Adolescent and Parent Perceptions of Long-Term Type 1 Diabetes Complications.

AIMS: Conversations about diabetes complications with adolescents and parents can be difficult and emotionally charged. To better inform conversations between providers and families, we sought adolescent and parent perspectives regarding their knowledge of long-term complications (LTCs), where they receive this information, and what they would like to learn from clinicians. METHODS: Adolescents with type 1 diabetes and parents of adolescents with type 1 diabetes participated in semistructured interviews querying knowledge of LTCs, sources of information, and preferred ways for providers to discuss LTCs. Interview transcripts were coded and categorized into central themes by content analysis. RESULTS: Participants included 22 adolescents (17.4 ± 1.7 years of age, diabetes duration 9.7 ± 4.0 years) and 25 parents (41-60 years of age, 84% mothers). Five themes related to complications were identified: 1) "Limited Adolescent Knowledge of Complications," 2) "Discussing Complications Is Important but Not Now or Not for Me," 3) "Outside Sources Overestimate Risk," 4) "Avoid Scare Tactics" and 5) "Emphasize Prevention." Adolescent and parent perspectives were similar, although parents showed greater understanding of complications. CONCLUSION: When discussing complications, individualized, factual, positive, and prevention-focused conversations may be better received by adolescents with type 1 diabetes and their families.

Management of cardiovascular disease risk in teens with type 1 diabetes: Perspectives of teens with and without dyslipidemia and parents.

Hypertension and dyslipidemia are often suboptimally managed in teens with type 1 diabetes (T1D). Teen and parent perspectives on hypertension and dyslipidemia management need further study to enhance the development of cardiovascular disease (CVD) risk factor management plans. We sought to describe barriers to and strategies for CVD risk factor management. Teens with T1D with and without dyslipidemia and parents of teens with T1D with and without dyslipidemia underwent one-on-one semi-structured interviews conducted by trained personnel at a diabetes center; interviews continued until thematic saturation was reached. Teens and parents of teens described their knowledge, attitudes, and beliefs regarding heart health and CVD risk factors (hypertension and dyslipidemia). Researchers undertook a content analysis and categorized central themes as strategies and barriers. In total, 22 teens and 25 parents completed interviews. Teens were 17.4 ± 1.7 years old with T1D duration 9.7 ± 4.0 years; 45% had dyslipidemia. Parents were between 41 and 60 years old, 84% were mothers, and 40% had teens with dyslipidemia. Barriers to heart health included an obesity-promoting environment, parental distrust of medications, and limited teen knowledge about hypertension and dyslipidemia. Strategies included specific and realistic guidance from providers, family support of teen lifestyle management, and having exercise partners. While teen and parent perspectives were often similar, some themes applied only to teens or parents. Central themes provide actionable guidance to enhance hypertension and dyslipidemia management. Providers should consider teen and parent perspectives when managing CVD risk factors to enhance engagement with CVD risk management.

Management of Hypertension and High Low-Density Lipoprotein in Pediatric Type 1 Diabetes.

OBJECTIVE: To evaluate hypertension and hyperlipidemia management patterns in youth with type 1 diabetes and to assess perceived effectiveness of management strategies and barriers to management. STUDY DESIGN: An electronic survey, including clinical scenarios, fielded to pediatric providers (members of the American Diabetes Association Diabetes in Youth Interest Group, Pediatric Endocrine Society, or T1D Exchange). RESULTS: Respondents (N = 207, 86% MDs, 68% female) were practicing clinicians for youth with type 1 diabetes. As an initial recommendation, the overwhelming majority of respondents (83%-99%) endorsed lifestyle and nonmedical recommendations (eg, improve glycemic control) for hypertension and hyperlipidemia. Yet, few (6%-17%) reported these recommendations as effective. Many respondents (57%) reported referring to another specialist for hypertension, whereas few (8%) reported referring to another specialist for hyperlipidemia management. Approximately one-fifth (21%) of respondents never initiate antihypertensive medications, whereas only 8% never initiate lipid-lowering medication. Among prescribers, the majority of respondents only started antihypertensive or lipid-lowering medications after persistent elevations and in the setting of either ineffective lifestyle or nonmedical interventions or additional cardiovascular risk factors. More than two-thirds of respondents endorsed medications as often effective for hypertension and hyperlipidemia (68% and 69%, respectively). CONCLUSIONS: Pediatric diabetes providers commonly defer prescribing antihypertensive and lipid-lowering medications until nonmedication interventions have been ineffective. Most providers describe medications, but not lifestyle interventions, as often effective. Efforts to align clinical practice with clinical guidelines are needed.

