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1.  Correlates of Treatment Patterns Among Youth With Type 2 Diabetes 
Diabetes Care  2013;37(1):64-72.
To describe treatment regimens in youth with type 2 diabetes and examine associations between regimens, demographic and clinical characteristics, and glycemic control.
This report includes 474 youth with a clinical diagnosis of type 2 diabetes who completed a SEARCH for Diabetes in Youth study visit. Diabetes treatment regimen was categorized as lifestyle alone, metformin monotherapy, any oral hypoglycemic agent (OHA) other than metformin or two or more OHAs, insulin monotherapy, and insulin plus any OHA(s). Association of treatment with demographic and clinical characteristics (fasting C-peptide [FCP], diabetes duration, and self-monitoring of blood glucose [SMBG]), and A1C was assessed by χ2 and ANOVA. Multiple linear regression models were used to evaluate independent associations of treatment regimens and A1C, adjusting for demographics, diabetes duration, FCP, and SMBG.
Over 50% of participants reported treatment with metformin alone or lifestyle. Of the autoantibody-negative youth, 40% were on metformin alone, while 33% were on insulin-containing regimens. Participants on metformin alone had a lower A1C (7.0 ± 2.0%, 53 ± 22 mmol/mol) than those on insulin alone (9.2 ± 2.7%, 77 ± 30 mmol/mol) or insulin plus OHA (8.6 ± 2.6%, 70 ± 28 mmol/mol) (P < 0.001). These differences remained significant after adjustment (7.5 ± 0.3%, 58 ± 3 mmol/mol; 9.1 ± 0.4%, 76 ± 4 mmol/mol; and 8.6 ± 0.4%, 70 ± 4 mmol/mol) (P < 0.001) and were more striking in those with diabetes for ≥2 years (7.9 ± 2.8, 9.9 ± 2.8, and 9.8 ± 2.6%). Over one-half of those on insulin-containing therapies still experience treatment failure (A1C ≥8%, 64 mmol/mol).
Approximately half of youth with type 2 diabetes were managed with lifestyle or metformin alone and had better glycemic control than individuals using other therapies. Those with longer diabetes duration in particular commonly experienced treatment failures, and more effective management strategies are needed.
PMCID: PMC3867996  PMID: 24026554
2.  Peripheral Neuropathy in Adolescents and Young Adults With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-up Cohort 
Diabetes Care  2013;36(12):3903-3908.
To estimate the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in a pilot study among youth participating in the SEARCH for Diabetes in Youth study.
DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI) (examination for foot abnormalities, distal vibration perception, and ankle reflexes). An MNSI exam (MNSIE) score >2 is diagnostic for DPN.
The MNSIE was completed in 399 subjects, including 329 youth with type 1 diabetes (mean age 15.7 ± 4.3 years, duration 6.2 ± 0.9 years) and 70 with type 2 diabetes (mean age 21.6 ± 4.1 years, duration 7.6 ± 1.8 years). Glycated hemoglobin (A1C) was similar in both groups (8.8 ± 1.8% for type 1 vs. 8.5 ± 2.9% for type 2). The prevalence of DPN was significantly higher in youth with type 2 compared with those with type 1 diabetes (25.7 vs. 8.2%; P < 0.0001). In unadjusted analyses, diabetes type, older age, longer duration of diabetes, increased waist circumference, elevated blood pressure, lower HDL cholesterol, and presence of microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) were associated with DPN. The association between diabetes type and DPN remained significant after adjustment for age and sex (odds ratio 2.29 [95% CI 1.05–5.02], P = 0.03).
DPN prevalence among youth with type 2 diabetes approached rates reported in adult populations with diabetes. Our findings suggest not only that youth with diabetes are at risk for DPN but also that many already show measurable signs of DPN.
PMCID: PMC3836139  PMID: 24144652
3.  Cardiovascular Risk Factors Are Associated With Increased Arterial Stiffness in Youth With Type 1 Diabetes 
Diabetes Care  2013;36(12):3938-3943.
To evaluate if presence of cardiovascular (CV) risk factors and their clustering as metabolic syndrome (MetS) is associated with increased arterial stiffness and accelerated progression over time among youth with type 1 diabetes.
Longitudinal study of 298 youth with type 1 diabetes (age 14.5 years; 46.3% female; duration 4.8 years), with two research visits conducted 5 years apart. CV factors included: waist circumference, blood pressure (BP), fasting lipids (HDL cholesterol, LDL cholesterol [LDL-c], triglycerides), albumin/creatinine ratio, and HbA1c. MetS was based on Adult Treatment Panel III criteria modified for youth. Pulse wave velocity (PWV) in the carotid–femoral segment was measured by tonometry. Mixed models were used to assess the rate of progression in PWV and the association between CV factors and PWV over time.
