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1.  The Presence of GAD and IA-2 Antibodies in Youth With a Type 2 Diabetes Phenotype 
Diabetes Care  2010;33(9):1970-1975.
To determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings.
Children (10–17 years) diagnosed with type 2 diabetes were screened for participation in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Measurements included GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, a physical examination, and fasting lipid, C-peptide, and A1C determinations.
Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive; of these, 71 (5.9%) were positive for a single antibody, and 47 were positive (3.9%) for both antibodies. Diabetes autoantibody (DAA) positivity was significantly associated with race (P < 0.0001), with positive subjects more likely to be white (40.7 vs. 19%) (P < 0.0001) and male (51.7 vs. 35.7%) (P = 0.0007). BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype, although the range for BMI z score, blood pressure, fasting C-peptide, and serum lipids overlapped between antibody-positive and antibody-negative subjects.
Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes.
PMCID: PMC2928346  PMID: 20519658
2.  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
3.  The effect of insurance status and parental education on glycemic control and cardiovascular disease risk profile in youth with Type 1 Diabetes 
Adult studies have shown a correlation between low socioeconomic status and Type 1 Diabetes complications, but studies have not been done in children to examine the effect of socioeconomic status on risk for future complications. This study investigates the relationship between insurance status and parental education and both glycemic control and cardiovascular disease (CVD) risk factors in youth with type 1 diabetes.
A cross-sectional study of 295 youth with established type 1 diabetes who underwent examination with fasting blood draw and reported insurance status and parental education.
Youth with type 1 diabetes and public insurance had higher hemoglobin A1c (HbA1c), body mass index, hs-CRP, and blood pressure (p < 0.05) than those with private insurance. Insulin regimen varied between insurance groups, and differences in HbA1c and CVD risk factors, except for diastolic blood pressure (DBP), were no longer evident after controlling for insulin regimen. Parental education was not associated with HbA1c or CVD risk factors.
Youth with type 1 diabetes and public insurance have worse glycemic control and elevated CVD risk factors compared to those with private insurance, but this was no longer seen when insulin regimen was controlled for. Further research is needed to look at differences between those with public insurance and private insurance that contribute to differences in type 1 diabetes outcomes, and to identify modifiable risk factors in pediatric patients in order to focus earlier interventions to decrease and prevent future diabetes complications.
PMCID: PMC4064822  PMID: 24955334
Type 1 diabetes; Socioeconomic status; Parental education; Hemoglobin A1c; Cardiovascular disease
4.  Insulin Regimens and Clinical Outcomes in a Type 1 Diabetes Cohort 
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
5.  Randomized Nutrition Education Intervention to Improve Carbohydrate Counting in Adolescents with Type 1 Diabetes Study: Is More Intensive Education Needed? 
Background and Objectives
Youth with type 1 diabetes do not count carbohydrates (CHOs) accurately, yet it is an important strategy in blood glucose control. The study objective was to determine whether a nutrition education intervention would improve CHO counting accuracy and glycemic control.
Randomized, controlled, nutrition intervention trial recruited February 2009 to February 2010.
Participants and Methods
Youth (12-18 years, n=101) with type 1 diabetes were screened to identify those with poor CHO counting accuracy, using a previously developed CHO counting accuracy test covering commonly consumed foods and beverage items presented in six mixed meals and two snacks. All participants (n=66, age=15 ± 3 yrs, 41 male, diabetes duration=6 ± 4 yrs, HbA1c=8.3 ± 1.1%) were randomized to the control or intervention group at the baseline visit. The intervention group attended a 90 minute class with a RD/CDE and twice kept three-day food records, which were used to review CHO counting progress.
Main Outcome Measures
CHO counting accuracy (measured as described above) and HbA1c were evaluated at baseline and three months to determine the effectiveness of the intervention.
Statistical Analyses
T-tests, Spearman correlations, and repeated measures models were used.
At baseline, CHO content was over and underestimated in 16 and five of 29 food items, respectively. When foods were presented as mixed meals, participants either significantly over or underestimated 10 of the nine meals and four snacks. After three months of follow-up, HbA1c decreased in both the intervention and control groups by −0.19 ± 0.12% (p=0.12) and −0.08 ± 0.11% (p=0.51) respectively; however, the overall intervention effect was not statistically significant for change in HbA1c or CHO counting accuracy.
More intensive intervention may be required to improve adolescents’ CHO counting accuracy and nutrition management of type 1 diabetes. Further research is needed to translate nutrition education into improved health outcomes.
