DNA Methylation-Based Assessment of Cell Composition in Human Pancreas and Islets.

Assessment of pancreas cell type composition is crucial to the understanding of the genesis of diabetes. Current approaches use immunodetection of protein markers, for example, insulin as a marker of ß-cells. A major limitation of these methods is that protein content varies in physiological and pathological conditions, complicating the extrapolation to actual cell number. Here, we demonstrate the use of cell type-specific DNA methylation markers for determining the fraction of specific cell types in human islet and pancreas specimens. We identified genomic loci that are uniquely demethylated in specific pancreatic cell types and applied targeted PCR to assess the methylation status of these loci in tissue samples, enabling inference of cell type composition. In islet preparations, normalization of insulin secretion to ß-cell DNA revealed similar ß-cell function in pre-type 1 diabetes (T1D), T1D, and type 2 diabetes (T2D), which was significantly lower than in donors without diabetes. In histological pancreas specimens from recent-onset T1D, this assay showed ß-cell fraction within the normal range, suggesting a significant contribution of ß-cell dysfunction. In T2D pancreata, we observed increased α-cell fraction and normal ß-cell fraction. Methylation-based analysis provides an accurate molecular alternative to immune detection of cell types in the human pancreas, with utility in the interpretation of insulin secretion assays and the assessment of pancreas cell composition in health and disease.

Cost-Effectiveness of Low-Dose Antithymocyte Globulin Versus Other Immunotherapies for Treatment of New-Onset Type 1 Diabetes.

Objective: Several immunotherapies have shown efficacy in slowing C-peptide decline in new-onset type 1 diabetes. Although most of these biologic drugs are expensive, they offer the opportunity to reduce downstream disease management costs and risk of complications. The objective of this study is to examine the cost-effectiveness of immunotherapies versus no treatment for patients with new-onset type 1 diabetes. Methods: Using Markov microsimulation modeling and efficacy data from immunotherapy trials, we examined the cost-effectiveness of six immunotherapies for new-onset type 1 diabetes, namely, low-dose (2.5 mg/kg) antithymocyte globulin (ATG), high-dose (6.5 mg/kg) ATG, abatacept, alefacept, rituximab, and teplizumab, versus no treatment. Effectiveness was measured by quality-adjusted life-years (QALYs). Costs were estimated from a health system perspective. Results: Low-dose ATG treatment saves US$10,270, on average, over a patient's lifetime and generates 0.09 additional QALYs compared with no treatment. These cost savings arise as low-dose ATG generates downstream savings in disease management costs that more than offset its cost. In contrast, treatment with other immunotherapies yields smaller QALY gains (0.02-0.05 additional QALYs) and increases lifetime costs by US$9500-US$168,380 relative to no treatment, with incremental cost-effectiveness ratios that exceed the willingness-to-pay threshold of US$100,000 per QALY. Conclusions: Low-dose ATG treatment is both less costly and more effective relative to other immunotherapies and no treatment for new-onset type 1 diabetes.

Use of Ecological Momentary Assessment to Measure Self-Monitoring of Blood Glucose Adherence in Youth With Type 1 Diabetes.

OBJECTIVE: Daily self-monitoring of blood glucose (SMBG) is essential for type 1 diabetes management yet is challenging during adolescence. Ecological momentary assessment (EMA) is the repeated sampling of behaviors and experiences in real time in the natural environment. The purpose of this study was to evaluate 1) the validity of self-reported SMBG values via text message-delivered EMA surveys compared with objective SMBG values via glucose meters and 2) in-the-moment motivators and barriers to performing SMBG in a pediatric type 1 diabetes population. METHODS: Youth (n = 62, aged 11-21 years) with type 1 diabetes received three text messages daily for 10 days containing surveys inquiring about SMBG engagement. Objective SMBG values were downloaded from glucose meters. RESULTS: On average, participants reported performing SMBG 4 times/day. Of the self-reported SMBG values, 39.6% were accurate. Inaccurate values included additions (i.e., self-reported value with no objective value), omissions (i.e., objective value with no self-reported value), and alterations (difference between self-report and objective SMBG values ≥10 mg/dL). Of the matched pairs of self-reported and objective SMBG values, 41.3% were altered. Bland-Altman plots determined that the mean difference between self-reported and objective glucose data were -5.43 mg/dL. Participants reported being motivated to check their blood glucose because it was important for their health, and reported barriers included wanting to ignore the task, forgetting, and not having devices. CONCLUSION: Youth's self-reported SMBG values may not align with objective readings. The results of this study can facilitate future research to determine individual factors related to SMBG and accuracy of self-reporting.

Propelling Health Care into the Twenties.