PWV increased significantly over time (0.145 m/s/year; P < 0.0001). MetS (P = 0.0035), large waist (P < 0.0001), and elevated BP (P = 0.0003) at baseline were each associated with worse PWV over time. These baseline factors, however, did not significantly influence the rate of progression. Increases in waist circumference (P < 0.0001), LDL-c levels (P = 0.0156), and declining glucose control (HbA1c; P = 0.0419) were independently associated with higher PWV over time.
Presence, clustering, and worsening of CV risk factors are associated with increased arterial stiffness over time in youth with type 1 diabetes. Whether improvement in CV risk factors early in life will slow the progression of arterial stiffness and reduce the burden of CV disease in this population requires further study.
PMCID: PMC3836140  PMID: 24101697
4.  Impact of Glycemic Control on Heart Rate Variability in Youth with Type 1 Diabetes: The SEARCH CVD Study 
Diabetes Technology & Therapeutics  2013;15(12):977-983.
Aim: This study explored the role of glycemic control on cardiac autonomic function, measured by heart rate variability (HRV), in youth with type 1 diabetes.
Patients and Methods: A retrospective cohort of 345 youth with type 1 diabetes (mean age, 18.5 years; duration, 10 years) participating in the SEARCH for Diabetes in Youth study were enrolled in the ancillary SEARCH Cardiovascular Disease (CVD) study. Anthropometric, metabolic, and HRV parameters were collected at the current research visit. Glycemic control over time was assessed by the mean glycated hemoglobin (A1c) levels collected over the past 6 years. Multiple linear regression analysis assessed the association between A1c over time and HRV parameters, independent of demographic and CVD risk factors. Participants were categorized into four glycemic control categories based on their mean A1c over time: Group 1, optimal (mean A1c, ≤7.4%); Group 2 (mean A1c, 7.5–8.4%); Group 3 (mean A1c, 8.5–9.4%), and Group 4, poor (mean A1c, ≥9.5%), and a linear trend was explored across these categories.
Results: For every 1% increase in the average A1c over 6 years there was a 5% decrease in the SD of the normal RR interval (SDNN) (P=0.02) and 7% decrease in the root mean square successive difference of the RR interval (RMSSD) (P=0.02), independent of demographic and traditional CVD risk factors. A dose–response relationship between worsening glucose control categories and measures of overall reduced HRV was found.
Conclusions: Chronic hyperglycemia is the main determinant of early cardiac autonomic dysfunction, manifested as reduced overall HRV and parasympathetic loss, among youth with type 1 diabetes.
PMCID: PMC3868395  PMID: 24010960
5.  Albuminuria According to Status of Autoimmunity and Insulin Sensitivity Among Youth With Type 1 and Type 2 Diabetes 
Diabetes Care  2013;36(11):3633-3638.
To evaluate whether etiologic diabetes type is associated with the degree of albuminuria in children with diabetes.
SEARCH is an observational, longitudinal study of children with diabetes. Youth with newly diagnosed diabetes were classified according to diabetes autoantibody (DAA) status and presence of insulin resistance. We defined insulin resistance as an insulin sensitivity score <25th percentile for the United States general youth population. DAA status was based on positivity for the 65-kD isoform of glutamate decarboxylase and insulinoma-associated protein 2 antigens. The four etiologic diabetes type groups were as follows: DAA+/insulin-sensitive (IS) (n = 1,351); DAA+/insulin-resistant (IR) (n = 438); DAA−/IR (n = 379); and DAA−/IS (n = 233). Urinary albumin:creatinine ratio (UACR) was measured from a random urine specimen. Multivariable regression analyses assessed the independent relationship between the four diabetes type groups and magnitude of UACR.
Adjusted UACR means across the four groups were as follows: DAA+/IS = 154 μg/mg; DAA+/IR = 137 μg/mg; DAA−/IR = 257 μg/mg; and DAA−/IS = 131 μg/mg (P < 0.005). Only DAA−/IR was significantly different. We performed post hoc multivariable regression analysis restricted to the two IR groups to explore the contribution of DAA status and insulin sensitivity (continuous) to the difference in UACR between the IR groups. Only insulin sensitivity was significantly associated with UACR (β = −0.54; P < 0.0001).
In youth with diabetes, the DAA−/IR group had a greater UACR than all other groups, possibly because of the greater magnitude of insulin resistance. Further exploration of the relationships between severity of insulin resistance, autoimmunity, and albuminuria in youth with diabetes is warranted.
PMCID: PMC3816857  PMID: 23846811
6.  Correlates of Medical Nutrition Therapy and Cardiovascular Outcomes in Youth with Type 1 Diabetes 
Journal of nutrition education and behavior  2013;45(6):10.1016/j.jneb.2013.06.003.
