Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

Self-Reported Food Security in Adolescents with Type 1 Diabetes: Association with Hemoglobin A1c and Mental Health Symptoms Independent of Household Food Security.

BACKGROUND: Typically, child exposure to food insecurity is assessed by caregiver reports of household food security. Child report has the potential for greater accuracy because it pertains only to the child whose experiences may differ from caregiver reports. OBJECTIVE: We assessed if adolescent-reported food insecurity was associated with levels of hemoglobin A1c (HbA1c), acute diabetes-related complications, depressive symptoms, and disordered eating behaviors in adolescents with type 1 diabetes, independently from household food security. METHODS: In a cross-sectional analysis of the multicenter SEARCH for Diabetes in Youth Cohort Study (phase 4, 2016-2019) including 601 adolescents aged 10-17 y with type 1 diabetes and their caregivers, household food security, and adolescent-reported food security were assessed using the 18-item Household Food Security Survey Module and the 6-item Child Food Security Assessment questionnaire. Age-stratified (10-13 and 14-17) regression models were performed to estimate independent associations, adjusting for sociodemographics, clinical factors, and household food security. RESULTS: Food insecurity was reported by 13.1% (n = 79) of adolescents and 15.6% (n = 94) of caregivers. Among adolescent-caregiver dyads, 82.5% (n = 496) of reports were concordant and 17.5% (n = 105) discordant, Cohen's κ= 0.3. Adolescent-reported food insecurity was not independently associated with HbA1c, diabetic ketoacidosis, and severe hypoglycemia, including in age-stratified analyses. Adolescent-reported food insecurity was independently associated with elevated odds of depressive symptoms [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.3, 10.3] and disordered eating behaviors (OR: 2.5, 95% CI: 1.4, 4.6) compared with adolescents reporting food security; these associations remained in both age groups for disordered eating behaviors and in the older group for depressive symptoms. CONCLUSIONS: Adolescents with type 1 diabetes may experience food insecurity differently than caregivers. Adolescent-reported food insecurity was independently associated with depressive symptoms and disordered eating behaviors and thus may be an important attribute to assess in addition to household food security in adolescents with type 1 diabetes.

Properties of the Household Food Security Survey Module Scale in Young Adults with Diabetes.

BACKGROUND: The Household Food Security Survey Module (HFSSM) was not tailored to people with chronic diseases or young adults (YAs). OBJECTIVES: We aim to evaluate whether the 18-item HFSSM meets assumptions underlying the scale among YAs with diabetes. METHODS: Data from 1887 YAs with youth-onset type 1 diabetes or type 2 diabetes were used from the SEARCH for Diabetes in Youth Study, 2016-2019, and on 925 who returned for the SEARCH Food Security Cohort Study, 2018-2021, all of whom had completed the HFSSM. Guttman scaling properties (affirmation of preceding less severe items) and Rasch model properties (probability to answer an item based on difficulty level) were assessed. RESULTS: Items 3 (balanced meals) and 6 (eating less than one should) were affirmed more frequently than expected (nonmonotonic response pattern). At 1.2%-3.5%, item nonresponse was rare among type 1 diabetes but higher among type 2 diabetes (range: 3.1%-10.6%). Items 9 (not eating the whole day) and 3 did not meet the Guttman scaling properties. Rasch modeling revealed that item 3 had the smallest difficulty parameter. INFIT indices suggested that some responses to item 3 did not match the pattern in the rest of the sample. Classifying household food insecurity (HFI) based on items 1 and 2 compared with other 2-item combinations, including item 3, revealed a substantial undercount of HFI ranging from 5% to 8% points. CONCLUSIONS: Use of the HFSSM among YAs with diabetes could potentially result in biased HFI reporting and affect estimates of HFI prevalence in this population.

Estimating incidence of type 1 and type 2 diabetes using prevalence data: the SEARCH for Diabetes in Youth study.

