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Browsing by Author "Woerner, Stephanie E."
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Item Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes(Elsevier, 2023) Sims, Emily K.; Kulkarni, Abhishek; Hull, Audrey; Woerner, Stephanie E.; Cabrera, Susanne; Mastrandrea, Lucy D.; Hammoud, Batoul; Sarkar, Soumyadeep; Nakayasu, Ernesto S.; Mastracci, Teresa L.; Perkins, Susan M.; Ouyang, Fangqian; Webb-Robertson, Bobbie-Jo; Enriquez, Jacob R.; Tersey, Sarah A.; Evans-Molina, Carmella; Long, S. Alice; Blanchfield, Lori; Gerner, Eugene W.; Mirmira, Raghavendra G.; DiMeglio, Linda A.; Pediatrics, School of MedicineIn preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing β cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with β cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during β cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125-1,000 mg/m2) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve β cell function in T1D through islet cell-autonomous effects.Item Nighttime is the worst time: Parental fear of hypoglycemia in young children with type 1 diabetes(Wiley, 2018-02) Van Name, Michelle A.; Hilliard, Marisa E.; Boyle, Claire T.; Miller, Kellee M.; DeSalvo, Daniel J.; Anderson, Barbara J.; Laffel, Lori M.; Woerner, Stephanie E.; DiMeglio, Linda A.; Tamborlane, William V.; Pediatrics, School of MedicineBACKGROUND: Fear of hypoglycemia is common in parents of young children with type 1 diabetes (T1D), but little is known about the specific fears that parents most often experience. Hypoglycemia fear has been associated with poorer glycemic control in older children, though not yet studied in a large cohort of very young children. MATERIALS AND METHODS: Parents of 549 children <7 years (mean 5.2 ± 1.2 years [19% <3 years]) with a mean diabetes duration of 2.4 ± 1.0 years (range 1-6 years) and mean HbA1c 8.2% ± 1.1% (66 ± 12 mmol/mol) registered in the T1D Exchange completed the worry scale of the Hypoglycemia Fear Survey modified for parents (HFS-P). RESULTS: Mean parental fear of hypoglycemia worry score was 36.1 ± 23.1 (possible range 0-100), with most frequent worries related to the child having a low while asleep and the child not recognizing a low. The mean worry score was not associated with the child's age, glycemic control, or recent severe hypoglycemic event. Parental worries about lows while sleeping were significantly higher in pump users than non-users (61% vs. 45%; P < .001), and tended to be higher in CGM users than non-users (62% vs 51%; P = .02). CONCLUSIONS: The greatest worries of parents of young children with T1D were related to hypoglycemia during sleep and other times/circumstances during which it would be difficult to detect hypoglycemia. Using advanced diabetes technologies may be an effort to temper fears about hypoglycemia during sleep, though the directionality of this relationship is undetermined. Additional studies can clarify this association and leverage use of diabetes technologies to improve glycemic control.Item Optimizing the use of continuous glucose monitoring in young children with type 1 diabetes with an adaptive study design and multiple randomizations(Elsevier, 2019) Berget, Cari; Driscoll, Kimberly A.; Lagges, Ann; Lange, Samantha; DiMeglio, Linda A.; Hannon, Tamara S.; Woerner, Stephanie E.; Iturralde, Esti; Barley, Regan C.; Hanes, Sarah; Hood, Korey K.; Buckingham, Bruce B.; Psychiatry, School of MedicineParents of young children with type 1 diabetes (T1D) experience unique, developmental challenges in managing their child's T1D, resulting in psychosocial distress. Only a small portion of young children reach glucose goals and adherence to diabetes devices that help improve T1D management have historically been low in this population. The purpose of this study is to test four interventions that couple developmentally tailored behavioral supports with education to optimize use of diabetes devices, improve glucose control, and reduce psychosocial distress for parents of young children with T1D. The study team designed four behavioral interventions, two aimed at improving glucose control and two aimed at optimizing use of diabetes devices. The goal of this paper is to describe the behavioral interventions developed for this study, including the results of a pilot test, and describe the methods and analysis plan to test this intervention strategy with ninety participants in a large-scale, randomized trial using a sequential multiple assignment randomization trial (SMART) design. A SMART design will permit a clinically relevant evaluation of the intervention strategy, as it allows multiple randomizations based on individualized assessments throughout the study instead of a fixed intervention dose seen in most traditional randomized controlled trials.Item Peripheral immune circadian variation, synchronisation and possible dysrhythmia in established type 1 diabetes(Springer, 2021-08) Beam, Craig A.; Beli, Eleni; Wasserfall, Clive H.; Woerner, Stephanie E.; Legge, Megan