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.

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.

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.

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.

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.

Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial.

BACKGROUND: Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM. STUDY DESIGN: Observational prospective cohort study. SETTING & PARTICIPANTS: 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control. PREDICTORS: Natural log-transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension. OUTCOMES: Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (≥140mL/min/1.73m2) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio ≥ 30µg/mg at 3 consecutive annual visits. RESULTS: Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A1c concentration, but not estimated insulin sensitivity. LIMITATIONS: Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM. CONCLUSIONS: Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM.

The influence of body mass index and age on C-peptide at the diagnosis of type 1 diabetes in children who participated in the diabetes prevention trial-type 1.

BACKGROUND/OBJECTIVE: The extent of influence of BMI and age on C-peptide at the diagnosis of type 1 diabetes (T1D) is unknown. We thus studied the impact of body mass index Z-scores (BMIZ) and age on C-peptide measures at and soon after the diagnosis of T1D. METHODS: Data from Diabetes Prevention Trial-Type 1 (DPT-1) participants <18.0 years at diagnosis was analyzed. Analyses examined associations of C-peptide measures with BMIZ and age in 2 cohorts: oral glucose tolerance tests (OGTTs) at diagnosis (n = 99) and mixed meal tolerance tests (MMTTs) <6 months after diagnosis (n = 80). Multivariable linear regression was utilized. RESULTS: Fasting and area under the curve (AUC) C-peptide from OGTTs (n = 99) at diagnosis and MMTTs (n = 80) after diagnosis were positively associated with BMIZ and age (P < .001 for all). Associations persisted when BMIZ and age were included as independent variables in regression models (P < .001 for all). BMIZ and age explained 31%-47% of the variance of C-peptide measures. In an example, 2 individuals with identical AUC C-peptide values had an approximate 5-fold difference in values after adjustments for BMIZ and age. The association between fasting glucose and C-peptide decreased markedly when fasting C-peptide values were adjusted (r = 0.30, P < .01 to r = 0.07, n.s.). CONCLUSIONS: C-peptide measures are strongly and independently related to BMIZ and age at and soon after the diagnosis of T1D. Adjustments for BMIZ and age cause substantial changes in C-peptide values, and impact the association between glycemia and C-peptide. Such adjustments can improve assessments of ß-cell impairment at diagnosis.

Relationship of adiponectin and leptin with autoimmunity in children with new-onset type 1 diabetes: a pilot study.

AIM: To explore racial differences in adiponectin, and leptin and their relationship with islet autoimmunity in children with new-onset type 1 diabetes (T1D). METHODS: Medical records were reviewed from a cohort of new-onset clinically diagnosed T1D subjects matched by race, age, gender, and year of diagnosis. Sera were available for 156 subjects (77 African American (AA), 79 Caucasian (C), 48% male, age of 11.1 ± 3.8 yr) and assayed for adiponectin and leptin prior to (D0), 3, 5 d, and 2-4 months (M3) after insulin therapy and islet autoantibodies to GAD, IA2, insulin, and ICA were measured at onset. RESULTS: Adiponectin levels increased significantly following insulin therapy by day 5 (D5) (D0: 13.7 ± 7.2 vs. D5: 21.3 ± 9.9 µg/mL, p < 0.0001), but no further significant increase from D5 to M3. At DO, AA had lower adiponectin levels (10.5 vs. 15.7 µg/mL, p = 0.01), were more often overweight than C (55 vs. 18%, BMI ≥ 85th‰) and fewer had positive autoantibodies (72 vs. 87%, p = 0.05). Racial differences in adipocytokines disappeared after adjustment for BMI. At M3, subjects with more number of positive autoantibodies had higher adiponectin levels (p = 0.043) and adiponectin/leptin ratio (ALR) (p = 0.01), and lower leptin levels (p = 0.016). CONCLUSION: Adiponectin levels increased acutely with insulin therapy. Significantly lower adiponectin levels in AA were related to greater adiposity and not race. These pilot data showing those with the fewest autoantibodies had the lowest adiponectin levels, supporting the concept that insulin-resistant subjects may present with clinical T1D at earlier stages of ß-cell damage.

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.

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining ß-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS: A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS: Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

From Antiquity to Modern Times: A History of Diabetes Mellitus and Its Treatments.