Challenges and Opportunities in the Management of Cardiovascular Risk Factors in Youth With Type 1 Diabetes: Lifestyle and Beyond.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in persons with type 1 diabetes (T1D). Specific risk factors associated with diabetes, such as hyperglycemia and kidney disease, have been demonstrated to increase the incidence and progression of CVD. Nevertheless, few data exist on the effects of traditional risk factors such as dyslipidemia, obesity, and hypertension on CVD risk in youth with T1D. Improvements in understanding and approaches to the evaluation and management of CVD risk factors, specifically for young persons with T1D, are desirable. Recent advances in noninvasive techniques to detect early vascular damage, such as the evaluation of endothelial dysfunction and aortic or carotid intima-media thickness, provide new tools to evaluate the progression of CVD in childhood. In the present review, current CVD risk factor management, challenges, and potential therapeutic interventions in youth with T1D are described.

Effect of Metformin Added to Insulin on Glycemic Control Among Overweight/Obese Adolescents With Type 1 Diabetes: A Randomized Clinical Trial.

IMPORTANCE: Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results. OBJECTIVE: To assess the efficacy and safety of metformin as an adjunct to insulin in treating overweight adolescents with type 1 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Multicenter (26 pediatric endocrinology clinics), double-blind, placebo-controlled randomized clinical trial involving 140 adolescents aged 12.1 to 19.6 years (mean [SD] 15.3 [1.7] years) with mean type 1 diabetes duration 7.0 (3.3) years, mean body mass index (BMI) 94th (4) percentile, mean total daily insulin 1.1 (0.2) U/kg, and mean HbA1c 8.8% (0.7%). INTERVENTIONS: Randomization to receive metformin (n = 71) (≤2000 mg/d) or placebo (n = 69). MAIN OUTCOMES AND MEASURES: Primary outcome was change in HbA1c from baseline to 26 weeks adjusted for baseline HbA1c. Secondary outcomes included change in blinded continuous glucose monitor indices, total daily insulin, BMI, waist circumference, body composition, blood pressure, and lipids. RESULTS: Between October 2013 and February 2014, 140 participants were enrolled. Baseline HbA1c was 8.8% in each group. At 13-week follow-up, reduction in HbA1c was greater with metformin (-0.2%) than placebo (0.1%; mean difference, -0.3% [95% CI, -0.6% to 0.0%]; P = .02). However, this differential effect was not sustained at 26-week follow up when mean change in HbA1c from baseline was 0.2% in each group (mean difference, 0% [95% CI, -0.3% to 0.3%]; P = .92). At 26-week follow-up, total daily insulin per kg of body weight was reduced by at least 25% from baseline among 23% (16) of participants in the metformin group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% CI, 11% to 32%]; P = .003), and 24% (17) of participants in the metformin group and 7% (5) of participants in the placebo group had a reduction in BMI z score of 10% or greater from baseline to 26 weeks (mean difference, 17% [95% CI, 5% to 29%]; P = .01). Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group (mean difference, 36% [95% CI, 19% to 51%]; P < .001). CONCLUSIONS AND RELEVANCE: Among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control after 6 months. Of multiple secondary end points, findings favored metformin only for insulin dose and measures of adiposity; conversely, use of metformin resulted in an increased risk for gastrointestinal adverse events. These results do not support prescribing metformin to overweight adolescents with type 1 diabetes to improve glycemic control. TRIAL REGISTRATION: clinicaltrials.org Identifier: NCT01881828.

Family-based psychoeducation and Care Ambassador intervention to improve glycemic control in youth with type 1 diabetes: a randomized trial.