The scope and potential of personalised health care are underappreciated and underrealised, often because of resistance to change. The consequence is that many inadequacies of health care in Europe persist unnecessarily, and many opportunities for improvement are neglected. This article identifies the principal challenges, outlines possible approaches to resolving them, and highlights the benefits that could result from greater adoption of personalised health care. It locates the discussion in the context of European policy, focusing particularly on the most recent and authoritative reviews of health care in the EU Member States, and on the newly acquired spirit of readiness and pragmatism among European officials to embrace change and innovative technologies in a new decade. It highlights the attention now being given by policymakers to incentives, innovation, and investment as levers to improve European citizens' prospects in a rapidly evolving world, and how these distinct and disruptive themes contribute to a renaissance in thinking about delivering optimal health care in Europe. It explores the chances offered to patients by specific initiatives in health domains such as cancer and antimicrobial resistance, and by innovative science, novel therapies, earlier diagnosis tools, and deeper understanding of health promotion and prevention. And it reflects on how health care providers could benefit from a shift towards better primary care and towards deploying health data more effectively, including the use of artificial intelligence, coupled with a move to a smoother organisational/regulatory structure and realigned professional responsibilities. The conclusion is that preparing Europe's health care systems for the inevitable strains of the coming years is both possible and necessary. A more courageous approach to embracing personalised health care could guarantee the sustainability of Europe's health care systems before rising demands and exponential costs overwhelm them - an exercise in future-proofing, in ensuring that they are equipped to withstand whatever lies ahead. A focus on the potential and implementation of personalised care would permit more efficient use of resources and deliver better quality health-preserving care.

Addressing health disparities in type 1 diabetes through peer mentorship.

Pronounced health disparities exist in type 1 diabetes (T1D) based on socioeconomic status (SES) yet there are a lack of programs designed to promote health equity for vulnerable communities. The All for ONE (Outreach, Networks, and Education) mentoring program was piloted pairing college students and publicly insured teenagers with T1D to assess feasibility as a possible intervention. There were 22 mentors recruited (mean age 20 ± 2 years; 17 [77%] females; mean HbA1c 8.4 ± 1.5%) and matched with mentees based on gender. There were 42 teens randomized to treatment and control groups including 22 teens in the treatment group (age 14 ± 2 years; 17 [77%] females; HbA1c 9.8 ± 2.3%) and 20 teens in the control group (age 14 ± 2 years; 15 [75%] females; HbA1c 8.9 ± 2.0%) followed over 9 months. Outcome measures included HbA1c and the Children's Hope Scale. The intervention included automated text reminders for blood glucose monitoring, text exchanges, social events with education, and clinic visits with mentors/mentees. Mean change in HbA1c for teens was +0.09% in the intervention group, compared with +0.28% in the control group (P = .61); college students had a reduction in HbA1c of -0.22% (P = .38). Treatment group teens had marked improvement in their hope for the future compared to control group teens (P = .04) and were more likely to attend clinic visits (P = .02). This program established feasibility for a model that could be replicated and modified for other types of settings. Additional research is warranted to study the potential long-term benefits of participating in the All for ONE mentoring program.

International Consensus on Risk Management of Diabetic Ketoacidosis in Patients With Type 1 Diabetes Treated With Sodium-Glucose Cotransporter (SGLT) Inhibitors.

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.

Hemoglobin A1c (HbA1c) changes over time among adolescent and young adult participants in the T1D exchange clinic registry.

OBJECTIVE: Hemoglobin A1c (HbA1c) levels among individuals with type 1 diabetes (T1D) influence the longitudinal risk for diabetes-related complications. Few studies have examined HbA1c trends across time in children, adolescents, and young adults with T1D. This study examines changes in glycemic control across the specific transition periods of pre-adolescence-to-adolescence and adolescence-to-young adulthood, and the demographic and clinical factors associated with these changes. RESEARCH DESIGN AND METHODS: Available HbA1c lab results for up to 10 yr were collected from medical records at 67 T1D Exchange clinics. Two retrospective cohorts were evaluated: the pre-adolescent-to-adolescent cohort consisting of 85 016 HbA1c measurements from 6574 participants collected when the participants were 8-18 yr old and the adolescent-to-young adult cohort, 2200 participants who were 16-26 yr old at the time of 17 279 HbA1c measurements. RESULTS: HbA1c in the 8-18 cohort increased over time after age 10 yr until ages 16-17; followed by a plateau. HbA1c levels in the 16-26 cohort remained steady from 16-18, and then gradually declined. For both cohorts, race/ethnicity, income, health insurance, and pump use were all significant in explaining individual variations in age-centered HbA1c (p < 0.001). For the 8-18 cohort, insulin pump use, age of onset, and health insurance were significant in predicting individual HbA1c trajectory. CONCLUSIONS: Glycemic control among patients 8-18 yr old worsens over time, through age 16. Elevated HbA1c levels observed in 18 yr-olds begin a steady improvement into early adulthood. Focused interventions to prevent deterioration in glucose control in pre-adolescence, adolescence, and early adulthood are needed.