To examine whether the types of medical nutrition therapies (MNTs) taught to and used by youth with type 1 diabetes (T1D) varies by socio-demographic characteristics and cardiovascular (CVD) risk factors
Cross-sectional study
The SEARCH for Diabetes in Youth study is a population-based cohort of individuals with clinical diagnosed diabetes
1,191 individuals with T1D
Main Outcome Measures
Types of MNTs and frequency of use
Bivariate analysis and multivariate linear regression (P<0.05)
More race/ethnic minorities (vs. whites), individuals with parents
Conclusions and Implications
In individuals with T1D, race/ethnic minorities, individuals with parents
PMCID: PMC3825757  PMID: 23891147
medical nutrition therapy; type 1 diabetes; cardiovascular risk
Diabetes Care  2013;36(9):2597-2599.
Type 1 diabetes mellitus causes increased carotid intima-media thickness (IMT) in adults. We evaluated IMT in young subjects with type 1 diabetes.
Participants with type 1 diabetes (N = 402) were matched to controls (N = 206) by age, sex, and race or ethnicity. Anthropometric and laboratory values, blood pressure, and IMT were measured. ANCOVA was used to assess differences controlling for demographic risk factors, cardiovascular risk factors, and HbA1c.
Subjects were 18.9 ± 3.3 years old (50% male, 82.7% non-Hispanic white). Youth with type 1 diabetes had thicker bulb IMT, which remained significantly different after adjustment for demographics and cardiovascular risk factors. Age, sex, adiposity, and systolic blood pressure were consistent significant determinants of IMT. Adjustment for HbA1c eliminated the difference, suggesting the difference was attributable to poor glycemic control.
Carotid IMT may be increased in youth with type 1 diabetes at high risk for cardiovascular disease. Better control of diabetes may be essential in preventing progression of atherosclerosis.
PMCID: PMC3747912  PMID: 23564920
Diabetes Care  2013;36(8):2351-2358.
Reduced heart rate variability (HRV) and increased arterial stiffness (AS) are both present in youth with type 1 diabetes. However, it is unclear whether they are associated and whether their association is independent of cardiovascular disease (CVD) risk factors.
The SEARCH Cardiovascular Disease (SEARCH CVD) study explored the cross-sectional relationships between HRV and several measures of AS in youth with (n = 344) and without (n = 171) type 1 diabetes. The SphygmoCor device (AtCor Medical, Sydney, Australia) was used to measure HRV using SD of normal R-R interval (SDNN), as well as AS, using pulse wave velocity in the carotid to femoral segment (PWV-trunk) and augmentation index adjusted to a heart rate of 75 bpm (AIx75). Brachial distensibility (BrachD), another index of AS, was measured with a DynaPulse instrument (Pulse Metric, San Diego, CA). Multiple linear regression analyses explored the associations between HRV and each of the three AS measures, after adjusting for demographic characteristics and traditional CVD risk factors (blood pressure, lipids, obesity, microalbuminuria, and smoking) separately, for youth with and without type 1 diabetes.
Among youth with type 1 diabetes, lower SDNN was associated with peripheral AS (lower BrachD, P = 0.01; r2 = 0.30) and central AS (higher PVW-trunk, P < 0.0001; r2 = 0.37; and higher AIx75, P = 0.007; r2 = 0.08). These associations were attenuated with adjustment for CVD risk factors, but remained statistically significant for BrachD and PWV-trunk. While a similar association between HRV and BrachD was present in control youth, lower HRV was not associated with increased central AS or with AIx75.
Longitudinal studies are needed to understand the pathways responsible for these associations.
PMCID: PMC3714513  PMID: 23435158
Pediatric diabetes  2012;14(3):174-180.
Neonatal diabetes mellitus (NDM) is defined as diabetes with onset before 6 months of age. Nearly half of individuals with NDM are affected by permanent neonatal diabetes mellitus (PNDM). Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of PNDM.
To estimate the prevalence of PNDM among SEARCH for Diabetes in Youth (SEARCH) study participants (2001-2008) and to identify the genetic mutations causing PNDM.
SEARCH is a multi-center population-based study of diabetes in youth < 20 years of age. Participants diagnosed with diabetes before 6 months of age were invited for genetic testing for mutations in the KCNJ11, ABCC8 and INS genes.
Of the 15,829 SEARCH participants with diabetes, 39 were diagnosed before 6 months of age. Thirty five of them had PNDM (0.22% of all diabetes cases in SEARCH), 3 had transient neonatal diabetes that had remitted by 18 months and one was unknown. The majority of them (66.7%) had a clinical diagnosis of type1 diabetes by their health care provider. Population prevalence of PNDM in youth <20 years was estimated at 1 in 252,000. Seven participants underwent genetic testing; mutations causing PNDM were identified in five (71%), (two KCNJ11, three INS).
