Characterising the age-dependent effects of risk factors on type 1 diabetes progression.

AIMS/HYPOTHESIS: Age is known to be one of the most important stratifiers of disease progression in type 1 diabetes. However, what drives the difference in rate of progression between adults and children is poorly understood. Evidence suggests that many type 1 diabetes disease predictors do not have the same effect across the age spectrum. Without a comprehensive analysis describing the varying risk profiles of predictors over the age continuum, researchers and clinicians are susceptible to inappropriate assessment of risk when examining populations of differing ages. We aimed to systematically assess and characterise how the effect of key type 1 diabetes risk predictors changes with age. METHODS: Using longitudinal data from single- and multiple-autoantibody-positive at-risk individuals recruited between the ages of 1 and 45 years in TrialNet's Pathway to Prevention Study, we assessed and visually characterised the age-varying effect of key demographic, immune and metabolic predictors of type 1 diabetes by employing a flexible spline model. Two progression outcomes were defined: participants with single autoantibodies (n=4893) were analysed for progression to multiple autoantibodies or type 1 diabetes, and participants with multiple autoantibodies were analysed (n=3856) for progression to type 1 diabetes. RESULTS: Several predictors exhibited significant age-varying effects on disease progression. Amongst single-autoantibody participants, HLA-DR3 (p=0.007), GAD65 autoantibody positivity (p=0.008), elevated BMI (p=0.007) and HOMA-IR (p=0.002) showed a significant increase in effect on disease progression with increasing age. Insulin autoantibody positivity had a diminishing effect with older age in single-autoantibody-positive participants (p<0.001). Amongst multiple-autoantibody-positive participants, male sex (p=0.002) was associated with an increase in risk for progression, and HLA DR3/4 (p=0.05) showed a decreased effect on disease progression with older age. In both single- and multiple-autoantibody-positive individuals, significant changes in HR with age were seen for multiple measures of islet function. Risk estimation using prediction risk score Index60 was found to be better at a younger age for both single- and multiple-autoantibody-positive individuals (p=0.007 and p<0.001, respectively). No age-varying effect was seen for prediction risk score DPTRS (p=0.861 and p=0.178, respectively). Multivariable analyses suggested that incorporating the age-varying effect of the individual components of these validated risk scores has the potential to enhance the risk estimate. CONCLUSIONS/INTERPRETATION: Analysing the age-varying effect of disease predictors improves understanding and prediction of type 1 diabetes disease progression, and should be leveraged to refine prediction models and guide mechanistic studies.

Challenges and Opportunities in Using Telehealth for Diabetes Care.

The ongoing coronavirus pandemic led to a rapid and dramatic increase in the use of telehealth for diabetes care. In the wake of this transition, we examine new opportunities and ongoing challenges for using telehealth within diabetes management, based on data and experiences from the pre-pandemic and pandemic time frames.

Barriers to retinopathy screening in youth and young adults with type 1 diabetes.

Early detection of diabetic retinopathy (DR) is imperative; however, adherence to screening guidelines is poor. We hypothesized that youth and young adults with type 1 diabetes (T1D) who met American Diabetes Association criteria for recommended DR screening at the time of the study (10 years old or greater with diabetes duration of 5 years or more) would report multiple barriers to screening and that targeted barriers and subpopulations could be identified to improve access to care. 271 youth aged 10 to 26 years with T1D of at least 5 years duration were recruited from clinic, diabetes camp, and a diabetes conference and completed a patient-reported questionnaire. 113 (41.7%) reported at least one barrier to DR screening, with missed school and work being the most common (20.7%). Older participants (P = 0.007) and those with a longer diabetes duration (P = 0.018) were more likely to report barriers to screening. Recruitment location, sex, race and ethnicity, HbA1c, insulin regimen, and clinic visit frequency were not associated with reporting at least one barrier. Slightly less than two-thirds (62.1%) of participants who responded (n = 235 out of 271) adhered to recommended screening guidelines of the time and reported having an eye exam within the past year, 24.7% 12-23 months ago, 9.8% 2 years ago or more, and 3.4% had never had a DR exam. As older patients and those with longer duration of diabetes are more likely to have DR, targeted interventions to address barriers to care, such as, missed school and work should be implemented in these groups.

Real-World Screening for Retinopathy in Youth With Type 1 Diabetes Using a Nonmydriatic Fundus Camera.

