined.

One-Hour Oral Glucose Tolerance Tests for the Prediction and Diagnostic Surveillance of Type 1 Diabetes.

Once islet autoantibody-positive individuals are identified, predicting which individuals are at highest risk for type 1 diabetes (T1D) is important. A metabolic risk score derived from 2-hour oral glucose tolerance test (OGTT) data, the Diabetes Prevention Trial-Type 1 risk score (DPTRS), can accurately predict T1D. However, 2-hour OGTTs are time-consuming and costly. We aimed to determine whether a risk score derived from 1-hour OGTT data can predict T1D as accurately as the DPTRS. Secondarily, we evaluated whether a 1-hour glucose value can be used for diagnostic surveillance. The DPTRS was modified to derive a 1-hour OGTT risk score (DPTRS60) using fasting C-peptide, 1-hour glucose and C-peptide, age, and body mass index. Areas under receiver operating curves (ROCAUCs) were used to compare prediction accuracies of DPTRS60 with DPTRS in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 654) and TrialNet Pathway to Prevention (TNPTP) (n = 4610) participants. Negative predictive values (NPV) for T1D diagnosis were derived for 1-hour glucose thresholds. ROCAUCs for T1D prediction 5 years from baseline were similar between DPTRS60 and DPTRS (DPT-1: 0.805 and 0.794; TNPTP: 0.832 and 0.847, respectively). DPTRS60 predicted T1D significantly better than 2-hour glucose (P < .001 in both cohorts). A 1-hour glucose of less than 180 mg/dL had a similar NPV, positive predictive value, and specificity for T1D development before the next 6-month visit as the standard 2-hour threshold of less than 140 mg/dL (both ≥ 98.5%). A 1-hour OGTT can predict T1D as accurately as a 2-hour OGTT with minimal risk of missing a T1D diagnosis before the next visit.

344-OR: Slowed Metabolic Decline after Oral Insulin (OI) in Relatives at High Risk for Type 1 Diabetes (T1D)

We assessed whether OI slowed metabolic decline after 1 yr of treatment among highest risk relatives who participated in the Diabetes Prevention Trial-Type 1 (DPT1) and TrialNet (TN) T1D prevention trials for OI. As published, with a diagnosis of T1D as the endpoint, both OI trials (7.5 mg/day) were negative overall. However, subgroup analyses suggested efficacy for those at high risk in each trial (DPT1: higher titer of insulin autoantibodies; TN: lower first-phase insulin response). Thus, we assessed whether OI slowed metabolic decline among the OI trial participants at highest risk, defined by DPT1 Risk Scores over a 6.75 threshold (DPTRS; OGTT C-peptide and glucose, age, and BMI), above which T1D risk increases sharply as DPTRS increases. Of 73% in DPT1 and 89% in TN with 1 yr OGTTs, 32% in DPT1 (90/282; age: 8.7±4.8 yrs) and 35% in TN (118/340; age: 6.9±3.3 yrs) were in the highest risk groups (3 yr risks: 56% in DPT-1; 55% in TN). In the analysis, area under curve (AUC) C-peptide increased from baseline to 1 yr in both OI groups (DPT1: p&amp;lt;0.01; TN: p&amp;lt;0.05) but not in the placebo groups, while AUC glucose increased more in the placebo groups (DPT1: p&amp;lt;0.01; TN: p&amp;lt;0.01) than in the OI groups (DPT1: p&amp;lt;0.05; TN: n.s.). Consistent with those changes, in both trials the 1 yr AUC C-peptide/AUC glucose ratio (x100; AUC ratio) was greater in the OI group than in the placebo group [DPT1: 2.86±1.06 vs. 2.42±1.03 (ng/ml)/(mg/dl); TN: 3.06±1.13 vs. 2.57±0.96 (ng/ml)/(mg/dl); p-value&amp;lt;0.05 for each (baseline adjusted)]. For DPT1 and TN combined (no interaction for treatment between trials), the p-value for the AUC ratio difference was &amp;lt;0.001. Of those with DPTRS &amp;lt;6.75 (3 yr risk: 24% for both DPT1 and TN), the AUC ratio did not differ between OI and placebo. In conclusion, when DPTRS was &amp;gt;6.75 metabolic outcomes at 1 yr appeared similarly favorable for OI in the DPT1 and TN trials, suggesting OI slows insulin decline in those at high risk for T1D. Moreover, metabolic measures could be useful endpoints for T1D prevention trials. Disclosure J. Sosenko: None. J.P. Palmer: None. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. A. Pugliese: None. D. Schatz: None.