We report the first population-based frequency of PNDM in the US based on the frequency of PNDM in SEARCH. Patients with NDM are often misclassified as having type1 diabetes. Widespread education is essential to encourage appropriate genetic testing and treatment of NDM.
PMCID: PMC4101463  PMID: 23050777
neonatal diabetes; KCNJ11; INS; ABCC8; infant
Diabetes Care  2013;36(7):1842-1850.
To test the novel hypothesis that nutritional factors previously associated with type 1 diabetes etiology or with insulin secretion are prospectively associated with fasting C-peptide (FCP) concentration among youth recently diagnosed with type 1 diabetes.
Included were 1,316 youth with autoantibody-positive type 1 diabetes who participated in the SEARCH for Diabetes in Youth study (baseline disease duration, 9.9 months; SD, 6.3). Nutritional exposures included breastfeeding and age at introduction of complementary foods, baseline plasma long-chain omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), vitamin D, vitamin E, and, from a baseline food frequency questionnaire, estimated intake of the branched-chain amino acid leucine and total carbohydrate. Multiple linear regression models were conducted to relate each nutritional factor to baseline FCP adjusted for demographics, disease-related factors, and other confounders. Prospective analyses included the subset of participants with preserved β-cell function at baseline (baseline FCP ≥0.23 ng/mL) with additional adjustment for baseline FCP and time (mean follow-up, 24.3 months; SD, 8.2; n = 656). FCP concentration was analyzed as log(FCP).
In adjusted prospective analyses, baseline EPA (P = 0.02), EPA plus DHA (P = 0.03), and leucine (P = 0.03) were each associated positively and significantly with FCP at follow-up. Vitamin D was unexpectedly inversely associated with FCP (P = 0.002).
Increased intake of branched-chain amino acids and long-chain omega-3 fatty acids may support preservation of β-cell function. This represents a new direction for research to improve prognosis for type 1 diabetes.
PMCID: PMC3687285  PMID: 23801797
The Diabetes educator  2013;40(1):29-39.
The purpose of this study is to describe: 1) the receipt of diabetes self-management education (DSME) in a large, diverse cohort of US youth with type 1 diabetes (T1DM); 2) the segregation of self-reported DSME variables into domains; and 3) the demographic and clinical characteristics of youth who receive DSME.
Data are from the US population-based cohort, SEARCH for Diabetes in Youth. A cross-sectional analysis was employed using data from 1273 youth < 20 years of age at time of diagnosis of T1DM. Clusters of 19 self-reported DSME variables were derived using factor analysis and their associations with demographic and clinical characteristics were evaluated using polytomous logistic regression.
Nearly all participants reported receiving DSME content consistent with ‘survival skills’ (e.g., target blood glucose and what to do for low or high blood glucose), yet gaps in continuing education were identified [e.g., fewer than half of participants reported receiving specific medical nutrition therapy (MNT) recommendations]. Five DSME clusters were explored: Receipt of Specific MNT Recommendations, Receipt of Diabetes Information Resources, Receipt of Clinic Visit Information, Receipt of Specific Diabetes Information, and Met with Educator or Nutritionist. Factor scores were significantly associated with demographic and clinical characteristics, including race/ethnicity, socioeconomic status, and diabetes self-management practices.
Health care providers should work together to address reported gaps in DSME in order to improve patient care.
PMCID: PMC4076934  PMID: 24248833
Migration status and the accompanying diversity in culture, foods and family norms, may be an important consideration for practitioners providing individualized care to treat and prevent complications among youth with diabetes. Approximately 20% of youth in the US have ≥ 1 foreign-born parent. However, the proportion and characteristics of youth with diabetes and ≥ 1 foreign-born parent have yet to be described. Study participants (n = 3,086) were from SEARCH for Diabetes in Youth, a prospective multi-center study in the US. Primary outcomes of interest included HbA1c, body mass index and barriers to care. Multivariable analyses were carried out using logistic regression and analysis of covariance. Approximately 17% of participants with type 1 diabetes (T1D) and 22% with type 2 diabetes (T2D) had ≥ 1 foreign-born parent. Youth with T1D and ≥ 1 foreign-born parent were less likely to have poor glycemic control [adjusted odds ratio (OR) (95% confidence interval): 0.70 (0.53, 0.94)]. Among youth with T2D, those with ≥ 1 foreign-born parent had lower odds of obesity [adjusted OR (95% CI): 0.35 (0.17, 0.70)]. This is the first study to estimate the proportion and characteristics of youth with diabetes exposed to migration in the US. Research into potential mechanisms underlying the observed protective effects is warranted.