BACKGROUND: Incidence is one of the most important epidemiologic indices in surveillance. However, determining incidence is complex and requires time-consuming cohort studies or registries with date of diagnosis. Estimating incidence from prevalence using mathematical relationships may facilitate surveillance efforts. The aim of this study was to examine whether a partial differential equation (PDE) can be used to estimate diabetes incidence from prevalence in youth. METHODS: We used age-, sex-, and race/ethnicity-specific estimates of prevalence in 2001 and 2009 as reported in the SEARCH for Diabetes in Youth study. Using these data, a PDE was applied to estimate the average incidence rates of type 1 and type 2 diabetes for the period between 2001 and 2009. Estimates were compared to annual incidence rates observed in SEARCH. Precision of the estimates was evaluated using 95% bootstrap confidence intervals. RESULTS: Despite the long period between prevalence measures, the estimated average incidence rates mirror the average of the observed annual incidence rates. Absolute values of the age-standardized sex- and type-specific mean relative errors are below 8%. CONCLUSIONS: Incidence of diabetes can be accurately estimated from prevalence. Since only cross-sectional prevalence data is required, employing this methodology in future studies may result in considerable cost savings.

Household Food Insecurity and Cognition in Youth and Young Adults with Youth-Onset Diabetes.

Objective: We evaluated the association of household food insecurity (FI) with cognition in youth and young adults with type 1 diabetes (T1D) or type 2 diabetes (T2D). Design: In this cross-sectional study, age-adjusted scores for composite Fluid Cognition, and sub-domain scores for Receptive Language and Inhibitory Control and Attention, were modeled stratified by diabetes-type using linear regression, with FI in the past year as the predictor, controlling for covariates. Tests for processing speed, inhibitory control/attention, working memory, episodic memory, and cognitive flexibility were administered to measure composite Fluid Cognition score. The NIHT-CB Picture Vocabulary Test was used to assess Crystallized Cognition score and rapid identification of congruent versus noncongruent items were used to assess Inhibitory Control and Attention score. Setting: The SEARCH for Diabetes in Youth study, representative of 5 U.S. states. Participants: Included 1574 youth and young adults with T1D or T2D, mean age of 21 years, mean diabetes duration of 11 years, 51% non-Hispanic white, and 47% had higher HbA1c levels (>9% HbA1c). Results: Approximately 18% of the 1,240 participants with T1D and 31% of the 334 with T2D experienced FI. The food-insecure group with T1D had a lower composite Fluid Cognition score (ß= -2.5, 95% confidence interval (CI)= -4.8, -0.1) and a lower Crystallized Cognition score (ß= -3.4, CI= -5.6, -1.3) than food-secure peers. Findings were attenuated to non-significance after adjustment for demographics. Among T2D participants, no associations were observed. In participants with T1D effect modification by glycemic levels were found in the association between FI and composite Fluid Cognition score but adjustment for socioeconomic characteristics attenuated the interaction (p=0.0531). Conclusions: Food-insecure youth and young adults with T1D or T2D did not have different cognition compared to those who were food-secure after adjustment for confounders. Longitudinal research is needed to further understand relations amongst these factors.

Screening for Gastric Sensory Motor Abnormalities in Pediatric Patients With Type 1 Diabetes.

OBJECTIVE: To determine the frequency of gastric sensory motor symptoms in youth with type 1 diabetes. METHODS: A prospective cross-sectional study was performed to evaluate symptoms of delayed gastric emptying in participants with type 1 diabetes, aged 12 to 25 years, using the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire. In addition, a 5-year (January 2015 to December 2019), a retrospective study was completed on all gastric emptying scans performed in youth at our institution. RESULTS: A total of 359 participants (mean age, 17.7 ± 3.33 years) with type 1 diabetes completed the GCSI questionnaire. Compared with nonresponders, responders were more likely to be non-Hispanic White (90% vs 86%; P =.003) and female patients (58% vs 44%; P <.0001), with a lower HbA1c (8.1 ± 1.8 vs 9.0 ± 2.1; P <.0001). At least 1 gastrointestinal symptom was reported in 270 (75%) of responders, of which nausea was the most common (71%). A GCSI score of ≥1.9 suggestive of more severe gastrointestinal symptoms was reported in 17% of responders. Participants with scores ≥1.9 were older (19.1 ± 3.0 vs 17.8 ± 3.3 years; P =.01). In the retrospective study, 778 underwent gastric emptying scan, 29 participants had type 1 diabetes and 11 (38%) showed delayed gastric emptying. CONCLUSION: Gastrointestinal symptoms related to gastric sensory motor abnormalities are seen in youth and young adults with type 1 diabetes. In particular, for those with higher GCSI scores, earlier recognition and referral may be warranted.

