HOMA-IR and the Matsuda Index as predictors of progression to type 1 diabetes in autoantibody-positive relatives.

AIM/HYPOTHESIS: We assessed whether HOMA-IR and the Matsuda Index are associated with transitions through stages of type 1 diabetes. METHODS: Autoantibody (AAb)-positive relatives of individuals with type 1 diabetes (n=6256) from the TrialNet Pathway to Prevention were studied. Associations of indicators of insulin resistance (HOMA-IR) and insulin sensitivity (Matsuda Index) with BMI percentile (BMIp) and age were assessed with adjustments for measures of insulin secretion, Index60 and insulinogenic index (IGI). Cox regression was used to determine if tertiles of HOMA-IR and Matsuda Index predicted transitions from Not Staged (<2 AAbs) to Stage 1 (≥2 AAbs and normoglycaemia), from Stage 1 to Stage 2 (≥2 AAbs with dysglycaemia), and progression to Stage 3 (diabetes as defined by WHO/ADA criteria). RESULTS: There were strong associations of HOMA-IR (positive) and Matsuda Index (inverse) with baseline age and BMIp (p<0.0001). After adjustments for Index60, transitioning from Stage 1 to Stage 2 was associated with higher HOMA-IR and lower Matsuda Index (HOMA-IR: HR=1.71, p<0.0001; Matsuda Index, HR=0.40, p<0.0001), as with progressing from Stages 1 or 2 to Stage 3 (HOMA-IR: HR=1.98, p<0.0001; Matsuda Index: HR=0.46, p<0.0001). Without adjustments, associations of progression to Stage 3 were inverse for HOMA-IR and positive for Matsuda Index, opposite in directionality with adjustments. When IGI was used in place of Index60, the findings were similar. CONCLUSIONS/INTERPRETATION: Progression to Stages 2 and 3 of type 1 diabetes increases with HOMA-IR and decreases with the Matsuda Index after adjustments for insulin secretion. Indicators of insulin secretion appear helpful for interpreting associations of progression to type 1 diabetes with HOMA-IR or the Matsuda Index in AAb-positive relatives.

Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.

School-based diabetes care: A national survey of U.S. pediatric diabetes providers.

Objectives: To understand the practices, attitudes, and beliefs of type 1 diabetes (T1D) providers towards school-based diabetes care (SBDC), including counseling families and communicating with schools, and explore the barriers and facilitators which affect their support of SBDC. Research Design and Methods: We conducted a national survey of pediatric T1D providers about their perceived support of SBDC, including family counseling and school communication. We used descriptive statistics to analyze results and explored differences by practice size (<500, 500-999, and ≥1000 patients) and environment (academic vs non-academic). Results: A total of 149 providers completed the survey. Nearly all (95%) indicated SBDC was very important. Though most (63%) reported counseling families about SBDC multiple times per year, few (19%) spoke with school staff routinely, reporting that was a shared responsibility among different providers. Close to 90% agreed school feedback on T1D management plans would be helpful, yet only 31% routinely requested this input. Moderate to extremely significant barriers to SBDC communication included internal factors, such as staff resources (67%) and time (82%), and external factors, such as school nurse education needs (62%) and differing school district policies (70%). Individuals from large or academic practices reported more barriers in their knowledge of SBDC, including federal/state laws. Desired facilitators for SBDC included a designated school liaison (84%), electronic transmission for school forms (90%), and accessible school staff education (95%). Conclusions: Though providers universally agree that SBDC is important, there are multilevel internal (practice) and external (policy) barriers to facilitating a bidirectional relationship between schools and health teams.

School Nurse Confidence with Diabetes Devices in Relation to Diabetes Knowledge and Prior Training: A Study of Convergent Validity.