1618-P: Insulin Secretion Variability According to the Specific Type 1 Diabetes (T1D) Risk Predictor

The risk for T1D, a major criterion for entry into disease prevention trials, can be assessed in various ways, but usually includes autoantibody (Ab) and/or metabolic measures. Given inherent variations in these biomarkers, it is possible that informative characteristics differ between populations selected by different risk measures. Thus, we assessed whether indices of insulin secretion [C-pep; first phase insulin response (FPIR)] vary between groups defined by distinctive risk measures. We used data from Diabetes Prevention Trial-Type 1 (DPT-1) participants, all being ICA positive subjects with or without biochemical Ab (bAb) positivity (GADA, IA-2A, mIAA). C-pep and FPIR values from baseline oral and intravenous glucose tolerance tests were compared between those who had 2-3 bAbs (≥2bAb) and those who had 0-1 bAb plus Index60≥0.40 (≤1bAb+Ind60). Index60 is a composite C-pep and glucose measure. These groups were chosen so that T1D risk would be similar (50% 5-year risk for both, log rank p=0.95). Ages (mean±SD) for ≥2bAb (n=289) and ≤1bAb+Ind60 (n=175) were 12.8±8.2 and 13.3±9.6 yrs, respectively (p=0.53). BMI Z-score was greater for ≥2bAb (0.42±1.12 vs. 0.15±1.09, p=0.01). C-pep levels were consistently higher for ≥2bAb than ≤1bAb+Ind60 [30-0 minute C-pep: 2.73±1.58 vs. 2.04±1.12 ng/mL, p&amp;lt;0.0001; area under the curve (AUC) C-pep: 3.70±1.55 vs. 3.27±1.12 ng/ml, p=0.013; AUC C-pep/AUC glucose: 0.030±0.013 vs. 0.025±0.007 (ng/ml)/(mg/dl), p&amp;lt;0.001]. FPIR was also higher for ≥2bAb (122.0±87.3 vs. 96.2±47.1 µU/ml, p&amp;lt;0.01). All comparisons remained significant with adjustments for age and BMI Z-score. Of those with ≤1bAb+Ind60, 0 bAb did not differ from 1 bAb for C-pep indices or FPIR. In conclusion, C-pep and FPIR values can differ appreciably according to the measure that defines risk. This should be considered in choosing risk measures for prevention trials. Disclosure L.M. Jacobsen: None. B.M. Nathan: None. H.M. Ismail: None. M.J. Redondo: None. D. Schatz: None. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. E.K. Sims: None. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. J.P. Palmer: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. J. Sosenko: None.

99-OR: An Inflection Point (IP) of C-Peptide (C-P) Decline during Progression to Type 1 Diabetes (T1D)

Evidence suggests the presence of an IP for accelerated β-cell loss during progression to T1D. Importantly, identification of an IP could guide subject selection for prevention trials. We used a 2-dimensional grid of area under the curve (AUC) glucose vs. AUC C-P to detect a C-P IP among Diabetes Prevention Trial-Type 1 (DPT-1; n=54) and TrialNet (TN; n=59) autoantibody positive (Ab+) participants. All analyzed were required to have OGTTs at baseline and every 6 months, then 2.0, 1.5, 1.0 and 0.5 yrs before diagnosis. In DPT-1, an IP was evident 1.5 yrs from diagnosis (Figure) (AUC C-P change from baseline to 1.5 yrs: 0.22±0.60 ng/ml, p=0.006; from 1.5 to 0.5 yrs: -0.42±1.23 ng/ml, p=0.026). In TN, a 1.5 yr IP was also evident (from baseline to 1.5 yrs: 0.18±0.95 ng/ml, p=0.184; from 1.5 to 0.5 yrs: -0.53±1.57 ng/ml, p=0.015), despite an older TN cohort (14.9±12.1 vs. 10.5±6.8 yrs, p=0.023) with higher AUC C-P (5.0±1.9 vs. 3.3±1.6 ng/ml, p&amp;lt;0.001). There was no IP in non-progressors. In summary, an IP occurred 1.5 yrs before diagnosis when C-P began to decline as glucose continued to increase in DPT-1 and TN, suggesting that a 1.5 yr IP of C-P decline is consistent among Ab+ populations. These findings emphasize the importance of identifying at risk individuals as potential participants in prevention trials prior to the IP, when the loss of insulin secretion becomes more severe. Disclosure H.M. Ismail: None. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. J. Sosenko: None. J.P. Palmer: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. L. DiMeglio: None. M.J. Redondo: None. A. Steck: None. M.A. Atkinson: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. B.M. Nathan: None. Funding National Institutes of Health

Slowed Metabolic Decline After 1 Year of Oral Insulin Treatment Among Individuals at High Risk for Type 1 Diabetes in the Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Oral Insulin Prevention Trials.