PMCID: PMC4049129  PMID: 22481308
diabetes; youth; migration; US
Pediatric diabetes  2012;14(2):121-128.
To examine HLA DRB1-DQB1 haplotypes within a multi-ethnic cohort and assess their association with characteristics of diabetes onset.
The sample included 1,662 participants from the SEARCH for Diabetes in Youth Study who tested positive for GADA and/or IA-2A autoantibodies. Blood drawn at the study visit was used to measure fasting C-peptide and genotype HLA DRB1 and DQB1 loci. Diabetic ketoacidosis (DKA) at diagnosis was determined from medical records. Multivariable linear and logistic regression models stratified by race/ethnicity were used to assess associations with DRB1-DQB1 haplotypes.
The frequency of DRB1*03 susceptibility haplotypes ranged 27.5–28.9% in all racial/ethnic groups. The frequency of susceptibility DRB1*04-DQB1*0302 was higher in non-Hispanic white (NHW; 34.1%) and Hispanic (38.9%) compared to non-Hispanic black (NHB; 20.8%) youth. Neutral and protective haplotypes were low frequency in all groups. DBR1*03 haplotypes were associated with younger age at diagnosis in NHW and positivity for multiple autoantibodies in Hispanics. DRB1*04-DQB1*0302 haplotypes were associated with multiple autoantibody positivity in NHW and Hispanics, and lower fasting C-peptide and higher odds of DKA in Hispanics only. Although protective DRB1*04-DQB1*0301 haplotypes were associated with older age at diagnosis in NHW, they were also associated with multiple autoantibody positivity in these youth. Protective DRB1*13 haplotypes were associated with decreased odds of multiple autoantibody positivity in NHB youth.
The distribution of DRB1-DQB1 haplotypes and their association with onset-related characteristics of autoimmune diabetes varies across major racial/ethnic groups in the United States. This may contribute to variation in clinical presentation of autoimmune diabetes by race/ethnicity.
PMCID: PMC3932799  PMID: 22913598
HLA; type 1 diabetes; autoantibodies; diabetic ketoacidosis; fasting C-peptide
Health & place  2012;18(4):911-916.
Findings regarding type 1 diabetes mellitus (T1DM) and neighborhood-level characteristics are mixed, with few US studies examining the influence of race/ethnicity. We conducted an ecologic study using SEARCH for Diabetes in Youth Study data to explore the association of neighborhood characteristics and T1DM incidence. 2002–2003 incident cases among youth at four SEARCH centers were included. Residential addresses were geocoded to US Census Tract. Standardized incidence ratios tended to increase with increasing education and median household income. Results from Poisson regression mixed models were similar and stable across race/ethnic groups and population density. Our study suggests a relationship of T1DM incidence with neighborhood-level socioeconomic status, independent of individual-level race/ethnic differences.
PMCID: PMC3936317  PMID: 22464158
Type 1 Diabetes; Neighborhood; Socioeconomic status
The Journal of pediatrics  2010;158(4):594-601.e1.
To examine prevalence of tobacco use and coexistence of cardiometabolic risk factors according to smoking status in youth with diabetes mellitus.
Study design
Youth aged 10 to 22 years who participated in the SEARCH for Diabetes in Youth study (n = 3466) were surveyed about their tobacco use and examined for cardiometabolic risk factors: waist circumference, systolic and diastolic blood pressure, physical activity, and lipid profile.
The prevalence of tobacco use in youth aged 10 to 14 years, 15 to 19 years, and ≥20 years with type 1 diabetes mellitus was 2.7%, 17.1%, and 34.0%, respectively, and the prevalence in youth with type 2 diabetes mellitus was 5.5%, 16.4%, and 40.3%,respectively. Smoking was more likely in youth with annual family incomes <$50 000, regardless of diabetes mellitus type. Cigarette smoking was associated with higher odds of high triglyceride levels and physical inactivity in youth with type 1 diabetes mellitus. Less than 50% of youth aged 10 to 14 years (52.2% of participants) reported having ever been counseled by their healthcare provider to not smoke or to stop smoking.
Tobacco use is prevalent in youth with diabetes mellitus. Aggressive tobacco prevention and cessation programs should be a high priority to prevent or delay the development of cardiovascular disease.
PMCID: PMC3908882  PMID: 21129757
Diabetes Care  2012;36(1):27-33.
To examine the patterns and associations of insulin regimens and change in regimens with clinical outcomes in a diverse population of children with recently diagnosed type 1 diabetes.