Objective: The Diabetes Device Confidence Scale (DDCS) is a new scale designed to evaluate school nurse confidence with diabetes devices. We hypothesized that DDCS score would be associated with related constructs of school nurse diabetes knowledge, experience, and training. Research Design and Methods: In a cross-sectional study, we co-administered the DDCS and Diabetes Knowledge Test 2 (DKT2) questionnaires to school nurses in Pennsylvania. We summarized DDCS scores (range 1-5) descriptively. We evaluated the relationship between DKT2 percent score and DDCS mean score with the Spearman correlation coefficient. Simple linear regression examined school nurse characteristics as predictors of DDCS score. Results: A total of 271 completed surveys were received. Mean DDCS score was 3.16±0.94, indicating moderate confidence with devices overall. School nurses frequently reported low confidence in items representing specific skills, including suspending insulin delivery (40%), giving a manual bolus (42%), knowing when to calibrate a continuous glucose monitor (48%), changing an insulin pump site (54%), and setting a temporary basal rate (58%). Mean DKT2 score was 89.5±0.1%, which was weakly but not significantly correlated with DDCS score (r=0.12, p=0.06). Formal device training (p<0.001), assisting ≥5 students with diabetes devices in the past 5 years (p<0.01), and a student caseload between 1000-1500 students (p<0.001) were associated with higher mean DDCS score. Conclusions: DDCS score is related to prior training and experience, providing evidence for the scale's convergent validity. The DDCS may be a useful tool for assessing school nurse readiness to use devices and identify areas to enhance knowledge and practical skills.

Comparisons of school-day glycemia in different settings for children with type 1 diabetes using continuous glucose monitoring.

Objective: Using continuous glucose monitoring (CGM), we examined patterns in glycemia during school hours for children with type 1 diabetes, exploring differences between school and non-school time. Methods: We conducted a retrospective analysis of CGM metrics in children 7-12 years (n=217, diabetes duration 3.5±2.5 years, hemoglobin A1c 7.5±0.8%). Metrics were obtained for weekday school hours (8 AM to 3 PM) during four weeks in fall 2019. Two comparison settings included weekend (fall 2019) and weekday (spring 2020) data when children had transitioned to virtual school due to COVID-19. We used multilevel mixed models to examine factors associated with time in range (TIR) and compare glycemia between in-school, weekends, and virtual school. Results: Though CGM metrics were clinically similar across settings, TIR was statistically higher, and time above range (TAR), mean glucose, and standard deviation (SD) lower, for weekends and virtual school (p<0.001). Hour and setting exhibited a significant interaction for several metrics (p<0.001). TIR in-school improved from a mean of 40.9% at the start of the school day to 58.0% later in school, with a corresponding decrease in TAR. TIR decreased on weekends (60.8 to 50.7%) and virtual school (62.2 to 47.8%) during the same interval. Mean glucose exhibited a similar pattern, though there was little change in SD. Younger age (p=0.006), lower hemoglobin A1c (p<0.001), and insulin pump use (p=0.02) were associated with higher TIR in-school. Conclusion: Although TIR was higher for weekends and virtual school, glycemic metrics improve while in-school, possibly related to beneficial school day routines.

Support and Conflict Among Youth With Type 1 Diabetes: A Focus on Friends.

OBJECTIVE: The goal of the study was to examine the relations of general and diabetes-specific friend support and conflict to psychological and diabetes health among youth with type 1 diabetes. We examined gender as a moderator of these relations, and friend responsiveness and information-sharing as potential mediators. METHODS: Youth with type 1 diabetes (n = 167; M age 15.83 [SD = 0.78]; 50% female) were interviewed once in the Fall and once in the following Spring of the school year. Using multiple regression analysis, general friend support, general friend conflict, diabetes-specific support, and diabetes-specific conflict were investigated as simultaneous predictors of psychological and diabetes outcomes cross-sectionally and longitudinally over four months. RESULTS: Cross-sectionally friend conflict, including both general and diabetes-specific, was more predictive of outcomes than friend support. In cross-sectional and longitudinal analyses, gender was a significant moderator, such that several relations of general friend conflict to outcomes were significant for females but not nonfemales. Friend support revealed mixed relations to outcomes across cross-sectional and longitudinal analyses. Although we found links of friend relationship variables to mediators (perceived responsiveness; information sharing), we found little evidence of mediation. CONCLUSIONS: These findings show stronger evidence that conflictual friend relationships than supportive friend relationships are linked to health. Findings suggest that problematic friend relationships may have a stronger impact on the health of females than nonfemales. These results underscore the need to better understand the conditions under which friend support is helpful versus harmful and the reasons underlying these links.

Liraglutide in Children and Adolescents with Type 2 Diabetes.