OBJECTIVE: Youth with type 1 diabetes frequently do not achieve glycemic targets. We aimed to improve glycemic control with a Care Ambassador (CA) and family-focused psychoeducational intervention. RESEARCH DESIGN AND METHODS: In a 2-yr, randomized, clinical trial, we compared three groups: (i) standard care, (ii) monthly outreach by a CA, and (iii) monthly outreach by a CA plus a quarterly clinic-based psychoeducational intervention. The psychoeducational intervention provided realistic expectations and problem-solving strategies related to family diabetes management. Data on diabetes management and A1c were collected, and participants completed surveys assessing parental involvement in management, diabetes-specific family conflict, and youth quality of life (QOL). The primary outcome was A1c at 2 yr; secondary outcomes included maintaining parent involvement and avoiding deterioration in glycemic control. RESULTS: We studied 153 youth (56% female, median age 12.9 yr) with type 1 diabetes (mean A1c 8.4 ± 1.4%). There were no differences in A1c across treatment groups. Among youth with suboptimal baseline A1c ≥ 8%, more youth in the psychoeducation group maintained or improved their A1c and maintained or increased parent involvement than youth in the other two groups combined (77 vs. 52%, p = 0.03; 36 vs. 11%, p = 0.01, respectively) without negative impact on youth QOL or increased diabetes-specific family conflict. CONCLUSIONS: No differences in A1c were detected among the three groups at 2 yr. The psychoeducational intervention was effective in maintaining or improving A1c and parent involvement in youth with suboptimal baseline glycemic control.

Predictors of insulin pump initiation among people with type 2 diabetes from a US claims database using machine learning.

OBJECTIVE: Insulin pump use is increasing among people with type 2 diabetes (T2D), albeit at a slower rate compared to people with type 1 diabetes (T1D). Factors associated with insulin pump initiation among people with T2D in the real-world are understudied. METHODS: This retrospective, nested case-control study aimed to identify predictors of insulin pump initiation among people with T2D in the United States (US). Adults with T2D who were new to bolus insulin use were identified from the IBM MarketScan Commercial database (2015-2020). Candidate variables of pump initiation were entered into conditional logistic regression (CLR) and penalized CLR models. RESULTS: Of the 32,104 eligible adults with T2D, 726 insulin pump initiators were identified and matched to 2,904 non-pump initiators using incidence density sampling. Consistent predictors of insulin pump initiation across the base case, sensitivity, and post hoc analyses included continuous glucose monitor (CGM) use, visiting an endocrinologist, acute metabolic complications, higher count of HbA1c tests, lower age, and fewer diabetes-related medication classes. CONCLUSIONS: Many of these predictors could represent a clinical indication for treatment intensification, greater patient engagement in diabetes management, or proactive management by healthcare providers. Improved understanding of predictors for pump initiation may lead to more targeted efforts to improve access and acceptance of insulin pumps among persons with T2D.

Impact of type 1 diabetes mellitus on the family is reduced with the medical home, care coordination, and family-centered care.

OBJECTIVES: To examine whether the medical home, care coordination, or family-centered care was associated with less impact of type 1 diabetes mellitus (T1D) on families' work, finances, time, and school attendance. STUDY DESIGN: With the 2005 to 2006 National Survey of Children with Special Health Care Needs, we compared impact in children with T1D (n = 583) with that in children with other special health care needs (n = 39 944) and children without special health care needs (n = 4945). We modeled the associations of the medical home, care coordination, and family-centered care with family impact in T1D. RESULTS: Seventy-five percent of families of children with T1D reported a major impact compared with 45% of families of children with special health care needs (P < .0001) and 17% of families of children without special health care needs (P < .0001). In families of children with T1D, 35% reported restricting work, 38% reported financial impact, 41% reported medical expenses >$1000/year, 24% reported spending ≥11 hours/week caring or coordination care, and 20% reported ≥11 school absences/year. The medical home, care coordination, and family-centered care were associated with less work and financial impact. CONCLUSIONS: In childhood T1D, most families experience major impact. Better systems of health care delivery may help families reduce some of this impact.

Predictive Low-Glucose Suspend Necessitates Less Carbohydrate Supplementation to Rescue Hypoglycemia: Need to Revisit Current Hypoglycemia Treatment Guidelines.