OBJECTIVE: To assess the use of a portable retinal camera in diabetic retinopathy (DR) screening in multiple settings and the presence of associated risk factors among children, adolescents, and young adults with type 1 diabetes. DESIGN AND METHODS: Five hundred youth with type 1 diabetes of at least 1 year's duration were recruited from clinics, diabetes camp, and a diabetes conference and underwent retinal imaging using a nonmydriatic fundus camera. Retinal characterization was performed remotely by a licensed ophthalmologist. Risk factors for DR development were evaluated by a patient-reported questionnaire and medical chart review. RESULTS: Of the 500 recruited subjects aged 9-26 years (mean 14.9, SD 3.8), 10 cases of DR were identified (nine mild and one moderate nonproliferative DR) with 100% of images of gradable quality. The prevalence of DR was 2.04% (95% CI 0.78-3.29), at an average age of 20.2 years, with the youngest affected subject being 17.1 years of age. The rate of DR was higher, at 6.5%, with diabetes duration >10 years (95% CI 0.86-12.12, P = 0.0002). In subjects with DR, the average duration of diabetes was 12.1 years (SD 4.6, range 6.2-20.0), and in a subgroup of clinic-only subjects (n = 114), elevated blood pressure in the year before screening was associated with DR (P = 0.0068). CONCLUSION: This study in a large cohort of subjects with type 1 diabetes demonstrates that older adolescents and young adults (>17 years) with longer disease duration (>6 years) are at risk for DR development, and screening using a portable retinal camera is feasible in clinics and other locations. Recent elevated blood pressure was a risk factor in an analyzed subgroup.

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.

Exocrine Pancreas Dysfunction in Type 1 Diabetes.

OBJECTIVE: Type 1 diabetes (T1D) is characterized by autoimmune ß-cell destruction, but exocrine pancreas abnormalities may also play a role in the disease pathophysiology. Herein, we review the current evidence of exocrine damage in T1D and discuss its underlying pathophysiology, clinical evaluation, and treatment. METHOD: Extensive literature search was performed for "type 1 diabetes" and "exocrine dysfunction" on PubMed and Google Scholar databases. RESULTS: T1D pancreata are significantly smaller than controls, both in weight and volume. T cells, dendritic cells, neutrophils, and products of complement activation are seen in T1D exocrine tissues. Exocrine pancreas fibrosis, arteriosclerosis, fatty infiltration, and acinar atrophy are also observed on histology. Pancreatic exocrine insufficiency (PEI) can be assessed through direct exocrine testing, fecal elastase concentration, and measurement of serum exocrine enzymes. The prevalence of PEI in T1D varies by modality and study but is consistently greater than controls. The clinical relevance of PEI in T1D is debatable, as many patients with laboratory evidence of PEI are asymptomatic. However, in PEI-symptomatic patients reported benefits of pancreatic enzyme replacement therapy (PERT) include relief of gastrointestinal symptoms, improved quality of life, better glycemic control, and optimal nutrition. CONCLUSION: Exocrine pancreas abnormalities often occur in T1D. Whether exocrine dysfunction occurs simultaneously with ß-cell destruction, as a result of ß-cell loss, or as a combination of both remains to be definitively answered. In T1D with gastrointestinal complaints, PEI should be evaluated, usually via fecal elastase measurements. PERT is recommended for T1D patients with symptoms and laboratory evidence of PEI. ABBREVIATIONS: AAb+ = autoantibody positive; AAb- = autoantibody negative; FEC = fecal elastase concentration; PEI = pancreatic exocrine insufficiency; PERT = pancreatic enzyme replacement therapy; PP = pancreatic polypep-tide; T1D = type 1 diabetes.

Enhanced Understanding of the Natural History of Pre-Type 1 Diabetes: Fundamental to Prevention.

Due to well-designed studies of birth cohorts and at-risk individuals, our understanding of the natural history of pre- and early type 1 diabetes (T1D) has advanced considerably over the past decade. Genetic risk scores can predict with increasing precision and accuracy who is at risk for T1D, and early staging based upon islet autoantibody status allows for improved mechanistic and natural history studies as well as improved clinical trial design. A growing number of children are being diagnosed with islet autoimmunity prior to the onset of symptoms, and confusion remains surrounding their proper management. These patients should have access to appropriate counseling and should be referred to a center that can provide information regarding current prevention trials. In the future, a successful prevention strategy for T1D would justify population-based screening for all children.

Diabetes and Driving: A Statement of the American Diabetes Association.