Obese and Type 2 Diabetic Youth Have Increased Forward and Backward Wave Reflections.

OBJECTIVE: Pulse wave analysis estimates arterial wave reflections relating to left ventricular dysfunction and cardiovascular event risk in adults. Forward and backward waves (Pf and Pb) may improve risk stratification for cardiovascular events. Data in youth are lacking. We hypothesized that a significant difference in wave reflections would be identified in young subjects with adverse cardiovascular risk factors. Approach and Results: Vital signs and labs were obtained in 551 patients aged 10 to 24 years who were lean (L=199), obese (O=173), or had type 2 diabetes (T=179). Wave separation was performed. Differences in cardiovascular risk factors and wave reflections were assessed using ANOVA. General linear models were constructed to elucidate independent predictors of wave reflections. O and T subjects had an adverse cardiovascular risk profile versus L. O and T subjects had higher Pf and Pb versus L (P≤0.05). When adjusted for adiposity and other cardiovascular risk factors, reflection magnitude increased from L to O to T with higher T versus L values (P≤0.05) and near-significant O versus L values (P=0.06). Adiposity and blood pressure were major determinants of wave reflections. Pb influenced log left ventricular mass index, log E/e', and log composite carotid intima-media thickness. CONCLUSIONS: Adolescents and young adults with obesity and type 2 diabetes have altered forward and backward wave reflections versus lean controls related to adiposity, BP, and insulin levels. These parameters may help risk stratify patients with adverse cardiovascular risk factors.

Cerebral blood flow is lower in youth with type 2 diabetes compared to obese controls: A pilot study.

AIM: The cerebral vasculature may be susceptible to the adverse effects of type 2 diabetes. In this pilot study, we compared cerebral blood flow (CBF) in youth with type 2 diabetes to obese, euglycemic controls, and explored the association between CBF and a non-invasive measure of atherosclerosis, carotid intima-medial thickness (IMT). METHODS: Global and regional CBF were compared between youth with type 2 diabetes (mean age 16.7 ± 2.0 years, n = 20) and age, race, and sex similar obese youth without diabetes (17.4 ± 1.9 years, n = 19) using arterial spin labeling magnetic resonance imaging. Mean CBF values were compared between groups. Voxel-wise results were evaluated for statistical significance (p < 0.05) after adjustment for multiple comparisons. Carotid IMT in the type 2 diabetes group was correlated with CBF. RESULTS: Compared to obese controls, the type 2 diabetes group had significantly lower global CBF (49.7 ± 7.2 vs. 63.8 ± 11.5 ml/gm/min, p < 0.001). Significantly lower CBF was observed in multiple brain regions for the type 2 diabetes group, while no regions with higher CBF were identified. In the type 2 diabetes group, carotid IMT was inversely correlated with CBF, both globally (r = -0.70, p = 0.002) and in regional clusters. CONCLUSIONS: In this pilot study, lower CBF was seen in youth with type 2 diabetes compared to youth with obesity and IMT was inversely correlated with CBF. Cerebrovascular impairment may be present in youth with type 2 diabetes. These findings could represent a mechanistic link to explain previously reported brain volume and neurocognitive differences.

A longitudinal assessment of diabetes autoantibodies in the SEARCH for diabetes in youth study.

To assess changes in diabetes autoantibodies (DAs) over time in children and young adults with diabetes and determine whether observed changes were associated with demographic characteristics, clinical parameters and diabetes complications. Participants had DAs measured at baseline (10.3 ± 7.1 months after diabetes diagnosis) and at 12, 24 months and ≥5 years after the baseline measurement. At the ≥5-year follow-up, the presence of diabetes complications was assessed. We examined the associations between change in number of positive DAs and changes in individual DA status with the participants' characteristics and clinical parameters over time. Out of 4179 participants, 62% had longitudinal DA data and 51% had complications and longitudinal DA data. In participants with ≥1 baseline positive DA (n = 1699), 83.4% remained positive after 7.3 ± 2.3 years duration of diabetes. Decrease in number of positive DAs was associated with longer diabetes duration (p = 0.003 for 1 baseline positive DA; p < 0.001 for 2 baseline positive DAs) and younger age at diagnosis (p < 0.001 for 2 baseline positive DAs). No associations were found between change in number of positive DAs in participants with ≥1 baseline positive DA (n = 1391) and HbA1c, insulin dose, acute, or chronic complications after 7.7 ± 1.9 years duration of diabetes. DA status likely remains stable in the first 7 years after diabetes diagnosis. Younger age at diabetes diagnosis and longer duration were associated with less persistence of DAs. Measuring DAs after initial presentation may aid in diabetes classification but not likely in predicting the clinical course.