Defining pathways for development of disease-modifying therapies in children with type 1 diabetes: a consensus report.

Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course. Therefore, the efficacy of disease-modifying therapies may be different in the two populations. Understanding the developmental and regulatory pathways for type 1 diabetes-modifying therapies in children will enable industry, academia, funders, advocacy groups, and regulators to translate new science to clinical care. This consensus report characterizes the fundamental differences in type 1 diabetes between children and adults and proposes a thoughtful approach to better understand the development and regulatory pathways for type 1 diabetes therapies.

Screening for T1D risk to reduce DKA is not economically viable.

BACKGROUND: Children at high risk for developing type 1 diabetes (T1D) can be identified on the basis of human leukocyte antigen (HLA) genotype and the subsequent development of islet cell autoantibodies. Several studies have documented reduced incidence of diabetic ketoacidosis (DKA) in new-onset T1D when high-risk children are identified at an early age. Many have questioned whether general population screening for T1D risk should be standard of practice. We sought to perform a purely economic, cost-benefit analysis to determine if a screening program to reduce the incidence of DKA at diagnosis in children less than 5 yr is cost effective. METHODS: We compared the cost of population screening with the benefit of preventing DKA. The cost of screening included one-time HLA typing on the entire population followed by islet cell autoantibody testing in high-risk children every 6 months until age 5 yr. The potential benefits of screening included reductions in parental lost income, medical expenses, morbidity, and mortality. RESULTS: Screening for T1D risk for the sole purpose of reducing the cost of DKA at onset of T1D was not economically viable unless HLA testing and autoantibody testing could be performed for less than $1 and $0.03, respectively. CONCLUSIONS: Current screening costs far outweigh the economic benefits of preventing new-onset DKA in children under 5 yr of age.

Erratum: Disparities in Social Support for Youths With Type 1 Diabetes. Clinical Diabetes 2015;33:62-69.

[This corrects the article on p. 62 in vol. 33, PMID: 25897185.].

Disparities in social support systems for youths with type 1 diabetes.

IN BRIEF Low socioeconomic status (SES) is consistently identified as a major risk factor for poor health outcomes in youths with type 1 diabetes, yet little is known about the social factors that yield such disparities. This study used survey research to examine the role of SES by focusing on differential resourcing in social support systems for youths with type 1 diabetes and their parents/caregivers. We identified significant inequalities in social support systems and found that parents from lower-income households engage in few coping activities and rarely identify a primary care provider as the main point of contact when facing a diabetes-related problem. Our findings underscore the need to better connect low SES families to diabetes-specific professional resourcing and to raise awareness about the importance of extracurricular activities as a form of social support for youths.

Race, socioeconomic status, and treatment center are associated with insulin pump therapy in youth in the first year following diagnosis of type 1 diabetes.

BACKGROUND: Increasing numbers of children and adolescents with type 1 diabetes (T1D) have been placed on insulin pump therapy. Nevertheless, data are limited regarding patterns of pump use during the first year of treatment and the clinical and socioeconomic factors associated with early use of pump therapy. Therefore, we sought to determine factors associated with pump therapy within the first year of diagnosis in youth enrolled in the Pediatric Diabetes Consortium (PDC) T1D New-Onset (NeOn) Study. SUBJECTS AND METHODS: The NeOn Study includes youth <19 years old at T1D diagnosis who have been followed from the time of diagnosis at seven U.S. pediatric diabetes centers. Cox regression was used to determine factors associated with transition from injection to pump therapy during the first year of T1D in 1,012 participants. RESULTS: Twenty-seven percent (n=254) of participants began pump therapy within the first year of diagnosis, ranging from 18% to 59% among the seven centers. After adjusting for center effect, factors associated with pump use in multivariate analysis included private health insurance (37% vs. 7%; P<0.001), having annual household income over $100,000 (50% vs. 15%; P<0.001), and non-Hispanic white race (36% vs. 11%; P<0.001). The hemoglobin A1c level did not appear to influence the decision to initiate pump use. CONCLUSIONS: Participants of non-Hispanic white race and higher socioeconomic status were more likely to be placed on pumps during the first year. Further investigations are needed to gain a better understanding of barriers to use of pumps in youth with T1D, especially in disadvantaged and minority families.

Estimating the cost of type 1 diabetes in the U.S.: a propensity score matching method.

