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Item Analysis of Incident DKA in the Indiana New Onset T1D Patient Population(Indiana University, 2020) Beer, Brianna; Moors, Kelly; Evans-Molina, Carmella; Sims, Emily K.; Pediatrics, School of MedicineBackground/Objective: Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1D) resulting from ketone body production and metabolic acidosis occurring due to insulin deficiency. We sought to define the occurrence of DKA amongst pediatric patients presenting with new-onset T1D in Indiana and to determine whether patterns of DKA were affected by the COVID-19 pandemic. Methods: This was a retrospective chart review for patients <18 years admitted to Riley Children’s Hospital with a clinical diagnosis of new onset T1D who had available chemistry values. Patients diagnosed from March 23- June 30, 2020 and over the same period in 2019 were included. DKA was classified as mild (bicarbonate 10-15 mmol/L) or severe (bicarbonate <10 mmol/L). Results: Ninety-four patients met inclusion criteria. The total number of incident T1D cases in 2019 and 2020 were similar (48 vs. 46, respectively). Similarly, there was no significant difference in rates of DKA (21 in 2019 vs. 25 in 2020; p>0.05). Of the 94 patients, 49% met criteria for DKA; 79% of cases were classified as severe and 21% as mild. More males were diagnosed with DKA in both 2019 and 2020 (61% of DKA cases). Non-Hispanic whites comprised 75% of all new onset T1D patients and no differences in race or ethnicity were present amongst those presenting in DKA. Conclusion: DKA was present in nearly half of all new onset pediatric T1D cases in Indiana in 2019 and 2020. There was no observed impact of the COVID-19 pandemic on T1D or DKA. Impact and Implications: DKA is common amongst pediatric patients with new onset T1D in Indiana. Prompt recognition of symptoms is needed to prevent this life-threatening complication of T1D.Item Associations of HbA1c with the Timing of C‐peptide Responses during the Oral Glucose Tolerance Test at the Diagnosis of Type 1 Diabetes(Wiley, 2019) Ismail, Heba M.; Evans-Molina, Carmella; DiMeglio, Linda A.; Becker, Dorothy J.; Libman, Ingrid; Sims, Emily K.; Boulware, David; Herold, Kevan C.; Rafkin, Lisa; Skyler, Jay; Cleves, Mario A.; Palmer, Jerry; Sosenko, Jay; Pediatrics, School of MedicineBackground In new onset type 1 diabetes (T1D), overall C‐peptide measures such as area under the curve (AUC) C‐peptide and peak C‐peptide are useful for estimating the extent of β‐cell dysfunction, and for assessing responses to intervention therapy. However, measures of the timing of C‐peptide responsiveness could have additional value. Objectives We assessed the contribution of the timing of C‐peptide responsiveness during oral glucose tolerance tests (OGTTs) to HbA1c variation at T1D diagnosis. Methods We analyzed data from 85 individuals <18 years with OGTTs and HbA1c measurements at diagnosis. Overall [AUC and peak C‐peptide] and timing measures [30‐0 minute C‐peptide (early); 60 to 120 minute C‐peptide sum‐30 minutes (late); 120/30 C‐peptide; time to peak C‐peptide] were utilized. Results At diagnosis, the mean (±SD) age was 11.2±3.3 years, BMI‐z was 0.4±1.1, 51.0% were male and the HbA1c was 43.54±8.46 mmol/mol (6.1±0.8%). HbA1c correlated inversely with the AUC C‐peptide (p<0.001), peak C‐peptide (p<0.001), early and late C‐peptide responses (p<0.001 each), and 120/30 C‐peptide (p<0.001). Those with a peak C‐peptide occurring at ≤60 minutes had higher HbA1c values than those with peaks later (p=0.003). HbA1c variance was better explained with timing measures added to regression models (R2=11.6% with AUC C‐peptide alone; R2=20.0% with 120/30 C‐peptide added; R2=13.7% with peak C‐peptide alone, R2=20.4% with timing of the peak added). Similar associations were seen between the 2‐hr glucose and the C‐peptide measures. Conclusions These findings show that the addition of timing measures of C‐peptide responsiveness better explains HbA1c variation at diagnosis than standard measures alone.Item Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing(MDPI, 2020-10-01) Demine, Stephane; Schulte, Michael L.; Territo, Paul R.; Eizirik, Decio L.; Radiology and Imaging Sciences, School of MedicineThere are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2γa as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.Item Cambridge hybrid closed-loop algorithm in children and adolescents with type 1 diabetes: a multicentre 6-month randomised controlled trial.