C-peptide Area Under The Curve Research Articles

Liraglutide enhances insulin secretion and prolongs the remission period in adults with newly diagnosed type 1 diabetes (the NewLira study): A randomized, double-blind, placebo-controlled trial.

To test the effect of the glucagon-like peptide-1 receptor agonist, liraglutide, on residual beta-cell function in adults with newly diagnosed type 1 diabetes. In a multicentre, double-blind, parallel-group trial, adults with newly diagnosed type 1 diabetes and stimulated C-peptide of more than 0.2 nmol/L were randomized (1:1) to 1.8-mg liraglutide (Victoza) or placebo once daily for 52 weeks with 6 weeks of follow-up with only insulin treatment. The primary endpoint was the between-group difference in C-peptide area under the curve (AUC) following a liquid mixed-meal test after 52 weeks of treatment. Sixty-eight individuals were randomized. After 52 weeks, the 4-hour AUC C-peptide response was maintained with liraglutide, but decreased with placebo (P = .002). Six weeks after end-of-treatment, C-peptide AUCs were similar for liraglutide and placebo. The average required total daily insulin dose decreased from 0.30 to 0.23 units/kg/day with liraglutide, but increased from 0.29 to 0.43 units/kg/day in the placebo group at week 52 (P < .001). Time without the need for insulin treatment was observed in 13 versus two patients and lasted for 22 weeks (from 3 to 52 weeks) versus 6 weeks (from 4 to 8 weeks) on average for liraglutide and placebo, respectively. Patients treated with liraglutide had fewer episodes of hypoglycaemia compared with placebo-treated patients. The adverse events with liraglutide were predominantly gastrointestinal and transient. Treatment with liraglutide improves residual beta-cell function and reduces the dose of insulin during the first year after diagnosis. Beta-cell function was similar at 6 weeks postliraglutide treatment.

Novel Autologous Dendritic Cell Therapy AVT001 for Type 1 Diabetes

BackgroundCD8+ T regulatory (Treg) cells that recognize the nonclassical class 1b molecule Qa-1/human leukocyte antigen E (Q/E CD8+ Treg cells) are important in maintaining self-tolerance. We sought to investigate the role that these T cells play in type 1 diabetes (T1D) pathogenesis and whether an intervention targeting this mechanism may delay T1D progression.MethodsWe conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose.ResultsSixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were −0.17% (95% CI, −0.60 to 0.26%) for HbA1c and −0.06 U/kg/day (95% CI, −0.14 to 0.02) for daily insulin dose.ConclusionsIn this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.)

Timing of meal consumption on glucose profiles in Latino adolescents with obesity.

To date, there has been no study investigating how meal-timing impacts glucose and insulin resistance among Latino youth at high risk of type 2 diabetes. A proof-of-concept study was conducted to assess metabolic response to a test-meal consumed in the morning, afternoon, and evening among 15 Latino adolescents with obesity using a within-participant design. Youth, 13 to 19 years of age, with obesity, consumed the same test-meal after a 16 hour fast at three different times on separate days. Immediately after consumption of the test meal, a mixed meal tolerance test (MMTT) was performed. The co-primary outcomes were the area under the curve (AUC) for glucose, insulin, and c-peptide, and insulinogenic index (IGI). Twenty-two youth consented to participate for a 24% recruitment rate (78% female, 100% Latino, mean age 16.5±1.3 years, 70% publicly insured). There was a significantly greater rise in glucose and c-peptide levels following at 4 PM compared to 8 AM (glucose: p = 0.006; c-peptide: p &lt; 0.0001) with no significant association found between insulin levels and timing of meal consumption. Pairwise comparisons showed a greater rise in AUC glucose and c-peptide levels at 4 PM compared to 8 AM (glucose p = 0.003; c-peptide p &lt; 0.001) with no significant association found between insulin AUC and timing of meal consumption (p = 0.09). There was a greater reduction in IGI at 4 PM compared to 8 AM (p = 0.027). Similar to findings in adults at risk for diabetes, Latino youth with obesity show greater insulin resistance in response to a meal consumed in the afternoon and evening compared to early morning food consumption.