Many people with diabetes in the U.S. will seek or currently hold a license to drive. For many, a driver's license is essential for everyday life. Considerable discussion has focused on whether, and the extent to which, diabetes may be a relevant factor in determining driver ability and eligibility for a license. This statement addresses such issues in relation to current scientific and medical evidence. A diagnosis of diabetes on its own is not sufficient to make judgments about an individual driver's ability or safety. This statement provides an overview of existing licensing rules for people with diabetes in the U.S., addresses the factors that affect driving ability, identifies general guidelines for assessing driver fitness and determining appropriately tailored licensing restrictions, and provides practical guidance for health care professionals regarding clinical interventions and education for people with diabetes.

Low-Dose Antithymocyte Globulin: A Pragmatic Approach to Treating Stage 2 Type 1 Diabetes.

OBJECTIVE: Low-dose antithymocyte globulin (ATG) (2.5 mg/kg) preserves C-peptide and reduces HbA1c in new-onset stage 3 type 1 diabetes, yet efficacy in delaying progression from stage 2 to stage 3 has not been evaluated. RESEARCH DESIGN AND METHODS: Children (n = 6) aged 5-14 years with stage 2 type 1 diabetes received off-label, low-dose ATG. HbA1c, C-peptide, continuous glucose monitoring, insulin requirements, and side effects were followed for 18-48 months. RESULTS: Three subjects (50%) remained diabetes free after 1.5, 3, and 4 years of follow-up, while three developed stage 3 within 1-2 months after therapy. Eighteen months posttreatment, even disease progressors demonstrated near-normal HbA1c (5.1% [32 mmol/mol], 5.6% [38 mmol/mol], and 5.3% [34 mmol/mol]), time in range (93%, 88%, and 98%), low insulin requirements (0.17, 0.18, and 0.34 units/kg/day), and robust C-peptide 90 min after mixed meal (1.3 ng/dL, 2.3 ng/dL, and 1.4 ng/dL). CONCLUSIONS: These observations support additional prospective studies evaluating ATG in stage 2 type 1 diabetes.

Multicenter Evaluation of Ultra-Rapid Lispro Insulin with Control-IQ Technology in Adults, Adolescents, and Children with Type 1 Diabetes.

Objective: To evaluate the safety and explore the efficacy of use of ultra-rapid lispro (URLi, Lyumjev) insulin in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology in children, teenagers, and adults living with type 1 diabetes (T1D). Methods: At 14 U.S. diabetes centers, youth and adults with T1D completed a 16-day lead-in period using lispro in a t:slim X2 insulin pump with Control-IQ 1.5 technology, followed by a 13-week period in which URLi insulin was used in the pump. Results: The trial included 179 individuals with T1D (age 6-75 years). With URLi, 1.7% (3 participants) had a severe hypoglycemia event over 13 weeks attributed to override boluses or a missed meal. No diabetic ketoacidosis events occurred. Two participants stopped URLi use because of infusion-site discomfort, and one stopped after developing a rash. Mean time 70-180 mg/dL increased from 65% ± 15% with lispro to 67% ± 13% with URLi (P = 0.004). Mean insulin treatment satisfaction questionnaire score improved from 75 ± 13 at screening to 80 ± 11 after 13 weeks of URLi use (mean difference = 6; 95% confidence interval 4-8; P < 0.001), with the greatest improvement reported for confidence avoiding symptoms of high blood sugar. Mean treatment-related impact measure-diabetes score improved from 74 ± 12 to 80 ± 12 (P < 0.001), and mean TRIM-Diabetes Device (score improved from 82 ± 11 to 86 ± 12 (P < 0.001). Conclusions: URLi use in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology was safe for adult and pediatric participants with T1D, with quality-of-life benefits of URLi use perceived by the study participants. Clinicaltrials.gov registration: NCT05403502.

Type 1 Diabetes: A Disorder of the Exocrine and Endocrine Pancreas.

Type 1 diabetes has historically been described as an endocrine (ß-cell) specific autoimmune disease. However, a substantial reduction (20-50%) in pancreas organ size and subclinical to symptomatic exocrine pancreatic insufficiency are present at diagnosis and may begin even prior to the development of islet autoimmunity. The mechanisms of exocrine loss in type 1 diabetes are not well understood, but leading hypotheses include developmental defects, ß-cell loss resulting in exocrine atrophy, or autoimmune or inflammatory destruction of exocrine cells. Inflammatory changes including acute and chronic pancreatitis, exocrine T cell infiltration and classical complement activation, and serum exocrine autoantibodies within type 1 diabetes individuals suggest that an autoimmune or inflammatory process may contribute to exocrine pancreatic dysfunction. Exocrine pancreas atrophy primarily occurs prior to the onset of clinical disease. Indeed, recent work implicates exocrine-specific alterations in gene and protein expression as key in type 1 diabetes development. Measures of exocrine size and function could be useful additions in the prediction of disease onset and in identifying potential therapeutic responders to disease therapies, however, this is an underdeveloped area of research. Additionally, exocrine pancreatic insufficiency is underdiagnosed in individuals with type 1 diabetes and individualized treatment protocols are lacking. Much work remains to be done in this area, but we can definitively say that type 1 diabetes is a disorder of both the exocrine and endocrine pancreas likely from the start.