(Elsevier, 2022-04) Ware, Julia; Boughton, Charlotte K.; Allen, Janet M.; Wilinska, Malgorzata E.; Tauschmann, Martin; Denvir, Louise; Thankamony, Ajay; Campbell, Fiona M.; Wadwa, R. Paul; Buckingham, Bruce A.; Davis, Nikki; DiMeglio, Linda A.; Mauras, Nelly; Besser, Rachel E. J.; Ghatak, Atrayee; Weinzimer, Stuart A.; Hood, Korey K.; Fox, D. Steven; Kanapka, Lauren; Kollman, Craig; Sibayan, Judy; Beck, Roy W.; Hovorka, Roman; Pediatrics, School of MedicineBackground Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population. Methods In a multicentre, multinational, parallel randomised controlled trial, participants aged 6–18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbA1c levels between 53 and 86 mmol/mol (7·0–10·0%). Using block randomisation and central randomisation software, we randomly assigned participants to either closed-loop insulin delivery (closed-loop group) or to usual care with insulin pump therapy (control group) for 6 months. Randomisation was stratified at each centre by local baseline HbA1c. The Cambridge closed-loop algorithm running on a smartphone was used with either (1) a modified Medtronic 640G pump, Medtronic Guardian 3 sensor, and Medtronic prototype phone enclosure (FlorenceM configuration), or (2) a Sooil Dana RS pump and Dexcom G6 sensor (CamAPS FX configuration). The primary endpoint was change in HbA1c at 6 months combining data from both configurations. The primary analysis was done in all randomised patients (intention to treat). Trial registration ClinicalTrials.gov, NCT02925299. Findings Of 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbA1c was 8·2% (SD 0·7) in the closed-loop group and 8·3% (0·7) in the control group. At 6 months, HbA1c was lower in the closed-loop group than in the control group (between-group difference −3·5 mmol/mol (95% CI −6·5 to −0·5 [–0·32 percentage points, −0·59 to −0·04]; p=0·023). Closed-loop usage was low with FlorenceM due to failing phone enclosures (median 40% [IQR 26–53]), but consistently high with CamAPS FX (93% [88–96]), impacting efficacy. A total of 155 adverse events occurred after randomisation (67 in the closed-loop group, 88 in the control group), including seven severe hypoglycaemia events (four in the closed-loop group, three in the control group), two diabetic ketoacidosis events (both in the closed-loop group), and two non-treatment-related serious adverse events. There were 23 reportable hyperglycaemia events (11 in the closed-loop group, 12 in the control group), which did not meet criteria for diabetic ketoacidosis. Interpretation The Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX.Item Combination Immunotherapy for Type 1 Diabetes(Springer, 2017-07) Bone, Robert N.; Evans-Molina, Carmella; Medicine, School of MedicinePurpose of Review Type 1 diabetes (T1D) is an autoimmune disease marked by β-cell destruction. Immunotherapies for T1D have been investigated since the 1980s and have focused on restoration of tolerance, T cell or B cell inhibition, regulatory T cell (Treg) induction, suppression of innate immunity and inflammation, immune system reset, and islet transplantation. The purpose of this review is to provide an overview and lessons learned from single immunotherapy trials, describe recent and ongoing combination immunotherapy trials, and provide perspectives on strategies for future combination clinical interventions aimed at preserving insulin secretion in T1D. Recent Findings Combination immunotherapies have had mixed results in improving short-term glycemic control and insulin secretion in recent-onset T1D. Summary A handful of studies have successfully reached their primary end-point of improved insulin secretion in recent-onset T1D. However, long-term improvements glycemic control and the restoration of insulin independence remain elusive. Future interventions should focus