The past 200 years have brought an understanding of diabetes and its pathogenesis, as well as the development of treatments that could not have been predicted when the disorder was first clinically described 2000 years ago. Beginning in the late 19th century, the initial descriptions of the microscopic anatomy of the pancreatic islets by Langerhans led to recognition of pancreatic endocrine function. Many investigators attempted to isolate the hypoglycemic factor produced by the pancreas, but Banting, Best, Macleod, and Collip were able to extract and purify "isletin" to treat human diabetes in 1921. Rapid scientific progress over the next 100 years led to an understanding of insulin synthesis, structure and function, production of modified synthetic insulins, and the physiopathology that permitted classification of diabetes subtypes. Improvements in control of diabetes have reduced the risks of complications. In less than two hundred years, we have gone from being unable to measure glucose in blood to being able to offer people with diabetes continuous blood glucose monitoring, linked to continuous subcutaneous insulin infusion. We come ever closer with new drugs and treatments to repair the biochemical defects in type 2 diabetes and to biologically replace islets and their function in type 1 diabetes. This review addresses the history of continuing progress in diabetes care.

ß-cell autoimmunity in overweight non-diabetic youth: any implications?

BACKGROUND AND OBJECTIVE: The presence of ß-cell antibodies is associated with a high risk of type 1 diabetes. With increasing rates of obesity, the distinction between obese T1DM and T2DM has become difficult. Moreover, increasing body mass index (BMI) in at-risk children has been proposed not only as a possible contributor to T1DM by increasing insulin resistance, but also as exerting an effect via the immunomodulatory properties of certain adipokines. This study aimed to determine prevalence of ß-cell autoantibodies (AA) in overweight non-diabetic children and assess insulin sensitivity and secretion derived from an oral glucose tolerance test (OGTT) in those with vs. without ß-cell AA. RESEARCH DESIGN AND METHODS: A total of 357 overweight (BMI > 85%) youths underwent OGTTs, dual energy X-ray absorptiometry (DEXA) and measurement of GAD65 and IA-2 AA according to the NIDDK harmonization assay. Using the same methodology, AA were measured in 90 normal weight, non-diabetic individuals. RESULTS: About 1.9% of overweight and 4.4% of control normal weight children had evidence of ß-cell autoimmunity, with GAD65 AA detected in all subjects but none with IA-2. Youth with positive vs. those with negative AA had higher leptin/adiponectin ratio, glucose at 60 min and C-peptide at 90 min. CONCLUSIONS: These findings suggest that the prevalence of ß-cell AA in overweight youth may be similar to that in non-overweight children. Further studies using standardized methods are required.

Nutrition and Obesity in the Pathogenesis of Youth-Onset Type 1 Diabetes and Its Complications.

Since the 1980s, there has been a dramatic rise in the prevalence of overweight and obesity in pediatric populations, in large part driven by sedentary lifestyles and changing dietary patterns with more processed foods. In parallel with the rise in pediatric obesity in the general population, the prevalence of overweight and obesity has increased among children and adolescents with type 1 diabetes. Adiposity has been implicated in a variety of mechanisms both potentiating the risk for type 1 diabetes as well as exacerbating long-term complications, particularly cardiovascular disease. Treatment options targeting the unique needs of obese pediatric patients, both before and after diagnosis of type 1 diabetes, are limited. In this review, we discuss the history of the epidemiology of the obesity epidemic in the context of pediatric type 1 diabetes, highlight the possible role of obesity in type 1 diabetes pathogenesis and review the concept of "double diabetes". The impact of obesity at and after diagnosis will be discussed, including noted differences in clinical and biochemical markers, lipid abnormalities, and long-term cardiovascular complications. Finally, we will review the existing literature on pharmacologic and nutritional interventions as potential treatment strategies for youth with coexisting type 1 diabetes and obesity.

Implications of the School Day on Health Behaviors for Children With Type 1 Diabetes: A Survey of Parent Perspectives During the COVID-19 Pandemic.

PURPOSE: The purpose of this study is to survey parents of youth with type 1 diabetes during the COVID-19 pandemic with school closures to better understand the implications of the school day on health care behaviors. METHODS: A cross-sectional, online survey was distributed to parents of youth with type 1 diabetes ≤19 years of age in a large, academic diabetes center. Questions encompassed perceived changes in management behaviors and plans for return to school. Subgroup analysis compared parent responses by child's age, reported stressors, and socioeconomic markers. RESULTS: Parents reported a worsening in their child's diabetes health behaviors during school closures compared to what they perceived during a regular school day before the pandemic. More than half of parents reported feeling that their child was unable to maintain a normal routine, with particular implications for snacking between meals, daily physical activity, and sleep habits. Families with adolescents or those experiencing multiple pandemic-related stressors reported greater challenges. In open-ended responses, families highlighted difficulty in balancing school, work, and diabetes care and expressed concerns about the mental health repercussions of school closures for their children. Nearly half of parents reported being at least moderately worried about return to school, whereas only a minority reported seeking guidance from their diabetes provider. CONCLUSIONS: Parent-reported disruptions of school-day routines frequently had adverse consequences for diabetes management in this population. These findings highlight the importance of a school-day routine for children with type 1 diabetes; during closures, families may benefit from mitigating strategies to maintain effective habits.