We assessed whether oral insulin slowed metabolic decline after 1 year of treatment in individuals at high risk for type 1 diabetes. Two oral insulin trials that did not show efficacy overall and had type 1 diabetes as the primary end point were analyzed: the Diabetes Prevention Trial–Type 1 (DPT-1) and the TrialNet oral insulin trials. Oral glucose tolerance tests at baseline and after 1 year of treatment were analyzed. Among those at high risk (with a Diabetes Prevention Trial–Type 1 Risk Score [DPTRS] ≥6.75), the area under the curve (AUC) C-peptide increased significantly from baseline to 1 year in each oral insulin group, whereas the AUC glucose increased significantly in each placebo group. At 1 year, the AUC C-peptide/AUC glucose (AUC Ratio) was significantly higher in the oral insulin group than in the placebo group in each trial (P < 0.05; P = 0.057 when adjusted for age in the TrialNet trial) and in both trials combined (P < 0.01 with or without adjustment for age). For a DPTRS <6.75, oral insulin groups did not differ from placebo groups in the AUC Ratio. The findings suggest that 1 year of treatment with oral insulin slows metabolic deterioration in individuals at high risk for type 1 diabetes. Moreover, the findings further suggest that metabolic end points can be useful adjuncts to the diagnostic end point in assessments of preventive treatments for the disorder.

Early and late C-peptide responses during oral glucose tolerance testing are oppositely predictive of type 1 diabetes in autoantibody-positive individuals.

We examined whether the timing of the C-peptide response during an oral glucose tolerance test (OGTT) in relatives of patients with type 1 diabetes (T1D) is predictive of disease onset. We examined baseline 2-h OGTTs from 670 relatives participating in the Diabetes Prevention Trial-Type 1 (age: 13.8 ± 9.6 years; body mass index z-score: 0.3 ± 1.1; 56% male) using univariate regression models. T1D risk increased with lower early C-peptide responses (30-0 min) (χ2 = 28.8, P < 0.001), and higher late C-peptide responses (120-60 min) (χ2 = 23.3, P < 0.001). When both responses were included in a proportional hazards model, they remained independently and oppositely associated with T1D, with a stronger overall association for the combined model than either response alone (χ2 = 41.1; P < 0.001). Using receiver operating characteristic curve analysis, the combined early and late C-peptide response was more accurately predictive of T1D than area under the curve C-peptide (P = 0.005). Our findings demonstrate that lower early and higher late C-peptide responses serve as indicators of increased T1D risk.

Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice

Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice

1344-P: Persistent ß-Cell Responsiveness in Children at High Risk for Type 1 Diabetes (T1D) Is Associated with Decreased Progression to T1D in the Diabetes Prevention Trial-Type 1 (DPT-1)

High-risk individuals with islet autoantibody positivity (Ab+) vary in their rates of progression to T1D. We hypothesized that changes in C-peptide over time account for some of this variation. Among Ab+ children (&amp;lt;18.0 years) followed with 2-hour OGTTs for development of T1D in DPT-1, we compared Progressors to T1D with Non-Progressors for the change in AUC C-peptide from the baseline OGTT to the last available OGTT (last before diagnosis in Progressors). Results were stratified by low or high baseline DPT-1 Risk Score (DPTRS: fasting C-peptide, sum C-peptide and sum glucose values from 30-120 minutes, age and BMI; DPTRS &amp;lt;7.00= lower risk and ≥7.00= higher risk). As shown in the Table, Non-Progressors from each group exhibited increases in AUC C-peptide over time, while Progressors showed no significant changes in AUC C-peptide. A logistic regression model with adjustment for age indicated an inverse association of T1D development with increasing AUC-C-peptide/year [Odds ratio: 0.587 (0.430, 0.802), p&amp;lt;0.001]. In conclusion, even in individuals with high baseline risk assessments, increasing AUC C-peptide over time is associated with decreased progression to T1D. This persistent C-peptide responsiveness could result from increased β-cell reserve (either functional or mass) or β-cell regeneration. Disclosure E.K. Sims: None. H.M. Ismail: None. B.M. Nathan: None. J.M. Sosenko: None. Funding National Institutes of Health