Changes in Bone Marrow Adipose Tissue in Transgender and Gender Non-Conforming Youth Undergoing Pubertal Suppression: A Pilot Study.

Pubertal suppression with gonadotropin-releasing hormone (GnRH) agonists in transgender and gender non-conforming (TGNC) youth may affect acquisition of peak bone mass. Bone marrow adipose tissue (BMAT) has an inverse relationship with bone mineral density (BMD). To evaluate the effect of pubertal suppression on BMAT, in this pilot study we prospectively studied TGNC youth undergoing pubertal suppression and cisgender control participants with similar pubertal status over a 12-month period. BMD was measured by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Magnetic Resonance T1 relaxometry (T1-R) and spectroscopy (MRS) were performed to quantify BMAT at the distal femur. We compared the change in BMD, T1-R values, and MRS lipid indices between the two groups. Six TGNC (two assigned female and four assigned male at birth) and three female control participants (mean age 10.9 and 11.7 years, respectively) were enrolled. The mean lumbar spine BMD Z-score declined by 0.29 in the TGNC group, but increased by 0.48 in controls (between-group difference 0.77, 95% CI: 0.05, 1.45). Similar findings were observed with the change in trabecular volumetric BMD at the 3% tibia site (-4.1% in TGNC, +3.2% in controls, between-group difference 7.3%, 95% CI: 0.5%-14%). Distal femur T1 values declined (indicative of increased BMAT) by 7.9% in the TGNC group, but increased by 2.1% in controls (between-group difference 10%, 95% CI: -12.7%, 32.6%). Marrow lipid fraction by MRS increased by 8.4% in the TGNC group, but declined by 0.1% in controls (between-group difference 8.5%, 95% CI: -50.2%, 33.0%). In conclusion, we observed lower bone mass acquisition and greater increases in BMAT indices by MRI and MRS in TGNC youth after 12 months of GnRH agonists compared with control participants. Early changes in BMAT may underlie an alteration in bone mass acquisition with pubertal suppression, including alterations in mesenchymal stem cells within marrow.

A cross sectional study to compare cardiac structure and diastolic function in adolescents and young adults with youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study.

AIMS: To compare left ventricular structure (LV) and diastolic function in young adults with youth- onset diabetes by type, determine the prevalence of abnormal diastolic function by diabetes type using published values from age similar healthy controls, and examine the risk factors associated with diastolic function. METHODS: In a cross sectional analysis we compared LV structure and diastolic function from two dimensional echocardiogram in participants with type 1 (T1D) and type 2 diabetes (T2D) who participated in the SEARCH for Diabetes in Youth Study. Linear models were used to examine the risk factors associated with worse diastolic function. RESULTS: Of 479 participants studied, 258 had T1D (mean age 21.2 ± 5.2 years, 60.5% non-Hispanic white, 53.9% female) and 221 had T2D (mean age 24.8 ± 4.3 years, 24.4% non-Hispanic white, 73.8% female). Median diabetes duration was 11.6 years. Participants with T2D had greater LV mass index and worse diastolic function that persisted after adjustment for differences in risk factors compared with participants with T1D (all p < 0.05). Abnormal diastolic function, quantified using healthy controls, was pronounced in both groups but greater in those with T2D than T1D (T2D: 57.7% vs T1D: 47.2%, respectively), p < 0.05. Risk factors associated with worse diastolic function included older age at diabetes diagnosis, female sex, higher BP, heart rate and HbA1c and longer diabetes duration. CONCLUSIONS: LV structure and diastolic function is worse in individuals with T2D compared to T1D. However, abnormal diastolic function in seen in both groups compared to published values from age similar healthy controls.