on strategies that combine immunomodulation with efforts to alleviate β-cell stress and address the formation of antigens that activate autoimmunity.Item Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention(Elsevier, 2020-02-04) Nakayasu, Ernesto S.; Syed, Farooq; Tersey, Sarah A.; Gritsenko, Marina A.; Mitchell, Hugh D.; Chan, Chi Yuet; Dirice, Ercument; Turatsinze, Jean-Valery; Cui, Yi; Kulkarni, Rohit N.; Eizirik, Decio L.; Qian, Wei-Jun; Webb-Robertson, Bobbie-Jo M.; Evans-Molina, Carmella; Mirmira., Raghavendra G.; Metz, Thomas O.; Pediatrics, School of MedicineType 1 diabetes (T1D) results from the progressive loss of β cells, a process propagated by pro-inflammatory cytokine signaling that disrupts the balance between pro- and anti-apoptotic proteins. To identify proteins involved in this process, we performed comprehensive proteomics of human pancreatic islets treated with interleukin-1β and interferon-γ, leading to the identification of 11,324 proteins, of which 387 were significantly regulated by treatment. We then tested the function of growth/differentiation factor 15 (GDF15), which was repressed by the treatment. We found that GDF15 translation was blocked during inflammation, and it was depleted in islets from individuals with T1D. The addition of exogenous GDF15 inhibited interleukin-1β+interferon-γ-induced apoptosis of human islets. Administration of GDF15 reduced by 53% the incidence of diabetes in NOD mice. Our approach provides a unique resource for the identification of the human islet proteins regulated by cytokines and was effective in discovering a potential target for T1D therapy.Item Contracting and Monitoring Relationships for Adolescents with Type 1 Diabetes: A Pilot Study(2011-04) Carroll, Aaron E.; DiMeglio, Linda A.; Stein, Stephanie; Marrero, David G.Background: Adolescents are developmentally in a period of transition—from children cared for by their parents to young adults capable of self-care, independent judgment, and self-directed problem solving. We wished to develop a behavioral contract for adolescent diabetes management that addresses some negotiable points of conflict within the parent–child relationship regarding self-monitoring and then assess its effectiveness in a pilot study as part of a novel cell phone–based glucose monitoring system. Methods: In the first phase of this study we used semistructured interview techniques to determine the major sources of diabetes-related conflict in the adolescent–parent relationship, to identify factors that could facilitate or inhibit control, and to determine reasonable goals and expectations. These data were then used to inform development of a behavioral contract that addressed the negotiable sources of conflict between parents and their adolescent. The second phase of this research was a 3-month pilot study to measure how a novel cell phone glucose monitoring system would support the contract and have an effect on glucose management, family conflict, and quality of life. Results: Interviews were conducted with 10 adolescent–caregiver pairs. The major theme of contention was nagging about diabetes management. Two additional themes emerged as points of negotiation for the behavioral contract: glucose testing and contact with the diabetes clinical team. Ten adolescent–parent pairs participated in the pilot test of the system and contract. There was a significant improvement in the Diabetes Self-Management Profile from 55.2 to 61.1 (P < 0.01). A significant reduction in hemoglobin A1c also occurred, from 8.1% at the start of the trial to 7.6% at 3 months (P < 0.04). Conclusions: This study confirms previous findings that mobile technologies do offer significant potential in improving the care of adolescents with type 1 diabetes. Moreover, behavioral contracts may be an important adjunct to reduce nagging and improve outcomes with behavioral changes.Item COVID-19 Pandemic Effects on Caregivers of Youth With Type 1 Diabetes: Stress and Self-Efficacy(American Diabetes Association, 2022-03-11) Ismail, Heba M.; Hand, Breanne L.; DiMeglio, Linda A.; Oyetoro, Rebecca; Soni, Priya Y.; Adams, Janey; Westen, Sarah; Driscoll, Kimberly