BACKGROUND: Metformin is the regulatory-approved treatment of choice for most youth with type 2 diabetes early in the disease. However, early loss of glycemic control has been observed with metformin monotherapy. Whether liraglutide added to metformin (with or without basal insulin treatment) is safe and effective in youth with type 2 diabetes is unknown. METHODS: Patients who were 10 to less than 17 years of age were randomly assigned, in a 1:1 ratio, to receive subcutaneous liraglutide (up to 1.8 mg per day) or placebo for a 26-week double-blind period, followed by a 26-week open-label extension period. Inclusion criteria were a body-mass index greater than the 85th percentile and a glycated hemoglobin level between 7.0 and 11.0% if the patients were being treated with diet and exercise alone or between 6.5 and 11.0% if they were being treated with metformin (with or without insulin). All the patients received metformin during the trial. The primary end point was the change from baseline in the glycated hemoglobin level after 26 weeks. Secondary end points included the change in fasting plasma glucose level. Safety was assessed throughout the course of the trial. RESULTS: Of 135 patients who underwent randomization, 134 received at least one dose of liraglutide (66 patients) or placebo (68 patients). Demographic characteristics were similar in the two groups (mean age, 14.6 years). At the 26-week analysis of the primary efficacy end point, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of -1.06 percentage points (P<0.001); the difference increased to -1.30 percentage points by 52 weeks. The fasting plasma glucose level had decreased at both time points in the liraglutide group but had increased in the placebo group. The number of patients who reported adverse events was similar in the two groups (56 [84.8%] with liraglutide and 55 [80.9%] with placebo), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide. CONCLUSIONS: In children and adolescents with type 2 diabetes, liraglutide, at a dose of up to 1.8 mg per day (added to metformin, with or without basal insulin), was efficacious in improving glycemic control over 52 weeks. This efficacy came at the cost of an increased frequency of gastrointestinal adverse events. (Funded by Novo Nordisk; Ellipse ClinicalTrials.gov number, NCT01541215.).

Development and psychometric analysis of the Diabetes Device Confidence Scale for school nurses.

BACKGROUND: School nurses need to be equipped to help students with diabetes devices. No existing tools assess school nurse self-efficacy in using devices. OBJECTIVE: To develop and evaluate the psychometric properties of a novel scale to measure school nurse confidence with diabetes devices. RESEARCH DESIGN AND METHODS: We generated a list of items with community partners and examined logical validity. We then revised and distributed the item set to school nurses in Pennsylvania to examine aspects of structural validity, convergent validity, and internal consistency reliability. We used item response theory to refine the scale. RESULTS: Facilitated discussion with collaborators generated an initial list of 50 potential items. Based upon the item-content validity index, we revised/eliminated 13 items. School nurses (n = 310) in Pennsylvania completed an updated 38-item scale; the majority had experience with insulin pumps or continuous glucose monitors. Exploratory factor analysis identified a one-factor solution, suggesting a unidimensional scale. We eliminated 13 additional items based upon significant inter-item correlation or skewed response patterns. Item response theory did not identify additional candidate items for removal. Despite a high degree of redundancy (Cronbach's alpha > 0.90), we retained all remaining items to maximize the future utility of the scale. CONCLUSION: The 25-item, unidimensional Diabetes Device Confidence Scale is a new tool to measure school nurse confidence with diabetes devices. This scale has future clinical, programmatic, and research applications. Combined with knowledge assessments, this scale can serve to evaluate school nurse device use readiness, assess training gaps, and tailor interventions.

A centennial review of discoveries and advances in diabetes: Children and youth.

Diabetes is an increasingly common chronic metabolic disorder in children worldwide. The discovery of insulin in 1921 resulted in unprecedented advancements that improved the lives of children and youth with diabetes. The purpose of this article is to review the history of diabetes in children and youth over the last century and its implications for future developments in the field. We identified 68 relevant events between 1921 and 2021 through literature review and survey of pediatric endocrinologists. Basic research milestones led to the discovery of insulin and other regulatory hormones, established the normal physiology of carbohydrate metabolism and pathophysiology of diabetes, and provided insight into strategies for diabetes prevention. While landmark clinical studies were initially focused on adult diabetes populations, later studies assessed etiologic factors in birth cohort studies, evaluated technology use among children with diabetes, and investigated pharmacologic management of youth type 2 diabetes. Technological innovations culminated in the introduction of continuous glucose monitoring that enabled semi-automated insulin delivery systems. Finally, professional organizations collaborated with patient groups to advocate for the needs of children with diabetes and their families. Together, these advances transformed type 1 diabetes from a terminal illness to a manageable disease with near-normal life expectancy and increased our knowledge of type 2 diabetes and other forms of diabetes in the pediatric population. However, disparities in access to insulin, diabetes technology, education, and care support remain and disproportionately impact minority youth and communities with less resources. The overarching goal of diabetes management remains promoting a high quality of life and improving glycemic management without undermining the psychological health of children and youth living with diabetes.