Genetic Associations with C-peptide Levels before Type 1 Diabetes Diagnosis in At-Risk Relatives.

We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) are associated with C-peptide preservation before type 1 diabetes diagnosis. We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known SNPs and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis. Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (β=-0.06, P<0.0001) and multivariate (β=-0.03, P=0.005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (β=-0.11, P=0.002) and multivariate (β=-0.06, P=0.018) analyses. The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC prior to diagnosis of type 1 diabetes, with implications for the design of prevention trials.

Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.

Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy. We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial. Among trials meeting their primary end point, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (P = 0.030 and P < 0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. The use of C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R2 for 12-month C-peptide AUC adjusted for age and baseline value was 0.80, P < 0.001), and this finding supported the concept of smaller trial sizes down to 54 participants. Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early-phase clinical trials.

The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00–0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04–0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, −0.07units/kg/day, 95% CI, −0.11 to −0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, −0.11units/kg/day, 95% CI, −0.23 to −0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

OR34-04 Defective FGFR1 Signaling Disrupts Glucose Regulation In Humans: Evidence From Patients With Isolated Hypogonadotropic Hypogonadism Harboring FGFR1 Mutations

Abstract Disclosure: M. Stamou: None. C.J. Chiu: None. S. Jadhav: None. K. Salnikov: None. L. Plummer: None. S.B. Seminara: None. R. Balasubramanian: None. Introduction: Recent studies have shown that antibody-mediated activation of FGFR1 receptor improves metabolic health in rodents, nonhuman primates, and humans. Hence, disruption of the FGFR1 receptor may lead to glucose dysregulation. FGFR1 mutations contribute to 12% of the genetic background of subjects with isolated hypogonadotropic hypogonadism (IHH), a rare Mendelian disease caused by GnRH deficiency. In this study, we examined glucose effectiveness and insulin sensitivity in IHH subjects with rare FGFR1 variants and hypothesized that these subjects will display defective glucose metabolism compared healthy non-carrier controls. Methods: Nine subjects with IHH (7 males and 2 females) with heterozygous rare FGFR1 variants were enrolled [7 subjects with protein truncating variants: p.Q680*, p.R622*, p.Q52*, p.I347Nfs*61, p.R576Pfs*77, p.Q309*, c.1553-2A&amp;gt;G and 2 subjects with deleterious missense variants: p.G97S &amp; p.Y701C. Thirty healthy controls (17 males and 13 females) with no FGFR1 variants were enrolled from the Mass General Brigham Biobank. Medical history, physical exam, laboratory evaluation, a bone density scan, and an intravenous glucose tolerance test (IVGTT) were performed. The area under the curve (AUC) for glucose, insulin, and C-peptide response to 50% dextrose (0.3g/kg, t=0min) and an insulin bolus (0.03u/kg, t=20 min) were estimated for each subject. The glucose effectiveness (Sg), insulin sensitivity (SI), acute insulin response to glucose (AIR), and the disposition index (DI= AIRG*SI) were calculated using the Minimal Model Analysis. Statistical comparisons were performed with t-test and non-parametric Wilcoxon rank sum test. A linear regression model was used to adjust the t-test outcomes for potential confounders. Results: Despite similar BMIs (28 vs. 26.5, p=0.29), IHH FGFR1 positive subjects demonstrated higher % fat mass compared to controls (38 vs. 31, p=0.02). IHH patients were supplemented with sex-steroids at the time of the study. Male patients demonstrated similar testosterone levels compared to controls (385 vs. 451 ng/dL, p=0.52). IHH FGFR1 positive subjects demonstrated a higher AUC for C-peptide compared to controls (167 vs. 92, p=0.001), that remained significant after adjusting for age, gender, BMI, and % fat mass. Non-parametric test showed higher AUC for glucose, insulin, and C-peptide (p 0.01, 0.01 &amp; 0.005 respectively) as well as lower SI (p=0.01) and higher AIRg (p=0.037) in the IHH FGFR1 positive group compared to non-carrier controls. Discussion: This is the first study to evaluate glucose metabolism in humans with naturally occurring FGFR1 variants. IHH FGFR1 positive subjects showed higher insulin response to glucose and lower insulin sensitivity during an IVGTT test compared to the healthy non-carrier controls. These findings confirm that FGFR1 signaling is a key regulator of insulin secretion and action in humans. Presentation: Sunday, June 18, 2023