Predicting healthcare utilization in youth with type 1 diabetes: The importance of family level variables.

OBJECTIVE: Little is known about how family factors impacting treatment adherence in type 1 diabetes are directly associated with unplanned healthcare utilization (e.g., emergency room visits and hospital admissions). Given the substantial financial burden of diabetes, understanding predictors of healthcare utilization in particular is important to inform behavioral interventions aimed toward improving adherence. RESEARCH DESIGN AND METHODS: The current study examined the relationship between family-level variables and healthcare utilization in a sample of 239 youth with type 1 diabetes and their parents. Healthcare utilization was determined via parent report and chart review. Parent- and youth-reports regarding levels of family conflict, youth autonomy, and parent support related to diabetes management were obtained via questionnaire, and negative reciprocity was obtained by coding observations of parent and youth interactions. Generalized Estimating Equations were used to examine the longitudinal association between healthcare utilization and family-level factors. RESULTS: Higher levels of observed negative reciprocity were associated with more frequent hospital admissions, while higher levels of youth-reported parent involvement in diabetes management were associated with fewer hospital admissions and ED visits. CONCLUSIONS: These findings highlight how family-level factors are directly related to healthcare utilization and point to the continued importance of integrating family-focused behavioral interventions in routine medical care for improving type 1 diabetes outcomes and reducing healthcare costs.

Diabetic ketoacidosis at diagnosis among youth with type 1 and type 2 diabetes: Results from SEARCH (United States) and YDR (India) registries.

BACKGROUND: There is significant global variation in the prevalence of diabetic ketoacidosis (DKA) at diagnosis among youth with type 1 diabetes (T1D). However, data for youth with type 2 diabetes (T2D) are limited, even in developed countries. We compared the prevalence of DKA at diagnosis among individuals with T1D and T2D from the SEARCH for Diabetes in Youth (SEARCH) and the Registry of Youth Onset Diabetes in India (YDR) registries. METHODS: We harmonized the SEARCH and YDR registries to the structure and terminology in the Observational Medical Outcome Partnership Common Data Model. Data used were from youth with T1D and T2D diagnosed before 20 years and newly diagnosed between 2006 and 2012 in YDR and 2009 and 2012 in SEARCH. RESULTS: There were 5366 US youth (4078 with T1D, 1288 with T2D) and 2335 Indian youth (2108 with T1D, 227 with T2D). More than one third of T1D youth enrolled in SEARCH had DKA at diagnosis which was significantly higher than in YDR (35.3% vs 28.7%, P < .0001). The burden of DKA in youth with T1D was significantly higher among younger age groups; this relationship was similar across registries (P = .4). The prevalence of DKA among T2D in SEARCH and YDR were 5.5% and 6.6% respectively (P = .4). CONCLUSIONS: There is significant burden of DKA at diagnosis with T1D among youth from United States and India, especially among the younger age groups. The reasons for this high prevalence are largely unknown but are critical to developing interventions to prevent DKA at diagnosis.

Comparison of the incidence of diabetes in United States and Indian youth: An international harmonization of youth diabetes registries.

OBJECTIVE: Incidence of youth-onset diabetes in India has not been well described. Comparison of incidence, across diabetes registries, has the potential to inform hypotheses for risk factors. We sought to compare the incidence of diabetes in the U.S.-based registry of youth onset diabetes (SEARCH) to the Registry of Diabetes with Young Age at Onset (YDR-Chennai and New Delhi regions) in India. METHODS: We harmonized data from both SEARCH and YDR to the Observational Medical Outcomes Partnership (OMOP) Common Data Model. Data were from youth registered with incident diabetes (2006-2012). Denominators were from census and membership data. We calculated diabetes incidence by averaging the total cases across the entire follow-up period and dividing this by the estimated census population corresponding to the source population for case ascertainment. Incidence was calculated for each of the registries and compared by type and within age and sex categories using a 2-sided, skew-corrected inverted score test. RESULTS: Incidence of type 1 was higher in SEARCH (21.2 cases/100 000 [95% CI: 19.9, 22.5]) than YDR (4.9 cases/100 000 [95% CI: 4.3, 5.6]). Incidence of type 2 diabetes was also higher in SEARCH (5.9 cases/100 000 [95% CI: 5.3, 6.6] in SEARCH vs 0.5/cases/100 000 [95% CI: 0.3, 0.7] in YDR). The age distribution of incident type 1 diabetes cases was similar across registries, whereas type 2 diabetes incidence was higher at an earlier age in SEARCH. Sex differences existed in SEARCH only, with a higher rate of type 2 diabetes among females. CONCLUSION: The incidence of youth-onset type 1 and 2 diabetes was significantly different between registries. Additional data are needed to elucidate whether the differences observed represent diagnostic delay, differences in genetic susceptibility, or differences in distribution of risk factors.