The study sample consisted of youth with type 1 diabetes who completed a baseline SEARCH for Diabetes in Youth study visit after being newly diagnosed and at least one follow-up visit. Demographic, diabetes self-management, physical, and laboratory measures were collected at study visits. Insulin regimens and change in regimen compared with the initial visit were categorized as more intensive (MI), no change (NC), or less intensive (LI). We examined relationships between insulin regimens, change in regimen, and outcomes including A1C and fasting C-peptide.
Of the 1,606 participants with a mean follow-up of 36 months, 51.7% changed to an MI regimen, 44.7% had NC, and 3.6% changed to an LI regimen. Participants who were younger, non-Hispanic white, and from families of higher income and parental education and who had private health insurance were more likely to be in MI or NC groups. Those in MI and NC groups had lower baseline A1C (P = 0.028) and smaller increase in A1C over time than LI (P < 0.01). Younger age, continuous subcutaneous insulin pump therapy, and change to MI were associated with higher probability of achieving target A1C levels.
Insulin regimens were intensified over time in over half of participants but varied by sociodemographic domains. As more intensive regimens were associated with better outcomes, early intensification of management may improve outcomes in all children with diabetes. Although intensification of insulin regimen is preferred, choice of insulin regimen must be individualized based on the child and family’s ability to comply with the prescribed plan.
PMCID: PMC3526205  PMID: 22961571
Diabetes Care  2012;36(1):157-162.
This study compared heart rate variability (HRV) parameters in youth with and without type 1 diabetes and explored potential contributors of altered HRV.
HRV parameters were measured among 354 youth with type 1 diabetes (mean age 18.8 years, diabetes duration 9.8 years, and mean A1C 8.9%) and 176 youth without diabetes (mean age 19.2 years) participating in the SEARCH CVD study. Multiple linear regression was used to assess the relationship between diabetes status and HRV parameters, adjusting for covariates.
Compared with control subjects, youth with type 1 diabetes had reduced overall HRV (10.09 ms lower SD of NN intervals [SDNN]) and markers of parasympathetic loss (13.5 ms reduced root mean square successive difference of NN intervals [RMSSD] and 5.2 normalized units (n.u.) reduced high frequency [HF] power) with sympathetic override (5.2 n.u. increased low frequency [LF] power), independent of demographic, anthropometric, and traditional cardiovascular risk factors. Older age, female sex, higher LDL cholesterol and triglyceride levels, and presence of microalbuminuria were independently associated with lower HRV but did not account for the observed differences between youth with and without diabetes. Youth with type 1 diabetes and A1C levels ≥7.5% had significantly worse HRV parameters than control subjects; however, in youth with optimal glycemic control (A1C <7.5%), HRV parameters did not differ significantly from control subjects.
Youth with type 1 diabetes have signs of early cardiac autonomic neuropathy: reduced overall HRV and parasympathetic loss with sympathetic override. The main driver of these subclinical abnormalities appears to be hyperglycemia.
PMCID: PMC3526238  PMID: 22961570
Diabetes Care  2012;35(12):2443-2446.
Youth with diabetes are at increased risk for depression. The objectives of this study were to provide preliminary evidence that this at-risk status for depression is associated with metabolic and inflammatory markers and to inform future, more stringent examinations of the directionality of these associations.
Data from SEARCH for Diabetes in Youth (SEARCH), an observational study of U.S. children diagnosed with diabetes at <20 years of age, were used for these analyses. SEARCH participants were drawn from four geographically defined populations in Ohio, Washington, South Carolina, and Colorado; health plan enrollees in Hawaii and California; and Indian Health Service beneficiaries from four Native American populations. Participants were 2,359 youth with diabetes from the 2001 prevalent and 2002–2004 incident SEARCH cohorts. Depression was measured with the Center for Epidemiologic Studies Depression scale. Eight metabolic and inflammatory markers were measured: adiponectin, leptin, C-reactive protein, serum amyloid A, apolipoprotein B (apoB), lipoprotein A, interleukin-6, and LDL.
Six of eight markers were significantly (P < 0.006) associated with depression in youth with diabetes in bivariate analyses. In general, higher levels of depression were associated with indicators of worse metabolic or inflammatory functioning. In regression models stratified by diabetes type and accounting for demographic and clinical characteristics, only higher levels of apoB remained associated with higher levels of depression in youth with type 1 diabetes.
These data suggest that depression reported by youth with diabetes is partially associated with metabolic abnormalities and systemic inflammation.
PMCID: PMC3507554  PMID: 23033243
Diabetes Care  2012;35(12):2515-2520.
To forecast the number of U.S. individuals aged <20 years with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) through 2050, accounting for changing demography and diabetes incidence.