T.; Evans-Molina, Carmella; McGrail, Kieran M.; Silk, Ryan; Grant, Maria B.; Atkinson, Mark A.; DiMeglio, Linda A.; Pediatrics, School of MedicineAims/hypothesis: The circadian clock influences both diabetes and immunity. Our goal in this study was to characterise more thoroughly the circadian patterns of immune cell populations and cytokines that are particularly relevant to the immune pathology of type 1 diabetes and thus fill in a current gap in our understanding of this disease. Methods: Ten individuals with established type 1 diabetes (mean disease duration 11 years, age 18-40 years, six female) participated in a circadian sampling protocol, each providing six blood samples over a 24 h period. Results: Daily ranges of population frequencies were sometimes large and possibly clinically significant. Several immune populations, such as dendritic cells, CD4 and CD8 T cells and their effector memory subpopulations, CD4 regulatory T cells, B cells and cytokine IL-6, exhibited statistically significant circadian rhythmicity. In a comparison with historical healthy control individuals, but using shipped samples, we observed that participants with type 1 diabetes had statistically significant phase shifts occurring in the time of peak occurrence of B cells (+4.8 h), CD4 and CD8 T cells (~ +5 h) and their naive and effector memory subsets (~ +3.3 to +4.5 h), and regulatory T cells (+4.1 h). An independent streptozotocin murine experiment confirmed the phase shifting of CD8 T cells and suggests that circadian dysrhythmia in type 1 diabetes might be an effect and not a cause of the disease. Conclusions/interpretation: Future efforts investigating this newly described aspect of type 1 diabetes in human participants are warranted. Peripheral immune populations should be measured near the same time of day in order to reduce circadian-related variation.Item SAT107 Assessing Continuous Glucose Monitor Alarm Use By Families Of Children With Diabetes(The Endocrine Society, 2023-10-05) Ochs, Victoria S.; Woerner, Stephanie E.; Ustyol, Ala; DiMeglio, Linda A.; Graduate Medical Education, School of MedicineBackground: Continuous glucose monitors (CGM) offer customizable alarms which alert persons with diabetes and their caregivers of current or pending glycemic changes. However, there has been little work studying real-world CGM alert setting use in large clinical populations. We sought to understand CGM alarm use through report analyses. Methods: After IRB approval we analyzed data from two-week CGM reports obtained clinically to determine common settings and compared those to target guidelines. Results: CGM download data from 150 children using a Dexcom® G6 were analyzed (median age 14y, (range: 1-19), 89% white, 9.5% black, and 1.5% Asian, 47% female, 51% pump users). Median A1c was 7.8% (range: 5.4-15). Median CGM glucose was 190 (range: 56-374). Average time in range was 47.7% (range: 3.4-99.1).A Low Alarm alert was set for 131 participants (87%) with a median sensor glucose alert threshold of 74 mg/dL (range: 60-100). The High Alarm was used by 109 children (73%) with a median threshold of 272 mg/dL (range: 120-400). The Signal Loss alarm was used by 103 (69%) participants with a median time until notification of 20 min (range: 20-240). Low Repeat and High Repeat alarms were used by only 50 (33%) and 36 (24%) of children, respectively. Rise Rate and Fall Rate alarms were used by 18 (12%) and 34 (23%). There was a significant difference between the median High alarm cutoff of 272 mg/dL and a recommended standard (e.g. PantherProgram.org) of 250 mg/dL (p=0.0016). The same was true with the median Low alarm cutoff of 74 mg/dL and a recommended 70 mg/dL (p<0.0001). There was significant difference between the median High Repeat notification time of 1 hour and the recommended 2 hours (p<0.0001). Pump users were 2.2x more likely to use High Repeat alarms compared to injection users (95% CI: 1.18-4.15, p<0.01). The same was true with the Low Repeat alarm being 1.8x more likely to be used by pumpers compared to injection users (95% CI: 1.12-2.99, p=0.01). There were no significant differences in Low, High, Rise Rate, Fall Rate, Urgent Low Soon, Urgent Low Soon Repeat, or Signal Loss alarms. When the group was divided based on age, above 12 and <=12, younger CGM users were 1.2 times more likely to use the Low alarm compared to older users (95% CI: 1.03-1.30). Also, younger CGM users were more likely to use the Rise Rate (RR=3.6, 95% CI:1.37-9.67), Low Repeat (RR=1.7, 95% CI:1.09-2.71), Signal Loss (RR=1.3, 95% CI:1.04-1.60), Urgent Low Soon (RR=1.2, 95% CI:1.07-1.41), and Urgent Low Soon Repeat (RR=1.2, 95% CI:1.05-1.38) alarms. There were no significant differences in High, High Repeat, or Fall Rate alarm settings. Conclusions: The wide variability of alarm settings used by patients indicates likely educational gaps in CGM onboarding and use. Ensuring CGM alarm best practices will help children with diabetes and their caregivers get needed real-time glycemic data while minimizing alarm fatigue.