Glycemic control is associated with dyslipidemia over time in youth with type 2 diabetes: The SEARCH for diabetes in youth study.

BACKGROUND: Dyslipidemia has been documented in youth with type 2 diabetes. There is a paucity of studies examining dyslipidemia over time in youth with type 2 diabetes and associated risk factors. OBJECTIVE: To evaluate lipids at baseline and follow-up and associated risk factors in youth with type 2 diabetes. METHODS: We studied 212 youth with type 2 diabetes at baseline and after an average of 7 years of follow-up in the SEARCH for Diabetes in Youth Study. Abnormal lipids were defined as high-density lipoprotein cholesterol (HDL-C) < 35, low-density lipoprotein cholesterol (LDL-C) > 100, or triglycerides >150 (all mg/dl). We evaluated participants for progression to abnormal lipids (normal lipids at baseline and abnormal at follow-up), regression (abnormal lipids at baseline and normal at follow-up), stable normal, and stable abnormal lipids over time for HDL-C, LDL-C, and triglycerides. Associations between hemoglobin A1c (HbA1c) and adiposity over time (area under the curve [AUC]) with progression and stable abnormal lipids were evaluated. RESULTS: HDL-C progressed, regressed, was stable normal, and stable abnormal in 12.3%, 11.3%, 62.3%, and 14.2% of participants, respectively. Corresponding LDL-C percentages were 15.6%, 12.7%, 42.9%, and 28.8% and triglycerides were 17.5%, 10.8%, 55.7%, and 16.0%. Each 1% increase in HbA1c AUC was associated with a 13% higher risk of progression and stable abnormal triglycerides and a 20% higher risk of progression and stable abnormal LDL-C. Higher adiposity AUC was marginally (p = 0.049) associated with abnormal HDL-C. CONCLUSIONS: Progression and stable abnormal LDL-C and triglycerides occur in youth with type 2 diabetes and are associated with higher HbA1c.

The relationship between traffic-related air pollution exposures and allostatic load score among youth with type 1 diabetes in the SEARCH cohort.

OBJECTIVE: We investigated the effects of chronic exposures to particulate and traffic-related air pollution on allostatic load (AL) score, a marker of cumulative biological risk, among youth with type 1 diabetes. RESEARCH DESIGN AND METHODS: Participants were drawn from five clinical sites of the SEARCH for Diabetes in Youth (SEARCH) study (n = 2338). Baseline questionnaires, anthropometric measures, and a fasting blood test were taken at a clinic visit between 2001 and 2005. AL was operationalized using 10 biomarkers reflecting cardiovascular, metabolic, and inflammatory risk. Annual residential exposures to PM2.5 and proximity to heavily-trafficked major roadways were estimated for each participant. Poisson regression models adjusted for sociodemographic and lifestyle factors were conducted for each exposure. RESULTS: No significant associations were observed between exposures to PM2.5 or proximity to traffic and AL score, however analyses were suggestive of effect modification by race for residential distance to heavily-trafficked major roadways (p = 0.02). In stratified analyses, residing <100, 100-<200 and 200-<400 m compared to 400 m or more from heavily-trafficked major roadways was associated with 11%, 26% and 14% increases in AL score, respectively (95% CIs: -4, 29; 9, 45; -1, 30) for non-white participants compared to 6%, -2%, and -2% changes (95% CIs: -2, 15; -10, 7; -8, 6) for white participants. CONCLUSIONS: Among this population of youth with type 1 diabetes, we did not observe consistent relationships between chronic exposures to particulate and traffic-related air pollution and changes in AL score, however associations for traffic-related pollution exposures may differ by race/ethnicity and warrant further examination.