We used Markov modeling framework to generate yearly forecasts of the number of individuals in each of three states (diabetes, no diabetes, and death). We used 2001 prevalence and 2002 incidence of T1DM and T2DM from the SEARCH for Diabetes in Youth study and U.S. Census Bureau population demographic projections. Two scenarios were considered for T1DM and T2DM incidence: 1) constant incidence over time; 2) for T1DM yearly percentage increases of 3.5, 2.2, 1.8, and 2.1% by age-groups 0–4 years, 5–9 years, 10–14 years, and 15–19 years, respectively, and for T2DM a yearly 2.3% increase across all ages.
Under scenario 1, the projected number of youth with T1DM rises from 166,018 to 203,382 and with T2DM from 20,203 to 30,111, respectively, in 2010 and 2050. Under scenario 2, the number of youth with T1DM nearly triples from 179,388 in 2010 to 587,488 in 2050 (prevalence 2.13/1,000 and 5.20/1,000 [+144% increase]), with the greatest increase in youth of minority racial/ethnic groups. The number of youth with T2DM almost quadruples from 22,820 in 2010 to 84,131 in 2050; prevalence increases from 0.27/1,000 to 0.75/1,000 (+178% increase).
A linear increase in diabetes incidence could result in a substantial increase in the number of youth with T1DM and T2DM over the next 40 years, especially those of minority race/ethnicity.
PMCID: PMC3507562  PMID: 23173134
The Journal of pediatrics  2012;161(5):875-880.
To assess fat distribution, prevalence of obesity and the metabolic syndrome (MetS) among diverse 6–13 year old Colorado youth to better understand racial/ethnic influences on adiposity and metabolic syndrome.
Study design
We measured body mass index (BMI), subscapular-triceps skinfold ratio (STR), waist circumference (WC), dietary fat, and physical activity in 422 youth, 47% non-Hispanic White, 44% Hispanic, 9% African American. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and intramyocellular lipid (IMCL) were measured with magnetic resonance techniques. Multiple-linear regression was used to assess associations between race/ethnicity and adiposity patterns.
Hispanic and African American youth had a higher prevalence of obesity and metabolic syndrome compared with non-Hispanic White youth. Both groups displayed a more centralized fat distribution and larger volumes of SAT, compared with non-Hispanic White youth. After controlling for BMI, these differences were attenuated and for a given body size, African American youth showed significantly lower VAT than non-Hispanic White youth. However, both Hispanic and African American youth showed higher IMCL in skeletal muscle compared with non-Hispanic Whites, independent of body size.
Racial/ethnic minorities experience higher overall adiposity, and may also have an increased risk for early development of metabolic syndrome relative to non-Hispanic White youth, beyond their increased obesity risk.
PMCID: PMC3449014  PMID: 22703953
IMCL; race; ethnicity; Hispanic; African American; childhood obesity; subcutaneous fat; visceral fat; metabolic syndrome
Immunometabolism  2013;1:1-9.
Perturbations in early life environments, including intrauterine exposure to maternal gestational diabetes (GDM), are hypothesized to lead to metabolic imprinting resulting in increased risk of cardiometabolic outcomes later in life. We aimed to 1) identify candidate genes and biological pathways associated with differentially methylated regions (DMRs) in relation to exposure to GDM in utero and, 2) using mediation analysis, more definitively investigate the potential for mediation of the effect of exposure to maternal diabetes in utero on cardiometabolic traits in childhood risk through our identified DMRs. Genome-wide methylation analysis of peripheral blood mononuclear cell’s DNA was conducted in 21 healthy children, ages 8-12 years. P-values from multiple linear regression analyses for >27,000 CpG sites were ranked to identify DMRs between the exposure groups. Among the top 10 ranked DMRs, we identified several genes, including NPR1, PANK1, SCAND1, and GJA4, which are known to be associated with cardiometabolic traits. Gene enrichment analysis of the top 84 genes, each with p<=0.005, identified the ubiquitin proteasome system (UPS) as the most enriched biological pathway (p = 0.07). The UPS pathway reflects biological processes known to be associated with endothelial function, inflammation, lipid metabolism, insulin resistance and β-cell apoptosis, whose derangements are central to the pathogenesis of cardiometabolic diseases. Increased methylation of PYGO1 and CLN8 had the greatest relative mediation effect (RME = 87%, p=0.005 and RME=50%, p=0.01) on the impact of exposure to maternal diabetes in utero on VCAM-1 levels in the offspring. Multiple candidate genes and the UPS were identified for future study as possible links between exposure to maternal gestational diabetes in utero and adverse cardiometabolic traits in the offspring. In particular, increased methylation of PYGO1 and CLN8 may be biological links between intrauterine exposure to maternal diabetes and significantly increased VCAM-1 levels in the offspring.
PMCID: PMC3670583  PMID: 23741625
DNA methylation; Epigenetics; Gestational diabetes; Cardiometabolic; Intrauterine
Diabetes  2011;61(1):36-37.