PMCID: PMC3487717  PMID: 22975086
Type 1 Diabetes; Carbohydrate Counting; Nutrition Education; Randomized Clinical Trial
6.  Lower A1c among adolescents with lower perceived A1c goal: a cross-sectional survey 
The International Society for Pediatric and Adolescent Diabetes (ISPAD) and the American Diabetes Association (ADA) have established a hemoglobin A1c (A1c) target of less than 7.5% for adolescents with type 1 diabetes (T1D). However, many adolescents are unaware of their A1c target, and little data exist on how knowledge of this A1c target affects the actual A1c they achieve. We sought to evaluate the relationship between awareness of the A1c target and the actual A1c achieved in adolescents with T1D.
In a cohort of 240 adolescents with T1D age 13–19 years, we measured A1c and administered a questionnaire to assess their knowledge of the ISPAD guideline for A1c target.
Of the total cohort, 42 subjects (18%) had an A1c below target and 198 subjects (82%) had an A1c above target. Almost all subjects (98%) reported that they were told their A1c target by a healthcare provider, and most of those (88%) claimed to know their A1c target, but few (8%) were correct. More subjects with actual A1c below 7.5% thought their A1c goal was lower than the ISPAD target, compared to subjects with A1c above target (75% vs. 59%, p = 0.07), although this did not achieve statistical significance.
In this cohort of adolescents with T1D, there was a trend toward a lower achieved A1c in those with a lower perceived A1c goal. Further studies should focus on identification of factors influencing an adolescent’s ability to achieve a lower A1c.
PMCID: PMC4015741  PMID: 24156395
Type 1 diabetes; Hemoglobin A1c; Adolescents
7.  Accuracy and Precision of the Axis-Shield Afinion Hemoglobin A1c Measurement Device 
The Afinion HbA1c (Axis-Shield) is a newer point-of-care device for measurement of hemoglobin A1c (A1C) using a boronate affinity method unlike the more commonly used DCA immunoassay method (Siemens Medical Solutions Diagnostics). The Afinion’s accuracy and precision, when compared with high-performance liquid chromatography (HPLC) and DCA methods, have not been established in pediatric practice settings.
Capillary blood was collected from 700 subjects with diabetes mellitus at seven Pediatric Diabetes Consortium sites. Each subject’s A1C was measured locally using Afinion and DCA devices, and by a central laboratory (University of Minnesota) using a Tosoh HPLC method. In addition, repeated measurements on six whole blood samples provided by the National Glycohemoglobin Standardization Program (NGSP) were taken at three clinical centers using the Afinion and DCA methods and centrally using the Tosoh HPLC method to assess the precision of each device.
The coefficient of variation for measurements of whole blood samples for precision analysis was 2% for Afinion, 3% for DCA, and 1% for HPLC. In the patient samples measured at the seven clinic sites, the Afinion generated higher A1C results than the HPLC (mean difference = +0.15; p < 0.001), while the DCA produced lower values (mean difference = -0.19; p < 0.001). The absolute differences with HPLC were similar for the Afinion and DCA (median 0.2%) with a slight advantage for the Afinion when compared with DCA (p < 0.001 by rank test). The DCA tended to read lower than HPLC, particularly at high A1C levels (p < 0.001), while the Afinion’s accuracy did not vary by A1C.
When compared to the central laboratory HPLC method, the differences between the results of the Afinion and DCA devices are clinically insignificant, and the Afinion and DCA have similar accuracy and precision when used in pediatric practice settings.
PMCID: PMC3380782  PMID: 22538150
accuracy; diabetes mellitus; glycated hemoglobin; HbA1c; point-of-care testing; precision
8.  Etiological Approach to Characterization of Diabetes Type 
Diabetes Care  2011;34(7):1628-1633.
To describe an etiologic approach to classification of diabetes types in youth based on the 1997 American Diabetes Association (ADA) framework, using data from the SEARCH for Diabetes in Youth Study.
SEARCH conducted a comprehensive assessment of 2,291 subjects aged <20 years with recently diagnosed diabetes. Using autoimmunity (at least one of two diabetes autoantibodies) and insulin sensitivity (equation validated against hyperinsulinemic-euglycemic clamps) as the main etiologic markers, we described four categories along a bidimensional spectrum: autoimmune plus insulin-sensitive (IS), autoimmune plus insulin-resistant (IR), nonautoimmune plus IS, and nonautoimmune plus IR. We then explored how characteristics, including genetic susceptibility to autoimmunity (HLA genotypes), insulin deficiency, and clinical factors varied across these four categories.
Most subjects fell into either the autoimmune plus IS (54.5%) or nonautoimmune plus IR categories (15.9%) and had characteristics that align with traditional descriptions of type 1 or type 2 diabetes. The group classified as autoimmune plus IR (19.5%) had similar prevalence and titers of diabetes autoantibodies and similar distribution of HLA risk genotypes to those in the autoimmune plus IS group, suggesting that it includes individuals with type 1 diabetes who are obese. The group classified as nonautoimmune plus IS (10.1%) likely includes individuals with undetected autoimmunity but may also include those with monogenic diabetes and thus requires further testing.