Current guidelines recommend 15-20 g of carbohydrate (CHO) for treatment of mild to moderate hypoglycemia. However, these guidelines do not account for reduced insulin during suspensions with predictive low-glucose suspend (PLGS). We assessed insulin suspensions, hypoglycemic events, and CHO treatment during a 20-h inpatient evaluation of an investigational system with a PLGS feature, including an overnight basal up-titration period to activate the PLGS. Among 10 adults with type 1 diabetes, there were 59 suspensions; 7 suspensions were associated with rescue CHO and 5 with hypoglycemia. Rescue treatment consisted of median 9 g CHO (range: 5-16 g), with no events requiring repeat CHO. No rescue CHO were given during or after insulin suspension for the overnight basal up-titration. To minimize rebound hyperglycemia and needless calorie intake from hypoglycemia overtreatment, updated guidance for PLGS systems should reflect possible need to reduce CHO amounts for hypoglycemia rescue associated with an insulin suspension. The clinical trial was registered with ClinicalTrials.gov (NCT03890003).

Performance of an Automated Insulin Delivery System: Results of Early Phase Feasibility Studies.

Background: Automated insulin delivery (AID) systems have demonstrated improvements in time-in-range (TIR, blood glucose 70-180 mg/dL) without increasing hypoglycemia. Testing a closed-loop system in an inpatient environment with supervised challenges allows for initial evaluation of performance and safety of the system. Methods: Adults with type 1 diabetes (T1D) were enrolled into two similar studies (n = 10 per study), with 3-day inpatient analysis periods. Participants tested a Lilly hybrid closed-loop (HCL) system comprising an investigational insulin pump, insulin lispro, a pump-embedded model predictive control algorithm, a continuous glucose monitor (CGM), and an external dedicated controller. Each protocol included meal-related and exercise challenges to simulate real-world diabetes self-management errors. Only study staff interacted with the HCL system. Performance was assessed using standard CGM metrics overall and within prespecified periods. Results: Participants (25% male) had mean ± standard deviation (SD) age 44.7 ± 14.2 years, T1D duration 30.2 ± 11.1 years, A1C 7.2% ± 0.8%, and insulin usage 0.53 ± 0.21 U/(kg·day). Percentage TIR 70-180 mg/dL (mean ± SD) was 81.2 ± 8.4 overall, 85.2 ± 8.1 outside of challenge periods, 97.3 ± 5.3 during the nocturnal periods, and 74.5 ± 16.2 for the postprandial periods. During challenge periods, percentage TIR for the overbolus challenge was 65.4 ± 29.2 and that for the delayed bolus challenge was 57.1 ± 25.1. No adverse events (AEs), serious AEs, or unanticipated adverse device events occurred while participants were using the HCL system. Conclusions: In participants with T1D, Lilly AID system demonstrated expected algorithm performance and safety with satisfactory glycemic outcomes overall and in response to simulated diabetes management challenges. Additional studies in less supervised conditions and with broader patient populations are warranted. ClinicalTrials.gov Registration number NCT03743285, NCT03849612.

Risk Factors for Cardiovascular Disease (CVD) in Adults with Type 1 Diabetes: Findings from Prospective Real-life T1D Exchange Registry.

CONTEXT: Cardiovascular disease (CVD) is a major cause of mortality in adults with type 1 diabetes. OBJECTIVE: We prospectively evaluated CVD risk factors in a large, contemporary cohort of adults with type 1 diabetes living in the United States. DESIGN: Observational study of CVD and CVD risk factors over a median of 5.3 years. SETTING: The T1D Exchange clinic network. PATIENTS: Adults (age ≥ 18 years) with type 1 diabetes and without known CVD diagnosed before or at enrollment. MAIN OUTCOME MEASURE: Associations between CVD risk factors and incident CVD were assessed by multivariable logistic regression. RESULTS: The study included 8,727 participants (53% female, 88% non-Hispanic white, median age 33 years [interquartile ratio {IQR} = 21, 48], type 1 diabetes duration 16 years [IQR = 9, 26]). At enrollment, median HbA1c was 7.6% (66 mmol/mol) (IQR = 6.9 [52], 8.6 [70]), 33% used a statin, and 37% used blood pressure medication. Over a mean follow-up of 4.6 years, 325 (3.7%) participants developed incident CVD. Ischemic heart disease was the most common CVD event. Increasing age, body mass index, HbA1c, presence of hypertension and dyslipidemia, increasing duration of diabetes, and diabetic nephropathy were associated with increased risk for CVD. There were no significant gender differences in CVD risk. CONCLUSION: HbA1c, hypertension, dyslipidemia and diabetic nephropathy are important risk factors for CVD in adults with type 1 diabetes. A longer follow-up is likely required to assess the impact of other traditional CVD risk factors on incident CVD in the current era.