TCF7L2 Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

OBJECTIVE: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant. RESULTS: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. CONCLUSIONS: In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.

Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents.

OBJECTIVE: Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibody-positive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. RESEARCH DESIGN AND METHODS: We studied 706 single autoantibody-positive pediatric TrialNet participants (ages 1.6-18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ≥85th age- and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. RESULTS: At baseline, 175 children (25%) had a BMI ≥85th percentile. ceBMI range was -9.2 to 15.6 kg/m2 (median -1.91), with ceBMI ≥0 kg/m2 corresponding to persistently elevated BMI ≥85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ≥0 kg/m2, age, and HLA (P = 0.009). Among children ≥9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ≥0 kg/m2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P = 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. CONCLUSIONS: These data support that elevated BMI may exacerbate islet autoimmunity prior to clinical T1D, particularly in children with lower risk based on age and HLA. Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity.

The Pathological Evolution of Glucose Response Curves During the Progression to Type 1 Diabetes in the TrialNet Pathway to Prevention Study.

OBJECTIVE: Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody-positive individuals to assess 1) characteristic GRC changes during progression to type 1 diabetes and 2) GRC changes in relation to ß-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes. RESEARCH DESIGN AND METHODS: Among antibody-positive individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n = 298) to type 1 diabetes and nonprogressors (n = 2,216). GRC changes from last OGTT before diagnosis to diagnostic OGTTs were studied in progressors. RESULTS: GRCs changed more frequently from biphasic (two peaks) to monophasic (one peak) GRCs between first and last OGTTs in progressors than in nonprogressors (75.4% vs. 51.0%, respectively; P < 0.001). In contrast, GRCs of progressors changed less frequently from monophasic to biphasic than those of nonprogressors (12.6% vs. 30.6%; P < 0.001). Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30-0 min) C-peptide response decreased in progressors with GRCs changing from biphasic to monophasic between first and last OGTTs (P < 0.001) and from monophasic to monotonic between last and diagnostic OGTTs (P < 0.001). Conversely, the early C-peptide response increased among nonprogressors with GRCs changing from monophasic to biphasic (P < 0.001). Changes in GRCs were related to changes in GCRCs. CONCLUSIONS: Characteristic GRC changes, biphasic to monophasic to monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing ß-cell function.

Thyroid autoimmunity in children with features of both type 1 and type 2 diabetes.

AIM/HYPOTHESIS: To assess the prevalence of autoimmune thyroid disease (ATD) in insulin-treated youth with clinical features of type 2 diabetes mellitus (T2DM). METHODS: We evaluated prevalence of thyroid peroxidase (TPO) and thyroglobulin (TGA) antibodies at onset of insulin-treated diabetes and follow-up in 183 White and Black children. Of these, 136 had a body mass index (BMI) <85th percentile with 122 (89%) positive for beta-cell autoimmunity [type 1 diabetes mellitus (T1DM)/group I], 25 were overweight (BMI >or=85 th percentile) with or without acanthosis nigricans with beta-cell autoimmunity ['double' diabetes (DD)/group II], and 22 were overweight with no conventional beta-cell autoantibodies (group III). RESULTS: The prevalence of TPO and/or TGA was 39 and 29% (p = 0.19) in White and Black children and 39, 32, and 0% (p = 0.007) in groups I, II, and III, respectively. After a median follow-up of 60 months, 3.7, 4.3, and 0% developed hypothyroidism (increased thyroid-stimulating hormone with or without decreased free T4) in groups I, II, and III, respectively (p = 0.6). In subjects with TPO and/or TGA, hypothyroidism developed in 10 and 14% of groups I and II, respectively (p = 0.7). No child without thyroid antibodies developed hypothyroidism. CONCLUSIONS: In patients with clinical features of T2DM who have evidence of beta-cell autoimmunity (DD), the frequency of thyroid antibodies and ATD is similar to that in classical T1DM. This suggests that TIDM comorbidities may be common in clinical T2DM patients who have beta-cell autoimmunity. Despite their obesity, youth with insulin-requiring diabetes should be screened for thyroid and possibly other T1DM-associated autoimmune diseases.