The SEARCH study offers researchers and clinicians a practical application for the etiologic classification of diabetes type and at the same time identifies a group of youths who would benefit from further testing.
PMCID: PMC3120176  PMID: 21636800
9.  Additional Autoimmune Disease Found in 33% of Patients at Type 1 Diabetes Onset 
Diabetes Care  2011;34(5):1211-1213.
We sought to define the prevalence of nonislet, organ-specific autoantibodies at diagnosis of type 1 diabetes and to determine the prevalence of comorbid autoimmune diseases.
Children (n = 491) diagnosed with type 1 diabetes at the Barbara Davis Center for Childhood Diabetes were screened for autoimmune thyroid disease (thyroid peroxidase autoantibodies [TPOAb]), celiac disease (tissue transglutaminase autoantibodies [TTGAb]), and Addison disease (21-hydroxylase autoantibodies [21OHAb]).
Of the 491 children, 161 had at least one nonislet autoantibody, and of these, 122 (24.8%) were positive for TPOAb, and 15 of the 122 (12.3%) had autoimmune thyroid disease. There were 57 (11.6%) who were positive for TTGAb, of whom 14 (24.6%) had celiac disease. Five (1.0%) were positive for 21OHAb, of whom one had Addison disease.
Many autoantibody-positive subjects present with additional autoimmune disorders. Detection of these autoantibodies at type 1 diabetes onset may prevent complications associated with delayed diagnosis of these disorders.
PMCID: PMC3114477  PMID: 21430083
11.  Celiac Autoimmunity in Children with Type 1 Diabetes: A two-year follow-up 
The Journal of pediatrics  2011;158(2):276-281.e1.
To determine the benefits of screening for celiac autoimmunity via IgA transglutaminase autoantibodies (TG) in children with type 1 diabetes (T1D).
Study design
We followed 79 screening-identified TG+ and 56 matched TG− children with T1D for 2 years to evaluate growth, bone mineral density, nutritional status, and diabetes control. TG+ subjects self-selected to gluten-free or gluten-containing diet.
Of the initial cohort, 80% were available for re-examination after 2 years. TG+ subjects had consistently lower weight z-scores and higher urine N-telopeptides than TG− subjects, but similar measures of bone density and diabetes outcomes. TG+ children who remained on a gluten-containing diet had lower IGF-BP3 z-scores compared with TG+ subjects who reported following a gluten-free diet. Children who continued with high TG index throughout the study had lower bone mineral density z-scores, ferritin, and vitamin D 25OH levels, compared with the TG− group.
No significant adverse outcomes were identified in children with T1D with screening-identified TG+ who delay GFD therapy for 2 years. Children with persistently high levels of TG may be at greater risk. The optimal timing of screening and treatment for CD in children with T1D requires further investigation.
PMCID: PMC2999645  PMID: 20817171
type 1 diabetes; pediatric; celiac disease; tissue transglutaminase autoantibodies; screening; gluten; diet
12.  Menarchal Timing in Type 1 Diabetes Through the Last 4 Decades 
Diabetes Care  2010;33(12):2521-2523.
We sought to examine whether age at menarche has changed over the past 4 decades by comparing age at menarche by year of diagnosis with type 1 diabetes.
This work consisted of a cross-sectional study of age at menarche in two cohorts: adolescents (ages 11–24 years, n = 228) and adults (ages 19–55 years, n = 290, enrolled in the Coronary Artery Calcification in Type 1 Diabetes study).
The adolescent cohort reported a younger age of menarche than the adult women with type 1 diabetes (12.69 ± 0.08 vs. 13.22 ± 0.12 years, mean ± SE, P < 0.001). Age at menarche was later in both adolescent girls and adult women with type 1 diabetes diagnosed before menarche (12.82 ± 1.16 and 13.7 ± 2.23 years) than for individuals diagnosed after menarche (12.12 ± 1.25 and 12.65 ± 1.38 years, P < 0.001 for both). Age at menarche was then examined by decade of type 1 diabetes diagnosis (1970–1979, 1980–1989, 1990–1999, and 2000–2009). Age at menarche significantly declined over the 4 decades (P = 0.0002). However, the delay in menarche among girls diagnosed with type 1 diabetes before menarche compared with those diagnosed after menarche was also significant across all decades (P < 0.0001) and did not change significantly over time (P = 0.41 for interaction of cohort and diagnosis premenarche).
Age at menarche has declined over the past 4 decades among girls with type 1 diabetes, but a delay in age at menarche remains among individuals diagnosed before menarche compared with individuals diagnosed after menarche.