Trends in Prevalence of Type 1 and Type 2 Diabetes in Children and Adolescents in the US, 2001-2017.

Importance: Changes in the prevalence of youth-onset diabetes have previously been observed. Objective: To estimate changes in prevalence of type 1 and type 2 diabetes in youths in the US from 2001 to 2017. Design, Setting, and Participants: In this cross-sectional observational study, individuals younger than 20 years with physician-diagnosed diabetes were enumerated from 6 areas in the US (4 geographic areas, 1 health plan, and select American Indian reservations) for 2001, 2009, and 2017. Exposures: Calendar year. Main Outcomes and Measures: Estimated prevalence of physician-diagnosed type 1 and type 2 diabetes overall and by race and ethnicity, age, and sex. Results: Among youths 19 years or younger, 4958 of 3.35 million had type 1 diabetes in 2001, 6672 of 3.46 million had type 1 diabetes in 2009, and 7759 of 3.61 million had type 1 diabetes in 2017; among those aged 10 to 19 years, 588 of 1.73 million had type 2 diabetes in 2001, 814 of 1.85 million had type 2 diabetes in 2009, and 1230 of 1.85 million had type 2 diabetes in 2017. The estimated type 1 diabetes prevalence per 1000 youths for those 19 years or younger increased significantly from 1.48 (95% CI, 1.44-1.52) in 2001 to 1.93 (95% CI, 1.88-1.98) in 2009 to 2.15 (95% CI, 2.10-2.20) in 2017, an absolute increase of 0.67 per 1000 youths (95%, CI, 0.64-0.70) and a 45.1% (95% CI, 40.0%-50.4%) relative increase over 16 years. The greatest absolute increases were observed among non-Hispanic White (0.93 per 1000 youths [95% CI, 0.88-0.98]) and non-Hispanic Black (0.89 per 1000 youths [95% CI, 0.88-0.98]) youths. The estimated type 2 diabetes prevalence per 1000 youths aged 10 to 19 years increased significantly from 0.34 (95% CI, 0.31-0.37) in 2001 to 0.46 (95% CI, 0.43-0.49) in 2009 to 0.67 (95% CI, 0.63-0.70) in 2017, an absolute increase of 0.32 per 1000 youths (95% CI, 0.30-0.35) and a 95.3% (95% CI, 77.0%-115.4%) relative increase over 16 years. The greatest absolute increases were observed among non-Hispanic Black (0.85 per 1000 youths [95% CI, 0.74-0.97]) and Hispanic (0.57 per 1000 youths [95% CI, 0.51-0.64]) youths. Conclusions and Relevance: In 6 areas of the US from 2001 to 2017, the estimated prevalence of diabetes among children and adolescents increased for both type 1 and type 2 diabetes.

Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012.

BACKGROUND: Diagnoses of type 1 and type 2 diabetes in youths present a substantial clinical and public health burden. The prevalence of these diseases increased in the 2001-2009 period, but data on recent incidence trends are lacking. METHODS: We ascertained cases of type 1 and type 2 diabetes mellitus at five study centers in the United States. Denominators (4.9 million youths annually) were obtained from the U.S. Census or health-plan member counts. After the calculation of annual incidence rates for the 2002-2012 period, we analyzed trends using generalized autoregressive moving-average models with 2-year moving averages. RESULTS: A total of 11,245 youths with type 1 diabetes (0 to 19 years of age) and 2846 with type 2 diabetes (10 to 19 years of age) were identified. Overall unadjusted estimated incidence rates of type 1 diabetes increased by 1.4% annually (from 19.5 cases per 100,000 youths per year in 2002-2003 to 21.7 cases per 100,000 youths per year in 2011-2012, P=0.03). In adjusted pairwise comparisons, the annual rate of increase was greater among Hispanics than among non-Hispanic whites (4.2% vs. 1.2%, P<0.001). Overall unadjusted incidence rates of type 2 diabetes increased by 7.1% annually (from 9.0 cases per 100,000 youths per year in 2002-2003 to 12.5 cases per 100,000 youths per year in 2011-2012, P<0.001 for trend across race or ethnic group, sex, and age subgroups). Adjusted pairwise comparisons showed that the relative annual increase in the incidence of type 2 diabetes among non-Hispanic whites (0.6%) was lower than that among non-Hispanic blacks, Asians or Pacific Islanders, and Native Americans (P<0.05 for all comparisons) and that the annual rate of increase among Hispanics differed significantly from that among Native Americans (3.1% vs. 8.9%, P=0.01). After adjustment for age, sex, and race or ethnic group, the relative annual increase in the incidence of type 1 diabetes was 1.8% (P<0.001) and that of type 2 diabetes was 4.8% (P<0.001). CONCLUSIONS: The incidences of both type 1 and type 2 diabetes among youths increased significantly in the 2002-2012 period, particularly among youths of minority racial and ethnic groups. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Centers for Disease Control and Prevention.).