PMCID: PMC3237660  PMID: 22187373
Objectives. To examine trends in the prevalence and disparities of traditional cardiovascular disease (CVD) risk factors among the major race/ethnic groups in the USA: non-Hispanic Whites (NHWs), non-Hispanic Blacks (NHBs), and Mexican Americans (MAs). Methods. We used cross-sectional trend analysis in women and men aged 25–84 years participating in the NHANES surveys, years 1988–1994 (n = 14,341) and 1999–2004 (n = 12,360). Results. The prevalence of obesity and hypertension increased significantly in NHW and NHB, both in men and women; NHB had the highest prevalence of obesity and hypertension in each time period. Diabetes prevalence showed a nonsignificant increasing trend in all groups and was higher in MA in both periods. Smoking significantly decreased in NHW men and NHB, the latter with the largest decline although the highest prevalence in each period; no changes were noted in MA, who had the lowest prevalence in both periods. Race/ethnic CVD risk factors disparities widened for obesity and hypercholesterolemia, remained unchanged for diabetes and hypertension, and narrowed for smoking. Conclusions. The increasing prevalence of obesity and hypertension underscores the need for better preventive measures, particularly in the NHB group that exhibits the worst trends. The decline in smoking rates may offset some of these unfavorable trends.
PMCID: PMC3518078  PMID: 23243516
Menopause (New York, N.Y.)  2011;18(8):857-868.
The study objective was to examine the association between menopause status and diabetes risk among women with glucose intolerance and to determine if menopausal status modifies response to diabetes prevention interventions.
The study population included women in premenopause (n=708), natural postmenopause (n=328), and bilateral oophorectomy (n=201) in the Diabetes Prevention Program (DPP), a randomized placebo-controlled trial of lifestyle intervention and metformin among glucose intolerant adults. Associations between menopause and diabetes risk were evaluated using Cox proportional hazard models that adjusted for demographic variables (age, race/ethnicity, family history of diabetes, history of gestational diabetes mellitus), waist circumference, insulin resistance and corrected insulin response. Similar models were constructed after stratification by menopause type and hormone therapy (HT) use.
After adjustment for age, there was no association between natural menopause or bilateral oophorectomy and diabetes risk. Differences by study arm were observed in women who reported bilateral oophorectomy. In the lifestyle arm, women with bilateral oophorectomy had a lower adjusted hazard for diabetes (HR 0.19, 95% CI 0.04, 0.94), although observations were too few to determine if this was independent of HT use. No significant differences were seen in the metformin (HR 1.29, 95% CI 0.63, 2.64) or placebo arms (HR 1.37, 95% CI 0.74, 2.55).
Among women at high-risk for diabetes, natural menopause was not associated with diabetes risk and did not affect response to diabetes prevention interventions. In the lifestyle intervention, bilateral oophorectomy was associated with decreased diabetes risk.
PMCID: PMC3500880  PMID: 21709591
diabetes; impaired glucose tolerance; menopause; oophorectomy; women
Diabetes Care  2011;34(11):2347-2352.
Young children have an unacceptably high prevalence of diabetic ketoacidosis (DKA) at the clinical diagnosis of type 1 diabetes. The aim of this study was to determine whether knowledge of genetic risk and close follow-up for development of islet autoantibodies through participation in The Environmental Determinants of Diabetes in the Young (TEDDY) study results in lower prevalence of DKA at diabetes onset in children aged <2 and <5 years compared with population-based incidence studies and registries.
Symptoms and laboratory data collected on TEDDY participants diagnosed with type 1 diabetes between 2004 and 2010 were compared with data collected during the similar periods from studies and registries in all TEDDY-participating countries (U.S., SEARCH for Diabetes in Youth Study; Sweden, Swediabkids; Finland, Finnish Pediatric Diabetes Register; and Germany, Diabetes Patienten Verlaufsdokumenation [DPV] Register).
A total of 40 children younger than age 2 years and 79 children younger than age 5 years were diagnosed with type 1 diabetes in TEDDY as of December 2010. In children <2 years of age at onset, DKA prevalence in TEDDY participants was significantly lower than in all comparative registries (German DPV Register, P < 0.0001; Swediabkids, P = 0.02; SEARCH, P < 0.0001; Finnish Register, P < 0.0001). The prevalence of DKA in TEDDY children diagnosed at <5 years of age (13.1%) was significantly lower compared with SEARCH (36.4%) (P < 0.0001) and the German DPV Register (32.2%) (P < 0.0001) but not compared with Swediabkids or the Finnish Register.
Participation in the TEDDY study is associated with reduced risk of DKA at diagnosis of type 1 diabetes in young children.
PMCID: PMC3198296  PMID: 21972409

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