Baseline Psychosocial Characteristics Predict Frequency of Continuous Glucose Monitoring in Youth with Type 1 Diabetes.

BACKGROUND: Consistent use of continuous glucose monitoring (CGM) has been associated with improved glycemic control in youth with type 1 diabetes (T1D). There are many barriers to device uptake and continued use. There is a need to understand patient-specific characteristics when considering CGM. We evaluated patterns of CGM use and associations between baseline psychosocial measures and frequency of CGM use over 1 year. METHODS: Youth with T1D (n = 120), ages 8-18 years, completed questionnaires at CGM initiation and after 6 and 12 months assessing depressive symptoms, diabetes burden, and diabetes-specific and generic quality of life (QOL). RESULTS: Youth (51% male and 95% white) had mean age 12.7 ± 2.7 years, diabetes duration 6.1 ± 3.6 years, and glycated hemoglobin (HbA1c) 8.0 ± 0.8%. Over 1 year, 35% of youth used CGM 6 to 7 days per week, 45% used CGM 3-5 days per week, and 20% used CGM only 0-2 days per week. Youth who used CGM 3-7 days per week over 12 months had lower HbA1c at months 9 and 12 than youth who used CGM 0-2 days per week (9 months: 7.9 ± 0.9% vs. 8.5 ± 1.1%, P = 0.006 and 12 months: 8.0 ± 0.9% vs. 8.5 ± 1.1%, P = 0.02). Those using CGM 0-2 days per week had greater endorsement of depressive symptoms and diabetes burden and reported lower QOL at baseline compared with those using CGM 3-7 days per week. CONCLUSIONS: CGM use for 3 or more days per week over 12 months had a protective effect on HbA1c. Providers should consider addressing psychosocial parameters when initiating CGM to maximize uptake and promote continued use in youth with T1D.

Recruitment Into a Pediatric Continuous Glucose Monitoring RCT.

BACKGROUND: The purpose was to identify patient/family characteristics and recruitment process characteristics associated with the decision to participate in a 2-year continuous glucose monitoring (CGM) RCT for youth with type 1 diabetes and their families. METHOD: Study staff approached patients who were conditionally eligible according to medical record review or referred by a provider. We categorized families according to participation decision (agree vs decline) and timing of decision (day of approach vs later ["thinkers"]). RESULTS: Over 18 months, we approached 456 eligible patients; 19% agreed on the day of approach, 10% agreed later, 42% declined on the day of approach, and 30% declined later. Agreers were younger ( P = .002), had shorter diabetes duration ( P = .0003), had a lower insulin dose ( P = .02), checked blood glucose levels more often ( P = .002), and were more likely to use pump therapy ( P = .009) than decliners. Patients/families were more likely to agree in fall/winter (41%) than spring/summer (19%, P < .0001). Of decliners, 50% cited no interest in CGM as the reason for nonparticipation. Among thinkers, 49% of patients who made a decision within 2 weeks of being approached agreed; only 15% of thinkers who made a decision >2 weeks after being approached agreed to participate ( P < .0001). CONCLUSIONS: Recruitment is a critical and often challenging phase of clinical trials. Recruitment to pediatric CGM studies may be especially challenging due to youths' reluctance to use CGM. These data provide an opportunity to better understand and possibly optimize recruitment into future pediatric CGM studies and other studies of advanced diabetes technologies.

Influence of HbA1c and BMI on Lipid Trajectories in Youths and Young Adults With Type 1 Diabetes.

OBJECTIVE: To assess the influence of HbA1c and BMI (measured as BMI z score [zBMI]) on LDL, HDL, and non-HDL trajectories as youths with type 1 diabetes age into early adulthood. RESEARCH DESIGN AND METHODS: Dynamic, retrospective cohort study examining changes in lipid values in 572 youths with type 1 diabetes followed longitudinally for a median of 9.3 years. Through longitudinal modeling, we describe the relationship of HbA1c and zBMI on lipid values as subjects age after adjusting for other relevant factors, including lipid-lowering medication use. RESULTS: The median number of lipid assessments was 7 (range 2-39). Every 1% increase in HbA1c was associated with an ∼2-6 mg/dL increase in LDL levels, with a greater increase in LDL levels as subjects progressed from prepubertal to postpubertal age ranges. A 1-SD increase in BMI was associated with a mean LDL increase of 2.1 mg/dL when subjects were 10 years old and increased to a mean of 8.2 mg/dL when subjects were 19 years old. The association between changes in HbA1c level and zBMI and changes in non-HDL levels as youths aged were similar to the associations found with LDL. The influence of HbA1c and zBMI on HDL levels was small and not dependent on age. CONCLUSIONS: Changes in HbA1c level and zBMI modestly impact LDL and non-HDL cholesterol and have greater impacts as children age. Addressing elevations in HbA1c and zBMI as children enter into adolescence and beyond may lead to improvements in lipid levels.

Analysis of patient outcomes following proton radiation therapy for retinoblastoma.

PURPOSE: Proton radiotherapy (PRT) is used in the treatment of retinoblastoma (RB) and has the potential to minimize exposure of normal tissue to radiation and thus decrease risk of toxicity and second malignancies. However, comprehensive analyses of long-term patient outcomes are not available. METHODS: RB patients treated with PRT at our institution between 1986 and 2012 were invited to return for participation in a study designed to assess long-term outcomes. Enrolled patients underwent comprehensive analysis including oncologic, ophthalmic, endocrine, cephalometric, and quality of life (QOL) assessments. RESULTS: A total of 12 patients were enrolled in this study, and the average length of follow-up among enrolled patients was 12.9 years (range 4.8-22.2 years). All enrolled patients had bilateral disease, and the disease and visual outcomes for enrolled patients were similar to outcomes for all RB patients treated with PRT over the same time period at our institution. Endocrine evaluation revealed no growth abnormalities or hormonal deficiencies across the cohort. Based on MRI and external cephalometry, PRT was associated with less facial hypoplasia than enucleation. Patient and parent-proxy QOL assessments revealed that RB treatment did not appear to severely impact long-term QOL. CONCLUSIONS: In addition to providing an opportunity for long-term disease control and functional eye preservation, PRT does not appear to be associated with unexpected late visual, endocrine, or QOL effects in this cohort.

Youth and parent measures of self-efficacy for continuous glucose monitoring: survey psychometric properties.

BACKGROUND: This study aimed to describe the development and psychometric evaluation of novel youth and parent measures of self-efficacy related to continuous glucose monitoring (CGM) in pediatric patients with type 1 diabetes. This evaluation also assessed the predictive validity of the CGM Self-Efficacy (CGM-SE) surveys on CGM use and hemoglobin A1c (HbA1c) levels. SUBJECTS AND METHODS: Study participants included 120 youth with type 1 diabetes for ≥1 year enrolled in a 2-year randomized clinical trial comparing CGM use with and without the addition of a family-focused CGM behavioral intervention. Youth and parents completed the CGM-SE surveys at randomization after a 1-week run-in to assess CGM tolerability. Analyses of predictive validity excluded the intervention group and included 61 youth in the control group in order to assess CGM use and HbA1c outcomes 3 and 6 months after randomization. RESULTS: At study entry, youth were 12.7±2.7 years old with a diabetes duration of 6.1±3.6 years and an HbA1c level of 8.0±0.8% (64±9 mmol/mol); blood glucose monitoring frequency was 6.8±2.4 times/day, and 84% received pump therapy. CGM-SE surveys had acceptable internal consistency (Cronbach's α=0.80 for youth and 0.82 for parents). Youth reporting higher baseline CGM self-efficacy (CGM-SE score of >80) had significantly greater CGM use and lower HbA1c level after 3 and 6 months compared with youth reporting lower baseline CGM self-efficacy (CGM-SE score of ≤80). CONCLUSIONS: The CGM-SE surveys appear to have strong psychometric properties. CGM self-efficacy may offer an opportunity to assess the likelihood of CGM adherence and glycemic improvement in youth with type 1 diabetes in clinical and research settings.