FRI593 Ergocalciferol And Pancreatic β-Cell Function In New-onset Type 1 Diabetes: A Randomized Controlled Trial

Abstract Disclosure: B.U. Nwosu: None. S. Parajuli: None. R. Sharma: None. B.A. Barton: None. A.F. Lee: None. Background: The impact of high-dose vitamin D (ergocalciferol) on pancreatic β-cell function in youth with newly diagnosed type 1 diabetes (T1D) is unclear. Objective: To determine the effect of ergocalciferol on residual pancreatic β-cell function (RBCF) in youth with newly diagnosed T1D. Hypothesis: Ergocalciferol supplementation increases RBCF and prolongs the partial clinical remission (PR) phase of T1D. Design, Setting, and Participants: This 12-month randomized, double-blind, placebo-controlled trial of youth aged 10-21 years with newly diagnosed T1D of &amp;lt;3mo was conducted at a single center in the US between October 19, 2017 through April 20, 2021. Interventions: Participants were randomized 1:1 to once weekly dose of 50,000 IU of ergocalciferol for 2 months, and then once every 2 weeks for 10 months, versus placebo. Main outcomes and measures: The primary outcome was the percentage change from baseline in the area under the curve (AUC) of stimulated C-peptide over 12 months. Results: Thirty-six subjects were randomized to either the ergocalciferol arm: n=18, mean age 13.3±SD2.8 years, with 10 male and 8 female subjects; or to the placebo arm: n=18, mean age 14.3±2.9 years, with 14 male and 4 female subjects. Ergocalciferol significantly reduced the temporal trends in both the A1c (p=0.04) and the insulin-dose adjusted A1c (IDAA1c) (p=0.02), and the overall group means for IDAA1c versus placebo (p=0.02). A random intercept model, adjusted for age, sex, and race, showed that the percentage change in AUC C-peptide from baseline through the 12-month study period declined in both arms of the study. Specifically, by 28.4 ± 6.2 (p&amp;lt;.0001) in the ergocalciferol arm and by 41.5 ± 5.9 (p&amp;lt;.0001) in the placebo arm, with the decline in the ergocalciferol arm being significantly slower than that in the placebo arm, p=0.029 for the difference in the slopes of the trends between the two arms. There were no adverse events. Conclusion: High-dose ergocalciferol significantly slowed the rate of decline in C-peptide compared to placebo in children and adolescents with T1D. Presentation: Friday, June 16, 2023

Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial

Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6–15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving β cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004–0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41.

Anti-CD3 monoclonal antibodies in treatment of type 1 diabetes: a systematic review and meta-analysis.

This meta-analysis aimed to assess the efficacy and safety of anti-CD3 monoclonal antibodies (mAbs) for type 1 diabetes. We searched PubMed, Embase and Cochrane until 23 February 2023 for randomized controlled trials that compared anti-CD3 mAbs with placebo in type 1 diabetes. The primary outcome was the area under the curve (AUC) of C-peptide, daily insulin dose or HbA1c. Totally 12 trials that included 1870 participants were eligible for inclusion in the review. Compared with the control group, anti-CD3 mAbs increased AUC of C-peptide at 1 year (P = 0.0005, MD 0.14, 95% CI [0.06, 0.22], I2 = 94%), and 2 years (P = 0.0003, MD 0.20, 95% CI [0.09, 0.30], I2 = 88%). The use of anti-CD3 mAbs decreased insulin use at 1 year (P = 0.001, MD -0.09, 95% CI [-0.15, -0.04], I2 = 90%), and 2 years (P < 0.00001, MD -0.18, 95% CI [-0.25, -0.12], I2 = 86%). But there was no statistically significant effect on HbA1c levels. Vomiting, nausea, rash, pyrexia and headache were reported more frequently with anti-CD3 mAbs than with placebo. However, incidence of total adverse events and serious adverse events was similar when comparing anti-CD3 mAbs with placebo. Our results suggest that anti-CD3 mAbs were a potential therapy for improving AUC of C-peptide and insulin use in type 1 diabetes.