1343-P: A Comparison of C-Peptide and Glucose Responses between Children and Adolescents Who Progress to Type 1 Diabetes (T1D)

Type 1 diabetes is a heterogeneous disease with differences in β-cell dysfunction and rates of progression. We thus assessed whether there are differences in C-peptide and glucose responses during 2-hour oral (OGTTs) and intravenous (IVGTTs) glucose tolerance tests between children and adolescents at high risk for T1D. Data from the Diabetes Prevention Trial-type 1 (DPT-1) study participants who progressed to T1D was used for the analysis. We compared C-peptide and glucose responses between children (&amp;lt;10.0 years old; 7.1±1.9 years; n=125) and adolescents (10.0 years to &amp;lt;18.0 years old; 12.8±2.2 years; n=94). The risks for T1D were similar between the children and adolescents (mean 3-year T1D estimates from DPT-1 Risk Score: 63% and 56% respectively), as was the time to diagnosis (2.4±2.1 years vs. 2.5±2.2 years, respectively). Adolescents had higher OGTT derived AUC C-peptide levels (3.8±1.5 ng/ml vs. 1.9±1.4 ng/ml; p&amp;lt;0.001 with BMIZ adjustment), whereas their AUC glucose levels were similar to children (138.6±25.1 mg/dl vs. 139.6±22.8 mg/dl). The 0 to 30 minute C-peptide response from baseline OGTTs was significantly higher among adolescents compared to children (2.6±1.6 vs. 2.1±1.2, p=0.004 with BMIZ adjustment). However, C-peptide and glucose changes for each subsequent 30-minute OGTT interval were nearly identical between the children and adolescents. Similar to the 0 to 30 minute C-peptide response, the first-phase insulin response from baseline IVGTTs was higher in adolescents (114.1±74.0 µU/ml vs. 88.6±59.9 µU/ml; p&amp;lt;0.001 with BMIZ adjustment). In conclusion, the findings showed that despite a lower early insulin response in children, OGTT glucose levels were not higher. This suggests increased insulin sensitivity. The findings also showed that despite the lower early insulin response, the time to diagnosis did not differ. Other aspects of insulin responsiveness, and perhaps sensitivity, appear to also determine the progression rate to T1D. Disclosure H.M. Ismail: None. B.M. Nathan: None. J.P. Palmer: None. L. DiMeglio: Research Support; Self; Amgen Inc., Caladrius Biosciences, Inc., Janssen Research &amp; Development, Medtronic, Sanofi. Other Relationship; Self; Dexcom, Inc. J.M. Sosenko: None. Funding National Institutes of Health

1678-P: Comparisons of Combined C-Peptide and Glucose Intermediate Endpoints for Identifying Individuals at Very High Risk for Type 1 Diabetes

Type 1 diabetes (T1D) prevention trials can be shortened if intermediate endpoints indicative of a very high risk of progression are reached before diagnosis. Since Index60, a composite C-peptide and glucose measure, has been shown to have potential use as such an endpoint, we evaluated additional combinations of C-peptide and glucose as endpoints. Diabetes Prevention Trial-type 1 participants (n=702) with baseline values below threshold (set arbitrarily at 95th percentile for each endpoint) were followed at 0.5-1.0 year intervals with 2-hour OGTTs for the first (incident) OGTT that thresholds were exceeded. Participants were then followed for T1D. All endpoints were reached, on average, over 1 year prior to the diagnosis of T1D. Risks for subsequent T1D after the incident OGTT were substantial, but variable (3-year risk=0.66-0.81). There was also appreciable variation in numbers reaching endpoints (n=55-117) and positive predictive values for T1D (PPV=62-77%). Ages were lowest for Glucose/C-peptide measures at incident OGTTs. Index60 performed best regarding key endpoint criteria: number reaching endpoint, 3-year risk, and PPV. In conclusion, individuals highly likely to ultimately develop T1D can be identified over 1 year before diagnosis by combined C-peptide and glucose endpoints. It appears that such endpoints should be considered for T1D prevention trials. Disclosure L.M. Jacobsen: None. M.A. Clements: Advisory Panel; Self; Glooko, Inc. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Medtronic. M.J. Redondo: None. B.M. Nathan: None. D. Schatz: None. J.M. Sosenko: None. Funding National Institutes of Health; JDRF