BACKGROUND: Diabetes costs represent a large burden to both patients and the health care system. However, few studies that examine the economic consequences of diabetes have distinguished between the two major forms, type 1 and type 2 diabetes, despite differences in underlying pathologies. Combining the two diseases implies that there is no difference between the costs of type 1 and type 2 diabetes to a patient. In this study, we examine the costs of type 1 diabetes, which is often overlooked due to the larger population of type 2 patients, and compare them to the estimated costs of diabetes reported in the literature. METHODOLOGY/PRINCIPAL FINDINGS: Using a nationally representative dataset, we estimate yearly and lifetime medical and indirect costs of type 1 diabetes by implementing a matching method to compare a patient with type 1 diabetes to a similar individual without the disease. We find that each year type 1 diabetes costs this country $14.4 billion (11.5-17.3) in medical costs and lost income. In terms of lost income, type 1 patients incur a disproportionate share of type 1 and type 2 costs. Further, if the disease were eliminated by therapeutic intervention, an estimated $10.6 billion (7.2-14.0) incurred by a new cohort and $422.9 billion (327.2-519.4) incurred by the existing number of type 1 diabetic patients over their lifetime would be avoided. CONCLUSIONS/SIGNIFICANCE: We find that the costs attributed to type 1 diabetes are disproportionately higher than the number of type 1 patients compared with type 2 patients, suggesting that combining the two diseases when estimating costs is not appropriate. This study and another recent contribution provides a necessary first step in estimating the substantial costs of type 1 diabetes on the U.S.

Managed care organization characteristics and outpatient specialty care use among children with chronic illness.

BACKGROUND: Limited information is available about managed care organization (MCO) characteristics that influence outpatient physician specialist use among children with chronic conditions. OBJECTIVE: To examine the association between MCO characteristics and outpatient physician specialist use among children with chronic conditions who were receiving care in MCOs in which primary care providers (PCPs) served as gatekeepers for referrals and who were publicly insured. DESIGN AND METHODS: A total of 2333 children who had been diagnosed with a chronic condition and had functional limitations, an increased need for or use of health care services beyond what children normally use, and/or dependence on medications or home medical equipment were included in the study. The odds of an outpatient physician specialist visit 1 year after study entry were examined as a function of child health and sociodemographic characteristics, MCO characteristics, the child's prior specialty care use, and provider availability in the MCO service delivery area. RESULTS: Children cared for in MCOs with lower percentages of PCPs paid on a fee-for-service basis (odds ratio: 0.95; 95% confidence interval: 0.92-0.98), with higher percentages of pediatricians in the PCP network (odds ratio: 1.17; 95% confidence interval: 1.07-1.29), and offering financial incentives for meeting quality of care standards (odds ratio: 1.71; 95% confidence interval: 1.28-2.29) had greater odds of outpatient physician specialist visits. Black children had odds of specialty care that were approximately one half those of white children. Children with prior physician specialist use were 52% more likely to have a physician specialist visit in the year after study entry. The children's diagnoses and condition consequences were not related significantly to the odds of a specialty visit. CONCLUSIONS: Specific MCO characteristics were associated with greater specialty care use among a group of low-income children with chronic conditions. Such information should be used to improve the structure of managed care arrangements for these vulnerable children.

Prospective assessment in newborns of diabetes autoimmunity (PANDA): maternal understanding of infant diabetes risk.

PURPOSE: To assess accuracy of mothers' understanding of their newborns' genetic risk for type 1 diabetes and to identify predictors of the comprehension and retention of genetic information. METHODS: Mothers of 435 newborns genetically screened at birth were informed of the infant's risk for type 1 diabetes using a standard script that provided both categorical and numerical risk information. The mothers' comprehension and retention of this information were assessed by structured interview on two occasions, approximately 3.6 weeks and approximately 3.9 months postnotification. RESULTS: At the initial interview, 73.1% of mothers gave a correct estimate of their child's genetic risk, 3.2% overestimated risk, 13.3% underestimated risk, and 10.3% could not recall risk at all. At the follow-up interview, fewer mothers (61.9%) correctly estimated their child's risk and more mothers (24.4%) underestimated their child's risk. Maternal accuracy was associated with maternal education, ethnic minority status, infant risk status, maternal ability to spontaneously recall both categorical and numerical risk estimates, and length of time since risk notification. Underestimation of risk was associated with maternal education, family history of diabetes, time since risk notification, and maternal anxiety about the baby's risk. CONCLUSION: The accuracy of mothers' recall of infant risk declines over time, with an increasing number of mothers underestimating the infant's risk. Effective risk communication strategies need to be developed and incorporated into genetic screening programs.