Adipose Tissue-Derived Stromal/Stem Cells Transplantation with Cholecalciferol Supplementation in Recent-Onset Type 1 Diabetes Patients: Twelve Months Follow-Up.

To evaluate safety and therapeutic effect along 12 months of allogenic adipose tissue-derived stromal/stem cells (ASCs) transplantation with cholecalciferol (VITD) in patients with recent-onset type 1 diabetes (T1D). Prospective, phase II, open trial, pilot study in which patients with recent onset T1D received ASCs (1xKgx106 cells) and VITD 2000UI/day for 12 months (group 1) and were compared to controls with standard insulin therapy (group 2). Adverse events, C-peptide area under the curve (CPAUC), insulin dose, HbA1c and frequency of FoxP3+ in CD4+ or CD8+ T-cells(flow cytometry) were evaluated at baseline(T0), after 3(T3), 6(T6) and 12 months(T12). Eleven patients completed follow up (7:group 1;4:group 2). Group 1 had lower insulin requirement at T3(0.24±0.18vs0.53±0.23UI/kg,p=0.04), T6(0.24±0.15vs0.66±0.33 UI/kg,p=0.04) and T12(0.39±0.15vs0.74±0.29 UI/Kg,p=0.04).HbA1c was lower at T6 (50.57±8.56vs72.25±10.34 mmol/mol,p=0.01), without differences at T12 (57.14±11.98 in group 1 vs. 73.5±14.57 mmol/min in group 2, p=0.16). CPAUC was not significantly different between groups at T0(p=0.07), higher in group 1 at T3(p=0.04) and T6(p=0.006), but similar at T12(p=0.23). IDAA1c was significantly lower in group 1 than group 2 at T3,T6 and T12 (p=0.006, 0.006 and 0.042, respectively). IDDA1c was inversely correlated to FoxP3 expression in CD4 and CD8+ T cells at T6 (p<0.001 and p=0.01, respectively). In group 1, one patient had recurrence of a benign teratoma that was surgically removed, not associated to the intervention. ASCs with VITD without immunosuppression were safe and associated lower insulin requirements, better glycemic control, and transient better pancreatic function in recent onset T1D, but the potential benefits were not sustained.