Trends in Incidence of Type 1 and Type 2 Diabetes Among Youths - Selected Counties and Indian Reservations, United States, 2002-2015.

Diabetes is one of the most common chronic diseases among persons aged <20 years (1). Onset of diabetes in childhood and adolescence is associated with numerous complications, including diabetic kidney disease, retinopathy, and peripheral neuropathy, and has a substantial impact on public health resources (2,3). From 2002 to 2012, type 1 and type 2 diabetes incidence increased 1.4% and 7.1%, respectively, among U.S. youths (4). To assess recent trends in incidence of diabetes in youths (defined for this report as persons aged <20 years), researchers analyzed 2002-2015 data from the SEARCH for Diabetes in Youth Study (SEARCH), a U.S. population-based registry study with clinical sites located in five states. The incidence of both type 1 and type 2 diabetes in U.S. youths continued to rise at constant rates throughout this period. Among all youths, the incidence of type 1 diabetes increased from 19.5 per 100,000 in 2002-2003 to 22.3 in 2014-2015 (annual percent change [APC] = 1.9%). Among persons aged 10-19 years, type 2 diabetes incidence increased from 9.0 per 100,000 in 2002-2003 to 13.8 in 2014-2015 (APC = 4.8%). For both type 1 and type 2 diabetes, the rates of increase were generally higher among racial/ethnic minority populations than those among whites. These findings highlight the need for continued surveillance for diabetes among youths to monitor overall and group-specific trends, identify factors driving these trends, and inform health care planning.

The association of low-density lipoprotein cholesterol with elevated arterial stiffness in adolescents and young adults with type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth study.

AIM: Our aim was to explore the relationship of Low-Density Lipoprotein Cholesterol (LDL-C) with subclinical cardiovascular disease (CVD) in youth with T1D and T2D. We hypothesized the association of LDL-C with elevated arterial stiffness (AS) would be partially accounted by the co-occurrence of other CVD factors. METHOD: We included 1376 youth with T1D and 157 with T2D from the SEARCH study. CVD risk factors including LDL-C, waist to height ratio (WHtR), mean arterial pressure (MAP), HbA1c, albumin to creatinine ratio (ACR), and insulin sensitivity (IS) score were measured at both visits. At follow up, elevated carotid-femoral AS was defined as levels above 6.8 m/s. Multivariable logistic regression evaluated the odds of elevated AS as a function of the average CVD risk factors. RESULTS: At follow up, age was 18.0 ± 4.1 and 21.6 ± 3.5 years and duration of diabetes was 7.8 ± 1.9 and 7.7 ± 1.9 years in T1D and T2D, respectively. Elevated AS was found in 8.4% of T1D and 49.0% of T2D participants. Each SD increase in LDL-C was associated with 1.28 increased odds (95% CI 1.05-1.54, P = .013) of elevated AS in youth with T1D. The association was similar but not statistically significant in T2D. WHtR, IS, and MAP were associated with elevated AS in both groups. Adjustment for WHtR or IS attenuated to non-significance the relationship between LDL-C and AS in T1D. CONCLUSIONS: Obesity and insulin resistance attenuate the association of high LDL-C with AS suggesting they partially account for the adverse effects of LDL-C on cardiovascular health in youth with T1D.