PMCID: PMC2992181  PMID: 20843975
13.  Menarche delay and menstrual irregularities persist in adolescents with type 1 diabetes 
Menarche delay has been reported in adolescent females with type 1 diabetes (T1DM), perhaps due to poor glycemic control. We sought to compare age at menarche between adolescent females with T1DM and national data, and to identify factors associated with delayed menarche and menstrual irregularity in T1DM.
This was a cross-sectional study and females ages 12- 24 years (n = 228) with at least one menstrual period were recruited during their outpatient diabetes clinic appointment. The National Health and Nutrition Examination Survey (NHANES) 2001-2006 data (n = 3690) for females 12-24 years were used as a control group.
Age at menarche was later in adolescent females with T1DM diagnosed prior to menarche (12.81 +/- 0.09 years) (mean+/- SE) (n = 185) than for adolescent females diagnosed after menarche (12.17 0.19 years, p = 0.0015) (n = 43). Average age of menarche in NHANES was 12.27 +/- 0.038 years, which was significantly earlier than adolescent females with T1DM prior to menarche (p < 0.0001) and similar to adolescent females diagnosed after menarche (p = 0.77). Older age at menarche was negatively correlated with BMI z-score (r = -0.23 p = 0.0029) but not hemoglobin A1c (A1c) at menarche (r = 0.01, p = 0.91). Among 181 adolescent females who were at least 2 years post menarche, 63 (35%) reported usually or always irregular cycles.
Adolescent females with T1DM had a later onset of menarche than both adolescent females who developed T1DM after menarche and NHANES data. Menarche age was negatively associated with BMI z-score, but not A1c. Despite improved treatment in recent decades, menarche delay and high prevalence of menstrual irregularity is still observed among adolescent females with T1DM.
PMCID: PMC3100251  PMID: 21548955
14.  Early-Life Predictors of Higher Body Mass Index in Healthy Children 
Childhood obesity tracks into adulthood, and may increase diabetes and cardiovascular disease risk in adulthood. Prospective analyses may better define the pathways between early life factors and greater childhood body mass index (BMI), a measure of obesity.
The Diabetes Autoimmunity Study in the Young (DAISY) prospectively follows children from birth that are at increased genetic risk for type 1 diabetes. We examined longitudinal data for 1,178 DAISY subjects (mean age at last follow-up: 6.59 years (range: 2.0–11.5 years). Birth size and diabetes exposure in utero were collected in the enrollment interview. Infant diet information was collected via interviews throughout infancy. Infant weight gain and childhood BMI were measured at clinic visits.
Female gender, diabetes exposure in utero, larger size for gestational age, shorter breastfeeding duration, and more rapid infant weight gain predicted higher childhood BMI. Formal mediation analysis suggests the effect of shorter breastfeeding duration on childhood BMI may be mediated by more rapid infant weight gain. Also, the effect of diabetes exposure in utero on childhood BMI may be mediated by larger size for gestational age.
We identified strong interrelationships between early life factors and childhood BMI. Understanding these pathways may aid childhood obesity prevention efforts.
PMCID: PMC2855270  PMID: 19940472
Breastfeeding duration; Infant weight gain; Diabetes exposure in utero; Birth size; Mediator
16.  Trends in High-Risk HLA Susceptibility Genes Among Colorado Youth With Type 1 Diabetes  
Diabetes Care  2008;31(7):1392-1396.
OBJECTIVE—Type 1 diabetes is associated with a wide spectrum of susceptibility and protective genotypes within the HLA class II system. It has been reported that adults diagnosed with youth-onset type 1 diabetes more recently have been found to have fewer classical high-risk HLA class II genotypes than those diagnosed several decades ago. We hypothesized that such temporal trends in the distribution of HLA-DR, DQ genotypes would be evident, and perhaps even stronger, among 5- to 17-year-old Hispanic and non-Hispanic white (NHW) youth diagnosed with type 1 diabetes in Colorado between 1978 and 2004.
RESEARCH DESIGN AND METHODS—HLA-DR, DQ was typed using PCR and sequence-specific oligonucleotide hybridization in 100 youth diagnosed during the period of 1978–1988 and 264 diagnosed during 2002–2004. Logistic regression was used to adjust for confounders and assess temporal trends.
RESULTS—The frequency of the highest-risk genotype (DRB1*03-DQB1*02/DRB1*04-DQB1*03) was higher (39%) in children diagnosed during the period 1978–1988 than in those diagnosed during 2002–2004 (28%). A similar pattern was observed in NHWs and Hispanics.
CONCLUSIONS—We found that high-risk HLA genotypes are becoming less frequent over time in youth with type 1 diabetes of NHW and Hispanic origin. This temporal trend may suggest that increasing environmental exposure is now able to trigger type 1 diabetes in subjects who are less genetically susceptible.
PMCID: PMC2453682  PMID: 18356404

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