14-Year Longitudinal Trajectories of Depressive Symptoms Among Youth With and Without Type 1 Diabetes.

OBJECTIVE: There is evidence that youth with type 1 diabetes are at risk for depression, and depression is a significant risk factor for subsequent psychological and physical health problems. However, it is not clear if/when this depression risk emerges. The goal of this study was to determine if there are differences in levels of depressive symptoms between youth with and without type 1 diabetes that develop over the course of emerging adulthood. We also examined whether adolescent psychosocial variables predicted depressive symptoms during emerging adulthood. METHODS: Youth with (n = 132) and without (n = 131) type 1 diabetes were enrolled in the study at average age 12 and followed for 14 years. Depressive symptoms were measured throughout the study. Psychosocial variables of interest were measured during adolescence. RESULTS: Group differences in depressive symptoms emerged by study end at average age 26. Depressive symptoms appeared to decline over time for youth without diabetes and to increase over time for youth with diabetes. Parent relationship difficulties increased over adolescence as did peer conflict for the entire cohort. Supportive relationships with parent and peers predicted fewer end of study depressive symptoms (controlling for baseline depressive symptoms)-equally so for both groups. CONCLUSIONS: This study provides evidence that those with type 1 diabetes may be at risk for depressive symptoms many years after diagnosis and after adolescence. Although relational difficulties with parents and peers increase during adolescence, supportive relationships over the course of adolescence may help to mitigate depressive symptoms during young adulthood.

Cyber School Is a Marker of Youth with High-Risk Diabetes.

OBJECTIVE: To explore the health characteristics of youth with diabetes in cyber school compared with peers with diabetes in traditional brick-and-mortar schools. STUDY DESIGN: This was a single-center cross-sectional study of youth with type 1 or type 2 diabetes in K-12 education during academic year 2017-2018. Youth enrolled in cyber school were matched with traditional school peers by age, sex, race, diagnosis, and diabetes duration. Comparisons included insurance status, hemoglobin A1c, treatment, coexisting conditions, screening, and healthcare use. RESULTS: Of 1694 participants, 5% (n = 87) were enrolled in cyber school. Youth enrolled in cyber school were predominantly white (89%), female (60%), adolescents (median 15.2 years) with type 1 diabetes (91%). Youth with type 2 diabetes were excluded from analyses owing to the small sample (n = 7). Public insurance was more common among youth enrolled in cyber school (P = .005). Youth in cyber school had higher mean hemoglobin A1c, 9.1 ± 1.8% (76 ± 20 mmol/mol) vs 8.3 ± 1.2% (67 ± 13 mmol/mol) (P = .003), lower insulin pump use (OR, 0.36; 95% CI, 0.18-0.73), and more mental health conditions (OR, 4.48; 95% CI, 1.94-10.35) compared with peers in traditional schools. Youth in cyber school were less likely to have recommended vision (OR, 0.34; 95% CI, 0.15-0.75) and dental (OR, 0.33; 95% CI, 0.15-0.75) evaluations. The relationship between hemoglobin A1c and cyber school persisted after adjusting for insurance status, pump use, and mental health conditions (P = .02). Similar trends were observed for participants with type 2 diabetes. CONCLUSIONS: Youth with diabetes in cyber school may be a high-risk population. Understanding the potential impact of cyber school-related factors on health may encourage additional provider/system/school supports for these patients.

Evaluating the Impact of Stakeholder Engagement in a School-Based Type 1 Diabetes Study.

OBJECTIVE: Although the importance of stakeholder engagement (SE) for patient-centered research is recognized, few studies document SE processes and influence on research outcomes in the diabetes field. We applied a research-informed framework to evaluate the impact of SE on a pediatric diabetes study exploring school nurse perspectives on modern diabetes devices. METHODS: We recruited parents of children with type 1 diabetes, school nurses, and diabetes providers. Stakeholders convened virtually every 2 months for 12 months. Goals for SE included input on research materials, interpretation of findings, and future research directions. Processes were assessed using a validated survey. Immediate outcomes included changes to research materials and satisfaction. Secondary outcomes included research efficiency and value (acceptance by community partners). RESULTS: Each role was represented at every meeting. The majority of stakeholders (>70%) completed the survey at study midpoint and end points. All surveyed indicated that they had received all desired information, shared feedback, and felt valued. Stakeholders were satisfied with the meeting frequency. Participants appreciated learning from each other and expressed enthusiasm for continued research participation. They described their role as one of consultant rather than research team members. SE resulted in five additional interview questions. Nearly 70 comments added to the interpretation of qualitative themes. Findings were published within 12 months and recognized by the state school nursing organization. CONCLUSION: SE was well received and led to meaningful changes in content and dissemination of a diabetes study. A systematic approach to evaluating SE can increase scientific rigor and reproducibility and contribute to best practices for SE in diabetes research.