Blue Circle Health: A Novel Patient-Centered Model of Health Care Delivery for Low-Income Patients With Type 1 Diabetes.

Analog insulins, insulin pumps, and continuous glucose monitors (CGM) have revolutionized type 1 diabetes (T1D) treatment over the last 50 years. Nevertheless, less than 20% of patients in the United States reach guideline-based HbA1c targets. The dysfunctional delivery of U.S. health care has further worsened glycemic outcomes among structurally disadvantaged groups such as non-Hispanic Black and low-income populations. Administrative complexities resulting from mixed insurance coverage and delivery systems, incongruity between effective policies and reimbursement, structural racism, and implicit biases have led to high diabetes care-related costs, provider scarcity and burnout, and patient diabetes distress. The Extension for Community Healthcare Outcomes (ECHO) Diabetes tele-education outreach model was created to increase self-efficacy among primary care providers through a combination of weekly didactic sessions led by a team of diabetes experts and access to community-based peer coaches. As an evolution of ECHO Diabetes, Blue Circle Health has been established as a philanthropically funded health care delivery system, using a whole-person, individualized approach to T1D care for adults living in underserved communities. The program will provide direct-to-patient telehealth services, including diabetes education, management, and related psychological care regardless of ability to pay. Community-based diabetes support coaches will serve as the primary point of contact, or guide on the "Blue Circle Health Member Journey." Access to needed insulins, supplies, and CGMs will be provided at no cost to the individual. Through a continuous learning and improvement model, a person-centered, equitable, accessible, and effective health care delivery model will be built for people living with T1D.

Thyroid Storm Caused by Hyperemesis Gravidarum.

Background: Transient thyrotoxicosis has been documented in the setting of hyperemesis gravidarum (HG) with elevated human chorionic gonadotropin (hCG) levels. Thyroid storm in pregnancy is rarer and typically associated with autoimmune hyperthyroidism. We described thyroid storm in a primigravid 18-year-old patient due to hCG level elevation secondary to HG, which resolved in the second trimester of pregnancy. Case Report: Our patient presented with vomiting, hyperthyroidism, and cardiac and renal dysfunction at 16 weeks' gestation. She was clinically found to have a thyroid storm, with undetectable thyroid-stimulating hormone (TSH) and a free thyroxine level of >6.99 ng/dL. The hCG level was elevated at 246 030 mIU/L (9040-56 451 mIU/L). She was treated with methimazole, saturated solution potassium iodide, and propranolol. Because thyroid autoantibodies were absent, thyroid ultrasound yielded normal results, and thyroid function testing results rapidly improved as the hCG level decreased, the medications were tapered and ultimately discontinued by day 10 of hospitalization. The thyroid function remained normal after discharge. Discussion: Because hCG and TSH have identical alfa subunits and similar beta subunits, hCG can bind to the TSH receptor and stimulate thyroxine production. The hCG level peaks at around 8-14 weeks of gestation, correlating with decreased TSH levels in this same time frame. This case emphasizes the relevant physiology and importance of timely and thorough evaluation to determine the appropriate management, prognosis, and follow-up for patients with thyroid storm in the setting of HG. Conclusion: Although transient thyrotoxicosis is documented in patients with HG, thyroid storm is rare, and our case illustrates a severe example of these comorbidities.

Substance Use Affects Type 1 Diabetes Pancreas Pathology: Implications for Future Studies.

Access to human pancreas samples from organ donors has greatly advanced our understanding of type 1 diabetes pathogenesis; however, previous studies have shown that donors have a high rate of substance use, and its impact on pancreatic histopathology in this disease is not well described. One-hundred-thirty-one type 1 diabetes and 111 control organ donor pancreata from persons 12-89 years of age (mean 29.8 ± 15.5 years) within the Network for Pancreatic Organ donors with Diabetes (nPOD) were examined for insulin positivity, insulitis, amyloid staining, acute and chronic pancreatitis, and chronic exocrine changes (acinar atrophy, fibrosis, fatty infiltration, or periductal fibrosis); findings were compared by history of substance use. A secondary analysis compared exocrine pancreatic histopathologic findings in type 1 diabetes versus control organ donors regardless of substance use history. We observed a high but congruent rate of substance use in type 1 diabetes and control organ donors (66.4% and 64% respectively). Among donors with type 1 diabetes (but not controls), islet amyloid (OR 9.96 [1.22, 81.29]) and acute pancreatitis (OR 3.2 [1.06, 9.63]) were more common in alcohol users while chronic exocrine changes (OR 8.86 [1.13, 69.31]) were more common in cocaine users. Substance use impacted the pancreata of donors with type 1 diabetes more than controls. Overall, despite similar rates of substance use, acute pancreatitis (15.3% versus 4.5%, p=0.0061), chronic pancreatitis (29.8% versus 9.9%, p=0.0001), and chronic exocrine changes (73.3% versus 36.9%, p<0.0001) were more common in type 1 diabetes donors than controls. Alcohol and/or cocaine use in type 1 diabetes organ donors increases exocrine pancreas pathology and islet amyloid deposition but does not affect insulitis or insulin positivity. Exocrine pathology in type 1 diabetes donors is common, and further study of the pathophysiology of these changes is needed.

Low-Dose ATG/GCSF in Established Type 1 Diabetes: A Five-Year Follow-up Report.

Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes (n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data (n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo (P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders (n = 9) and nonresponders (n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA1c over 5 years (mean [95% CI] adjusted change 0.29% [-0.69%, 1.27%]), but the study was not powered for comparisons against nonresponders 1.75% (-0.57%, 4.06%) or placebo recipients 1.44% (0.21%, 2.66%). These data underscore the importance of long-term follow-up in previous and ongoing phase 2 trials of low-dose ATG in recent-onset type 1 diabetes.

An Iterative Process for Identifying Pediatric Patients With Type 1 Diabetes: Retrospective Observational Study.

BACKGROUND: The incidence of both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in children and youth is increasing. However, the current approach for identifying pediatric diabetes and separating by type is costly, because it requires substantial manual efforts. OBJECTIVE: The purpose of this study was to develop a computable phenotype for accurately and efficiently identifying diabetes and separating T1DM from T2DM in pediatric patients. METHODS: This retrospective study utilized a data set from the University of Florida Health Integrated Data Repository to identify 300 patients aged 18 or younger with T1DM, T2DM, or that were healthy based on a developed computable phenotype. Three endocrinology residents/fellows manually reviewed medical records of all probable cases to validate diabetes status and type. This refined computable phenotype was then used to identify all cases of T1DM and T2DM in the OneFlorida Clinical Research Consortium. RESULTS: A total of 295 electronic health records were manually reviewed; of these, 128 cases were found to have T1DM, 35 T2DM, and 132 no diagnosis. The positive predictive value was 94.7%, the sensitivity was 96.9%, specificity was 95.8%, and the negative predictive value was 97.6%. Overall, the computable phenotype was found to be an accurate and sensitive method to pinpoint pediatric patients with T1DM. CONCLUSIONS: We developed a computable phenotype for identifying T1DM correctly and efficiently. The computable phenotype that was developed will enable researchers to identify a population accurately and cost-effectively. As such, this will vastly improve the ease of identifying patients for future intervention studies.

Simple tests of cardiorespiratory fitness in a pediatric population.

A progressive, treadmill-based VO2max is the gold standard of cardiorespiratory fitness determination but is rarely used in pediatric clinics due to time requirements and cost. Simpler and shorter fitness tests such as the Squat Test or Step Test may be feasible and clinically useful alternatives. However, performance comparisons of these tests to treadmill VO2max tests are lacking. The primary aim of this cross-sectional study was to assess the correlation between Squat and Step Test scores and VO2max in a pediatric population. As secondary outcomes, we calculated correlations between Rated Perceived Exertion Scale (RPE) scores, NIH PROMIS Physical Activity scores, and BMI z-score with VO2max, and we also evaluated the ability of each fitness test to discriminate low and high-risk patients based on the FITNESSGram. Forty children aged 10-17 completed these simple cardiorespiratory fitness tests. Statistically significant correlations were observed between VO2max and the Step Test (r = -0.549) and Squat Test (r = -0.429) scores, as well as participant BMI z-score (r = -0.458). RPE and PROMIS scores were not observed to be correlated with VO2max. Area Under the Receiver Operator Curve was relatively high for BMI z-scores and the Step Test (AUC = 0.813, 0.713 respectively), and lower for the Squat Test (AUC = 0.610) in discriminating risk according to FITNESSGram Scores. In this sample, the Step Test performed best overall. These tests were safe, feasible, and may add great value in assessing cardiorespiratory fitness in a clinical setting.