825-P: Novel Autologous Dendritic Cell Therapy AVT001 for Type 1 Diabetes

Studies in several animal models and of humans with type 1 diabetes (T1D) have suggested that Qa-1/HLA-E restricted CD8+ T regulatory cells (Tregs) are important in maintaining self-tolerance and a defect thereof playing a key role in T1D pathogenesis. To evaluate the safety and efficacy of targeting this pathway in T1D we undertook a first in human, phase 1/2 study of AVT001, an investigational autologous dendritic cell-based vaccine designed to address this immunologic mechanism. This double-blind, randomized (2:1 treated vs placebo) trial enrolled individuals (n=25) who were 16 years and older, within 1 year of clinical diagnosis of T1D, and with an ex-vivo correctable defect in the function of HLA-E-restricted CD8+ Tregs. All participants underwent leukapheresis, the first step in the generation of AVT001. AVT001 treatment (n=16) or placebo (n=9) was delivered as a series of three-monthly intravenous infusions. The primary endpoint of the study was safety/tolerability at day 150. AVT001 was safe and well tolerated with all participants completing treatment, no peri-infusion reactions noted, and adverse events reported as being mild or moderate in the AVT001 treated group, with rates similar to placebo. A pre-specified efficacy endpoint was change from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal tolerance test utilizing a mixed-effect model for repeated measurements (MMRM). The baseline mean (SD) AUCs were treated 0.531 (0.363) and placebo 0.611 (0.178) nmol/L. At day 150, the C-peptide AUCs were significantly different between groups, namely 0.518 (0.430) and 0.472 (0.134) respectively. Per MMRM, the least square mean difference between AVT001 and placebo at day 150, is estimated to be 0.172 (p=&amp;lt;.0001). There was an increase in AUC or no change for 6 (37.5%) in the AVT001 treated group and 1 (11.1%) in the placebo group. These results indicate that AVT001 treatment was safe and well tolerated with evidence of significant preservation of endogenous insulin secretion. Disclosure J.L.Gaglia: Advisory Panel; Dompé, Consultant; Vertex Pharmaceuticals Incorporated, Abata Therapeutics, Avotres Inc., Current Health, Research Support; Avotres Inc., Dompé, Imcyse, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.Ritz: Advisory Panel; Novartis, Taleris, AvroBio, Clade Therapeutics, LifeVault Bio, Smart Immune, Garuda, Tscan, Research Support; Gilead Sciences, Inc., Novartis. H.Jiang: Employee; Avotres Inc. M.Mackey: None. H.L.Daley: None. N.Bryant: None. D.Y.Kim: None. T.Dong: Employee; Avotres Inc., Novartis. E.E.Fan: None. J.Vora: Other Relationship; Avotres Inc., Glyscend Inc. 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. Funding Avotres Inc.

216-LB: Genetic Influences on Beta-Cell Function before Type 1 Diabetes Diagnosis

Autoimmune loss of beta-cell function (measured by C-peptide) is the hallmark of type 1 diabetes (T1D) targeted by interventions that aim to prevent T1D or its progression after onset. We sought to determine whether T1D genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) that have been previously associated with C-peptide preservation after T1D diagnosis (e.g., SNPs in CLEC16A, G6CP2, INS, JAZF1, PTPN22, SLC30A8 and TCF7L2) influence C-peptide levels before diagnosis. We studied islet autoantibody (Ab)-positive participants in the TrialNet Pathway to Prevention Study who had T1DExomeChip data and assessed the influence of these 12 SNPs and the T1D-GRS2 on area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted between 0-9 months prior to the diagnosis of T1D. Participants (n=702) had a mean age of 13.5±10.3 years, 47% were female, mean BMI was 20.7±6.0 kg/m2, and mean HbA1c 5.4±0.4%. The T1D high-risk HLA-DR3-DQ2 haplotype was present in 47% and the high-risk HLA-DR4-DQ8 haplotype was present in 67% of participants. We performed univariate and multivariate analyses adjusting for BMI, age, sex, number of positive Ab, and the first 3 principal components of ancestry. A higher T1D-GRS2 was associated with lower C-peptide AUC 0-9 months prior to T1D diagnosis in univariate (β=-0.06, P&amp;lt;0.0001) and multivariate (β=-0.03, p=0.008) analyses. Participants with the JAZF1 rs864745 G allele had lower C-peptide AUC 0-9 months prior to T1D diagnosis in univariate (β=-0.10, p=0.003) and multivariate (β=-0.05, p=0.047) analysis. In conclusion, the JAZF1 rs864745 G allele (which has also been associated with type 2 diabetes risk) and higher T1D-GRS2 predict lower C-peptide AUC prior to the diagnosis of T1D. Studies on their effect on response to trials to prevent or delay T1D onset are warranted. Disclosure T. M. Triolo: None. S. S. Rich: None. A. Steck: None. M. J. Redondo: None. H. M. Parikh: None. M. Tosur: Advisory Panel; Provention Bio, Inc. L. A. Ferrat: Consultant; Johnson &amp; Johnson. L. You: None. P. Gottlieb: Advisory Panel; ViaCyte, Inc., Board Member; ImmunoMolecular Therapeutics, Research Support; Imcyse, Hemsley Charitable Trust, Novartis, National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Dompé, Nova Pharmaceuticals, Provention Bio, Inc. R. A. Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. S. Onengut-gumuscu: None. J. Krischer: None. Funding National Institutes of Health (R01DK121843, R01DK124395)

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.

Metabolic Outcomes in Pediatric Patients One-Year Post-Total Pancreatectomy with Islet Autotransplantation after Early Pump Initiation.

We previously published that insulin pump initiation immediately after IV insulin therapy was associated with improved post-surgical glycemic outcomes compared to multiple daily injections (MDI) in pediatric patients following a total pancreatectomy with islet autotransplantation (TPIAT). We investigated metabolic outcomes of this population at one-year post-TPIAT to assess if the improved outcomes in the early pump group were sustained over time. We retrospectively reviewed 40 patients post-TPIAT previously studied at 10-days post-surgery (15 used MDI and 25 used pump therapy immediately post-ICU, and all were discharged on pump therapy). Data analyzed included: demographics, islet equivalents per kilogram (IEQ/kg) transplanted, exogenous insulin use, and baseline vs. one-year (via mixed meal testing) HbA1c, fasting glucose, insulinogenic index, and the area under the curve (AUC) for insulin and c-peptide. More patients were off insulin at one year in the early pump group compared to the MDI group (45% vs. 13%, p = 0.07). Of all patients off insulin, 100% of the early pump users weaned off by six months post-TPIAT compared to 30% of the MDI users. Two known variables associated with favorable insulin outcomes, lower age and higher IEQ/kg, were not significantly different between groups. Fasting glucose was lower in the early pump group compared to the MDI group (median 97 vs. 122 mg/dL, p = 0.003), while AUC c-peptide was greater in early pump users at one-year post-TPIAT but did not reach significance (median 57.0 vs. 50.3 ng/mL × minutes, p = 0.14). Other metabolic outcomes did not differ between groups. Despite lower median age and higher IEQ/kg in the MDI group, the early pump group had a lower fasting glucose. Younger TPIAT age (p = 0.02) and early pump users (p = 0.04) were significantly associated with insulin independence at one year. This study was limited by sample size. Early pump use may have long-term benefits in post-TPIAT endogenous insulin secretion.

Verapamil improves One-Year C-Peptide Levels in Recent Onset Type-1 Diabetes: A Meta-Analysis.

Meta-analysis studying the role of verapamil in improving C-peptide in people with recent-onset type-1 diabetes (T1DM) has not been conducted to date. We undertook this meta-analysis to address this knowledge gap. Electronic databases were systematically reviewed for RCTs having individuals with T1DM receiving verapamil in the treatment arm and placebo in the control arm over the standard of care. The primary outcome was to evaluate changes in the C-peptide area under the curve (AUC) at a one-year follow-up. Secondary outcomes were to assess alterations in C-peptide AUC, glycated hemoglobin (HbA1c), blood pressure, heart rate, and side effects at different time intervals over a one-year follow-up. From the initially screened 27 articles, data from two RCTs (112 patients) satisfied the inclusion criteria and were analyzed. Compared to placebo, C-peptide AUC in individuals receiving verapamil was not different at three months [MD 0.17 nmol/L (95%CI: -0.05-0.38); P = 0.13; I2 = 86%] but significantly higher at 1-year [MD 0.27 nmol/L (95%CI: 0.19-0.35); P < 0.01; I2 = 12%]. The verapamil arm showed similar changes in HbA1C at three months [MD 0.23% (95%CI: -0.43-0.90); P = 0.49; I2 = 88%] and 1-year [MD 0.18% (95% CI: -0.74 - 1.10); P = 0.70; I2 = 89%] compared to placebo. Occurrence of treatment-emergent adverse events [Risk ratio (RR) 1.90 (95%CI: 0.52-6.91); P = 0.33; I2 = 63%], serious adverse events [RR 1.40 (95%CI: 0.50-3.93); P = 0.53], constipation [RR4.11 (95%CI: 0.93-18.13); P = 0.06; I2 = 0%], headache [RR0.48 (95%CI: 0.16-1.43); P = 0.19; I2 = 0%], severe hypoglycemia [RR 0.87 (95%CI: 0.06 - 13.51); P = 0.92] were comparable across groups. Verapamil was well tolerated, and its use over one year was associated with significant improvements in C-peptide AUC though the HbA1c remained unchanged.

Phenotypes Associated With Zones Defined by Area Under the Curve Glucose and C-peptide in a Population With Islet Autoantibodies.

Metabolic zones were developed to characterize heterogeneity of individuals with islet autoantibodies. Baseline 2-h oral glucose tolerance test data from 6,620 TrialNet Pathway to Prevention Study (TNPTP) autoantibody-positive participants (relatives of individuals with type 1 diabetes) were used to form 25 zones from five area under the curve glucose (AUCGLU) rows and five area under the curve C-peptide (AUCPEP) columns. Zone phenotypes were developed from demographic, metabolic, autoantibody, HLA, and risk data. As AUCGLU increased, changes of glucose and C-peptide response curves (from mean glucose and mean C-peptide values at 30, 60, 90, and 120 min) were similar within the five AUCPEP columns. Among the zones, 5-year risk for type 1 diabetes was highly correlated with islet antigen 2 antibody prevalence (r = 0.96, P < 0.001). Disease risk decreased markedly in the highest AUCGLU row as AUCPEP increased (0.88-0.41; P < 0.001 from lowest AUCPEP column to highest AUCPEP column). AUCGLU correlated appreciably less with Index60 (an indicator of insulin secretion) in the highest AUCPEP column (r = 0.33) than in other columns (r ≥ 0.78). AUCGLU was positively related to "fasting glucose × fasting insulin" and to "fasting glucose × fasting C-peptide" (indicators of insulin resistance) before and after adjustments for Index60 (P < 0.001). Phenotypes of 25 zones formed from AUCGLU and AUCPEP were used to gain insights into type 1 diabetes heterogeneity. Zones were used to examine GCRC changes with increasing AUCGLU, associations between risk and autoantibody prevalence, the dependence of glucose as a predictor of risk according to C-peptide, and glucose heterogeneity from contributions of insulin secretion and insulin resistance.

PSUN138 Demonstration of Progressive Beta-Cell Failure in Familial Partial Lipodystrophy

Abstract Background Familial Partial Lipodystrophy Type 2 (FPLD2) is an autosomal dominant disorder caused by inherited mutations on the LMNA gene, typically on exon 8 and 11. Insulin resistance and diabetes mellitus are common clinical manifestations in patients with partial lipodystrophy. Despite aggressive treatment aiming reduction in insulin resistance, patients usually require insulin treatment, highlighting the presence of insulin secretion defects. The sequence of events to develop metabolic derangement is not well studied. This study aims to compare the metabolic changes and insulin secretion in two generations of patients with FPLD2. Methods In a longitudinal study, we are studying the metabolic and morphometric changes in younger patients carrying the mutation who have not fully expressed the phenotype and comparing their findings to their affected older relatives. In the first year of the study, six affected young patients (age: 17±4 years, 4F/2M) and four affected older relatives (age: 46±7 years, all-female) have completed a 5-hour OGTT with 75g of glucose to determine the metabolic parameters at 30-minute intervals as well as the area under the curve (AUC) for these parameters. Results Patients in the younger group did not have a clinical diagnosis of diabetes (mean HbA1c of 5.3±0.3%), while all patients in the older generation had the diagnosis of diabetes mellitus with higher HbA1c (7.9±3.1%, p=0.05). Younger patients showed a lower AUC for glucose (28703±12037 mg/dL/min), triglycerides (38820±15305 mg/dL/min, p&amp;lt;0.05)) and free fatty acids (FFA) (78±29mmol/L/min) compared to older affected patients (glucose AUC: 67563±39089 mg/dL/min; triglycerides AUC: 96461±39989 mg/dL/min; FFA AUC: 159±125 mmol/L/min). However, insulin and C-peptide AUC were higher in the younger group compared to the older generation (insulin AUC: 60664±66802 vs. 29331±23341 mcU/mL/min; C-peptide AUC: 3466±1646 vs. 2548±1391 mg/L/min). The change in C-Peptide in the first 30 min post glucose was significantly higher in the younger group compared to the older group (12±1.8 vs. 5±4 mg/L; p&amp;lt;0.05). Insulin secretion during the first 30 min of the test was numerically higher in the younger group versus the older group (213±90 vs. 90±115 mcU/mL). Conclusion Our data (albeit limited) show that the clinical manifestation of diabetes mellitus in older patients with FPLD2 is associated with impairments in insulin secretion, therefore highlighting the importance of beta-cell failure in the development of diabetes mellitus in this population. These data draw attention to the need for further investigation of the pancreatic endocrine dysfunction to treat and better understand diabetes mellitus in this population. Strategies to address just insulin resistance may not be sufficient to prevent the development of diabetes in the long run. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

825-P: Composite Glucose and C-Peptide Endpoints Show Early Efficacy in Recent-Onset Type 1 Diabetes (T1D) Clinical Trials

C-peptide area under the curve (AUC) at ≥1 year, a standard endpoint of recent-onset T1D clinical trials, is derived from a 120-minute mixed meal tolerance test (MMTT) . We analyzed whether composite glucose and C-peptide endpoints, useful in post hoc analyses of prevention trials, could detect treatment effects as early as 3 months between the combined treated and placebo groups from 3 TrialNet recent-onset T1D trials that met their primary endpoint. Comparisons were made between treated and placebo groups after adjustments for age, sex, and BMI Z-score using AUC C-peptide (standard measure) , AUC C-peptide/AUC glucose (AUC ratio) , and a new measure, the centroid ratio. Centroids, geometric central points of shapes, were derived from MMTT shapes formed from mean glucose and C-peptide values at 30, 60, 90, and 120 minutes. The centroid ratio is the C-peptide coordinate/glucose coordinate of the centroid. A treatment effect at 3 months was evident for centroid and AUC ratios (p&amp;lt;0.0 and p=0.002, respectively) and not AUC C-peptide (p=0.056) . Similar results were seen when individual trials were compared. The difference between combined groups at 3, 6, and 12 months is demonstrated by vectors that start at baseline (Figure) . In conclusion, composite glucose and C-peptide endpoints appear to identify early treatment efficacy and should be considered in future new-onset pilot studies and trials. Disclosure L.M.Jacobsen: None. A.Pugliese: Advisory Panel; Provention Bio, Inc., Consultant; Quell Tx. P.Gottlieb: Advisory Panel; Janssen Research &amp; Development, LLC, ViaCyte, Inc., Other Relationship; IM Therapeutics, Research Support; Caladrius Biosciences, Inc., Immune Tolerance Network, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk, Precigen, Inc., Tolerion, Inc. J.Sosenko: None. D.D.Cuthbertson: None. M.J.Haller: Advisory Panel; SAB Biotherapeutics , Consultant; MannKind Corporation, Sanofi. H.M.Ismail: n/a. E.K.Sims: Other Relationship; Medscape, Patent. S.E.Gitelman: Advisory Panel; Abata Therapeutics, Avotres Inc., Biolojic Design, Ltd., Provention Bio, Inc., Rubius, SAB Biotherapeutics, Inc., Tolerion, Inc. D.K.Wherrett: n/a. A.Moran: Advisory Panel; Dompé, Other Relationship; Novo Nordisk, Research Support; Abbott Diabetes, Provention Bio, Inc. M.A.Atkinson: None.