Early and late C-peptide responses during oral glucose tolerance testing are oppositely predictive of type 1 diabetes in autoantibody-positive individuals.

We 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.

Modern diabetes devices in the school setting: Perspectives from school nurses.

OBJECTIVE: To explore the experiences, practices, and attitudes of school nurses related to modern diabetes devices (insulin pumps, continuous glucose monitors, and hybrid-closed loop systems). RESEARCH DESIGN AND METHODS: Semistructured interviews were conducted with 40 public school nurses caring for children in elementary and middle schools. Developed with stakeholder input, the interview questions explored experiences working with devices and communicating with the health care system. Deidentified transcripts were analyzed through an iterative process of coding to identify major themes. RESULTS: School nurses reported a range of educational backgrounds (58% undergraduate, 42% graduate), geographic settings (20% urban, 55% suburban, 25% rural), and years of experience (20% <5 years, 38%, 5-15 years, 42% >15 years). Four major themes emerged: (a) As devices become more common, school nurses must quickly develop new knowledge and skills yet have inconsistent training opportunities; (b) Enthusiasm for devices is tempered by concerns about implementation due to poor planning prior to the school year and potential disruptions by remote monitors; (c) Barriers exist to integrating devices into schools, including school/classroom policies, liability/privacy concerns, and variable staff engagement; and (d) Collaboration between school nurses and providers is limited; better communication may benefit children with diabetes. CONCLUSIONS: Devices are increasingly used by school-aged children. School nurses appreciate device potential but share structural and individual-level challenges. Guiding policy is needed as the technology progressively becomes standard of care. Enhanced training and collaboration with diabetes providers may help to optimize school-based management for children in the modern era.

Effects of Exercise Modality on Insulin Resistance and Ectopic Fat in Adolescents with Overweight and Obesity: A Randomized Clinical Trial.

OBJECTIVE: To examine whether a combined aerobic exercise and resistance exercise is more effective than either aerobic exercise or resistance exercise alone in improving insulin sensitivity and reducing total adiposity and ectopic fat in adolescents. STUDY DESIGN: A total of 118 sedentary adolescents with overweight/obesity (body mass index >85th percentile, 12-17 years) were recruited from October 2013 through April 2017 at Children's Hospital of Pittsburgh. Participants were randomized to 1 of the following 6-month exercise groups (3 d/wk, 180 min/wk): aerobic exercise (n = 38), resistance exercise (n = 40), and combined aerobic exercise and resistance exercise (n = 40). The primary outcome was the change in insulin-stimulated glucose disposal by a 3-hour hyperinsulinemic-euglycemic clamp. The secondary outcomes were changes in liver fat by proton magnetic resonance spectroscopy and intermuscular adipose tissue by computed tomography. RESULTS: Of the 118 participants randomized, 85 participants (72%) completed the study with 90% exercise attendance. Total adiposity reduced similarly in all groups (-2%, P < .05). After adjusting for age and sex, insulin-stimulated glucose disposal increased (P < .05) in all groups, with the increase in the aerobic exercise group being greater than the resistance exercise group (1.7 ± 0.1 vs 0.7 ± 0.1 mg/kg/min, P < .05) but not different from the combined group (1.2 ± 0.1 mg/kg/min). Liver fat was reduced (P < .05) in the aerobic exercise (-0.6%) and combined (-0.6%) groups but not in the resistance exercise group (-0.3%, P > .05). Intermuscular adipose tissue decreased (P < .05) similarly in all groups. CONCLUSION: Combined aerobic exercise and resistance exercise and aerobic exercise alone are similarly beneficial in improving insulin sensitivity and reducing ectopic fat in adolescents with obesity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01938950.