A.; Albanese-O’Neill, Anastasia; Pediatrics, School of MedicineBackground Little is known about the coronavirus disease 2019 (COVID-19) pandemic’s psychological effects on caregivers of children with type 1 diabetes. Objective This study aimed to investigate the experience of caregivers of youth with type 1 diabetes during the COVID-19 pandemic. Methods A 49-item questionnaire using a 5-point Likert scale and open-response questions was distributed via e-mail and type 1 diabetes–related social media platforms from 4 May to 22 June 2020. Quantitative data were analyzed using SPSS v.25 statistical software. Descriptive statistics were used. Relationships were compared using Pearson correlation. Qualitative data were coded and categorized. Results A total of 272 caregivers participated (mean ± SD respondent age 42.1 ± 7.8 years; 94.5% females; 81.3% with college degree or higher; 52.6% with annual income >$99,000; 80.1% with private insurance). The mean ± SD age of caregivers’ children with type 1 diabetes was 11.0 ± 4.1 years, and their mean ± SD diabetes duration was 4.2 ± 3.5 years. Participants reported being diagnosed with or knowing someone with COVID-19 (24.6%), increased stress (71.9%), job loss (10.3%), and financial difficulty (26.8%) as a result of the pandemic. General self-efficacy scores were high (mean ± SD 16.2 ± 2.6, range 8–20) and significantly correlated with COVID-19–related self-efficacy (mean ± SD 12.6 ± 2.1; R = 0.394, P <0.001) and type 1 diabetes self-efficacy during COVID-19 (mean ± SD 17.1 ± 2.5; R = 0.421, P <0.001). Conclusion Despite reporting high overall self-efficacy, caregivers of children with type 1 diabetes reported greater overall stress and challenges during the pandemic. Health care providers should be prepared to provide families with specific social and mental health support.Item Differences in COVID-19 Outcomes Among Patients With Type 1 Diabetes: First vs Later Surges(MDedge, 2022-01) Gallagher, Mary Pat; Rompicherla, Saketh; Ebekozien, Osagie; Wilkes, Meredith; Antal, Zoltan; Feuer, Alexis Jamie; Rioles, Nicole; Noor, Nudrat; Gabriel, Liana; O’Malley, Grenye; Golden, Lauren; Alonso, G. Todd; Ospelt, Emma; Odugbesan, Ori; Lyons, Sarah K.; Mungmode, Ann; Prahalad, Priya; Clements, Mark; Neyman, Anna; Demeterco-Berggren, Carla; Rapaport, Robert; Pediatrics, School of MedicineBackground Outcomes of the novel coronavirus SARS-CoV-2 (COVID-19) have improved throughout the pandemic. However, whether outcomes of COVID-19 in the type 1 diabetes (T1D) population improved over time is unknown. Therefore, we aim to investigate differences in COVID-19 outcomes for patients with T1D in the US. Method We analyzed data collected via a registry of patients with T1D and COVID-19 from 56 sites between April 2020 and January 2021. First, we grouped cases into First Surge (04/09/2020 - 07/31/2020, n=188) and Late Surge (08/01/2020 - 01/31/2021, n=410). Then, we compared outcomes between both groups using descriptive statistics and logistic regression models. Results Adverse outcomes were more frequent during the first surge including Diabetic Ketoacidosis (32% versus 15%, p<0.001), severe hypoglycemia (4% versus 1%, p=0.04) and hospitalization (52% versus 22%, p<0.001). The First surge cases were older (28 +/- 18.8 years versus 18.8 +/- 11.1 years, p<0.001), had higher hemoglobin A1c (HbA1c) levels (Median (IQR): 9.3 (4.0) versus 8.4(2.8), <0.001) and use public insurance (n(%): 107 (57) versus 154 (38), p <0.001). There were five times increased odds of hospitalization for adults (OR 5.01 (2.11,12.63) in the first surge compared to the late surge. Conclusion COVID-19 cases among patients with T1D reported during the first surge had a higher proportion of adverse outcomes than those presented in a later surge.Item Early and late C-peptide responses during oral glucose tolerance testing are oppositely predictive of type 1 diabetes in autoantibody-positive individuals(Wiley, 2020-01-31) Ismail, Heba M.; Becker, Dorothy J.; Libman, Ingrid; Herold, Kevan C.; Redondo, Maria J.; Atkinson, Mark A.; Cleves, Mario A.; Palmer, Jerry; Sosenko, Jay; Pediatrics, School of MedicineWe 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.