Associations of HbA1c with the timing of C-peptide responses during the oral glucose tolerance test at the diagnosis of type 1 diabetes.

BACKGROUND: 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 ß-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 hemoglobin A1c (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, body mass index (BMI)-z was 0.4 ± 1.1, 51.0% were male. The average 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-hour 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.

Ethnic differences in progression of islet autoimmunity and type 1 diabetes in relatives at risk.

AIMS/HYPOTHESIS: We hypothesised that progression of islet autoimmunity and type 1 diabetes mellitus differs among races/ethnicities in at-risk individuals. METHODS: In this study, we analysed the data from the Type 1 Diabetes TrialNet Pathway to Prevention Study. We studied 4873 non-diabetic, autoantibody-positive relatives of individuals with type 1 diabetes followed prospectively (11% Hispanic, 80.9% non-Hispanic white [NHW], 2.9% non-Hispanic black [NHB] and 5.2% non-Hispanic other [NHO]). Primary outcomes were time from single autoantibody positivity confirmation to multiple autoantibody positivity, and time from multiple autoantibody positivity to type 1 diabetes mellitus diagnosis. RESULTS: Conversion from single to multiple autoantibody positivity was less common in Hispanic individuals than in NHW individuals (HR 0.66 [95% CI 0.46, 0.96], p = 0.028) adjusting for autoantibody type, age, sex, Diabetes Prevention Trial Type 1 Risk Score and HLA-DR3-DQ2/DR4-DQ8 genotype. In participants who screened positive for multiple autoantibodies (n = 2834), time to type 1 diabetes did not differ by race/ethnicity overall (p = 0.91). In children who were <12 years old when multiple autoantibody positivity was determined, being overweight/obese had differential effects by ethnicity: type 1 diabetes risk was increased by 36% in NHW children (HR 1.36 [95% CI 1.04, 1.77], p = 0.024) and was nearly quadrupled in Hispanic children (HR 3.8 [95% CI 1.6, 9.1], p = 0.0026). We did not observe this interaction in participants who were ≥12 years old at determination of autoantibody positivity, although this group size was limited. No significant differential risks were observed between individuals of NHB and NHW ethnicity. CONCLUSIONS/INTERPRETATION: The risk and rate of progression of islet autoimmunity were lower in Hispanic compared with NHW at-risk individuals, while significant differences in the development of type 1 diabetes were limited to children <12 years old and were modified by BMI.

The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to examine: (1) whether specific glucose-response curve shapes during OGTTs are predictive of type 1 diabetes development; and (2) the extent to which the glucose-response curve is influenced by insulin secretion. METHODS: Autoantibody-positive relatives of people with type 1 diabetes whose baseline OGTT met the definition of a monophasic or biphasic glucose-response curve were followed for the development of type 1 diabetes (n = 2627). A monophasic curve was defined as an increase in OGTT glucose between 30 and 90 min followed by a decline of ≥ 0.25 mmol/l between 90 and 120 min. A biphasic response curve was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 0.25 mmol/l. Associations of type 1 diabetes risk with glucose curve shapes were examined using cumulative incidence curve comparisons and proportional hazards regression. C-peptide responses were compared with and without adjustments for potential confounders. RESULTS: The majority of participants had a monophasic curve at baseline (n = 1732 [66%] vs n = 895 [34%]). The biphasic group had a lower cumulative incidence of type 1 diabetes (p < 0.001), which persisted after adjustments for age, sex, BMI z score and number of autoantibodies (p < 0.001). Among the monophasic group, the risk of type 1 diabetes was greater for those with a glucose peak at 90 min than for those with a peak at 30 min; the difference persisted after adjustments (p < 0.001). Compared with the biphasic group, the monophasic group had a lower early C-peptide (30-0 min) response, a lower C-peptide index (30-0 min C-peptide/30-0 min glucose), as well as a greater 2 h C-peptide level (p < 0.001 for all). CONCLUSIONS/INTERPRETATION: Those with biphasic glucose curves have a lower risk of progression to type 1 diabetes than those with monophasic curves, and the risk among the monophasic group is increased when the glucose peak occurs at 90 min than at 30 min. Differences in glucose curve shapes between the monophasic and biphasic groups appear to be related to C-peptide responses.

Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study.

AIMS/HYPOTHESIS: Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of 'slow progressors' (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. METHODS: Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Bart's Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed <5 years old from BOX) using the χ2 test. RESULTS: In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele. CONCLUSION: No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes.