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1.  Improving Prediction of Type 1 Diabetes by testing Non-HLA Genetic Variants in addition to HLA Markers 
Pediatric diabetes  2013;15(5):355-362.
Objective
The purpose of this study was to explore whether non-HLA genetic markers can improve type 1 diabetes (T1D) prediction in a prospective cohort with high-risk HLA-DR,DQ genotypes.
Methods
The Diabetes Autoimmunity Study in the Young (DAISY) follows prospectively for development of T1D and islet autoimmunity (IA) children at increased genetic risk. A total of 1709 non-Hispanic White DAISY participants have been genotyped for 27 non-HLA single nucleotide polymorphisms and one microsatellite.
Results
In multivariate analyses adjusting for family history and HLA-DR3/4 genotype, PTPN22 (rs2476601) and two UBASH3A (rs11203203 and rs9976767) SNPs were associated with development of IA (HR=1.87, 1.55 and 1.54 respectively, all p≤0.003), while GLIS3 and IL2RA showed borderline association with development of IA. INS, UBASH3A and IFIH1 were significantly associated with progression from IA to diabetes (HR=1.65, 1.44 and 1.47 respectively, all p≤0.04), while PTPN22 and IL27 showed borderline association with progression from IA to diabetes. In survival analysis, 45% of general population DAISY children with PTPN22 rs2476601 TT or HLA-DR3/4 and UBASH3A rs11203203 AA developed diabetes by age 15, compared to 3% of children with all other genotypes (p<0.0001). Addition of non-HLA markers to HLA-DR3/4,DQ8 did not improve diabetes prediction in first-degree relatives.
Conclusion
Addition of PTPN22 and UBASH3A SNPs to HLA-DR,DQ genotyping can improve T1D risk prediction.
PMCID: PMC4116638  PMID: 25075402
Type 1 diabetes; islet autoimmunity; non-HLA genetic markers; prediction
2.  Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study 
Aims:
The Environmental Determinants of Diabetes in the Young (TEDDY) planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes (T1D) using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression.
Methods:
This paper describes the details of planning the TEDDY biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples, and reduction of batch effects along with proper sample allocation.
Results and Conclusion:
Our design is to reduce potential bias and retain study power while reduce the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of T1D). The resulting list of case-control matched samples for each laboratory was augmented with external quality control (QC) samples.
doi:10.1002/dmrr.2510
PMCID: PMC4058423  PMID: 24339168
batch effects; biomarker discovery; nested case-control design; TEDDY; type 1 diabetes
3.  Early Hyperglycemia Detected by Continuous Glucose Monitoring in Children at Risk for Type 1 Diabetes 
Diabetes Care  2014;37(7):2031-2033.
OBJECTIVE
We explore continuous glucose monitoring (CGM) as a new approach to defining early hyperglycemia and diagnosing type 1 diabetes in children with positive islet autoantibodies (Ab+).
RESEARCH DESIGN AND METHODS
Fourteen Ab+ children, free of signs or symptoms of diabetes, and nine antibody-negative (Ab−) subjects, followed by the Diabetes Autoimmunity Study in the Young, were asked to wear a Dexcom SEVEN CGM.
RESULTS
The Ab+ subjects showed more hyperglycemia, with 18% time spent above 140 mg/dL, compared with 9% in Ab− subjects (P = 0.04). Their average maximum daytime glucose value was higher, and they had increased glycemic variability. The mean HbA1c in the Ab+ subjects was 5.5% (37 mmol/mol). Among Ab+ subjects, ≥18–20% CGM time spent above 140 mg/dL seems to predict progression to diabetes.
CONCLUSIONS
CGM can detect early hyperglycemia in Ab+ children who are at high risk for progression to diabetes. Proposed CGM predictors of progression to diabetes require further validation.
doi:10.2337/dc13-2965
PMCID: PMC4067399  PMID: 24784826
4.  Risk of Type 1 Diabetes Progression in Islet Autoantibody-Positive Children Can Be Further Stratified Using Expression Patterns of Multiple Genes Implicated in Peripheral Blood Lymphocyte Activation and Function 
Diabetes  2014;63(7):2506-2515.
There is tremendous scientific and clinical value to further improving the predictive power of autoantibodies because autoantibody-positive (AbP) children have heterogeneous rates of progression to clinical diabetes. This study explored the potential of gene expression profiles as biomarkers for risk stratification among 104 AbP subjects from the Diabetes Autoimmunity Study in the Young (DAISY) using a discovery data set based on microarray and a validation data set based on real-time RT-PCR. The microarray data identified 454 candidate genes with expression levels associated with various type 1 diabetes (T1D) progression rates. RT-PCR analyses of the top-27 candidate genes confirmed 5 genes (BACH2, IGLL3, EIF3A, CDC20, and TXNDC5) associated with differential progression and implicated in lymphocyte activation and function. Multivariate analyses of these five genes in the discovery and validation data sets identified and confirmed four multigene models (BI, ICE, BICE, and BITE, with each letter representing a gene) that consistently stratify high- and low-risk subsets of AbP subjects with hazard ratios >6 (P < 0.01). The results suggest that these genes may be involved in T1D pathogenesis and potentially serve as excellent gene expression biomarkers to predict the risk of progression to clinical diabetes for AbP subjects.
doi:10.2337/db13-1716
PMCID: PMC4066338  PMID: 24595351
5.  Calcium and phosphate concentrations and future development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study 
Diabetologia  2014;57(7):1366-1374.
Aims/hypothesis
Low phosphate and high calcium concentrations have been linked to altered glucose tolerance and reduced insulin sensitivity in non-diabetic individuals. The aim of this study was to examine the relationships of calcium and phosphate levels and the calcium–phosphate product with the development of type 2 diabetes.
Methods
Participants were 863 African-Americans, Hispanics and non-Hispanic whites in the Insulin Resistance Atherosclerosis Study who were free of diabetes at baseline. The mean follow-up period was 5.2 years. The insulin sensitivity index (SI) and acute insulin response (AIR) were directly measured using the frequently sampled IVGTT.
Results
Calcium concentration (OR per 1 SD unit increase, 1.26 [95% CI 1.04, 1.53]) and calcium–phosphate product (OR 1.29 [95% CI 1.04, 1.59]) were associated with incident diabetes after adjustment for demographic variables, family history of diabetes, and 2 h glucose. The relationship between phosphate concentration and progression to diabetes was close to statistical significance (OR 1.21 [95% CI 0.98, 1.49]). Calcium concentration (OR 1.37 [95% CI 1.09, 1.72]) and calcium–phosphate product (OR 1.39 [95% CI 1.09, 1.77]) remained associated with incident diabetes after additional adjustment for BMI, plasma glucose, SI, AIR, C-reactive protein, estimated GFR, diuretic drugs and total calcium intake.
Conclusions/interpretation
Elevated serum calcium and calcium–phosphate product are associated with increased risk of developing type 2 diabetes independently of measured glucose, insulin secretion and insulin resistance. Future studies need to analyse the role of calcium–phosphate homeostasis in the pathophysiology of diabetes.
doi:10.1007/s00125-014-3241-9
PMCID: PMC4119943  PMID: 24763850
Keywords Clinical science; Epidemiology; Human; Insulin sensitivity and resistance; Pathogenic mechanisms; Prediction and prevention of type 2 diabetes
7.  Prevalence of Obesity was Related to HLA-DQ in 2–4 Year Old Children at Genetic Risk for Type 1 Diabetes 
OBJECTIVES
Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes.
METHODS
Repeated measures of weight and height were collected from 5 969 children 2–4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index of 25 and 30 kg/m2 at age 18.
RESULTS
The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HLA, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (p for trend = 0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age four (OR, 2.41; 95% CI, 1.21–4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes.
CONCLUSIONS
The HLA-DQ2/2 genotype may predispose to obesity among 2–4 year old children with genetic risk for type 1 diabetes.
doi:10.1038/ijo.2014.55
PMCID: PMC4185013  PMID: 24694666
Body Mass Index; HLA Genotype; Type 1 Diabetes; Pediatric; Autoantibodies
8.  Chromogranin A is a T Cell Antigen in Human Type 1 Diabetes 
Journal of autoimmunity  2013;50:38-41.
Chromogranin A (ChgA) is a beta cell secretory granule protein and a peptide of ChgA, WE14, was recently identified as a ligand for diabetogenic CD4 T cell clones derived from the NOD mouse. In this study we compared responses of human CD4 T cells from recent onset type 1 diabetic (T1D) and control subjects to WE14 and to an enzymatically modified version of this peptide. T cell responders to antigens were detected in PBMCs from study subjects by an indirect CD4 ELISPOT assay for IFN-γ. T1D patients (n=27) were recent onset patients within one year of diagnosis, typed for HLA-DQ8. Controls (n=31) were either 1st degree relatives with no antibodies or from the HLA-matched general population cohort of DAISY/TEDDY. A second cohort of patients (n=11) and control subjects (n=11) was tested at lower peptide concentrations. We found that WE14 is recognized by T cells from diabetic subjects vs. controls in a dose dependent manner. Treatment of WE14 with transglutaminase increased reactivity to the peptide in some patients. This work suggests that ChgA is an important target antigen in human T1D subjects and that post-translational modification may play a role in its reactivity and relationship to disease.
doi:10.1016/j.jaut.2013.10.003
PMCID: PMC3995825  PMID: 24239002
Type 1 Diabetes; Chromogranin A; WE14; Autoreactive CD4 T cells; Human; Transglutaminase; Post-translational Modification; Autoantigen
9.  Serum uric acid and insulin sensitivity in adolescents and adults with and without type 1 diabetes 
Hypothesis
Decreased insulin sensitivity (IS) exists in type 1 diabetes. Serum uric acid (SUA), whose concentration is related to renal clearance, predicts vascular complications in type 1 diabetes. SUA is also inversely associated with IS in non-diabetics, but has not been examined in type 1 diabetes. We hypothesized SUA would be associated with reduced IS in adolescents and adults with type 1 diabetes.
Methods
The cross-sectional and longitudinal associations of SUA with IS was investigated in 254 adolescents with type 1 diabetes and 70 without in the Determinants of Macrovascular Disease in Adolescents with Type 1 Diabetes Study, and in 471 adults with type 1 diabetes and 571 without in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study.
Results
SUA was lower in subjects with type 1 diabetes (p<0.0001), but still remained inversely associated with IS after multivariable adjustments- in adolescents (β±SE: −1.99±0.62, p=0.001, R2=2%) and adults (β±SE:−0.91±0.33, p=0.006, R2=6%) with type 1 diabetes, though less strongly than in non-diabetic controls (adolescents: β±SE: −2.70±1.19, p=0.03, R2=15%, adults: β±SE:−5.99±0.75, p<0.0001, R2=39%).
Conclusion
We demonstrated a significantly weaker relationship between SUA and reduced IS in subjects with type 1 diabetes than non-diabetic controls.
doi:10.1016/j.jdiacomp.2013.12.007
PMCID: PMC4004676  PMID: 24461546
insulin sensitivity; type 1 diabetes; serum uric acid; adolescents and adults
10.  Serum Uric Acid and Hypertension in Adults: a Paradoxical Relationship in Type 1 Diabetes 
Adults with type 1 diabetes have lower serum uric acid levels compared to non-diabetic adults. Little is known about the relationship between serum uric acid and blood pressure in type 1 diabetes and whether it differs from the positive relationship found in non-diabetic adults.
We assessed the cross-sectional and longitudinal relationships over 6-years between serum uric acid and blood pressure in adults with (35±9 years, n=393) and without (38±9 years n=685) T1D in the Coronary Artery Calcification in Type 1 Diabetes study.
In non-diabetic adults, serum uric acid was associated with systolic blood pressure in multivariable-models adjusted for cardiovascular risk-factors. In adults with type 1 diabetes, a negative association was observed between serum uric acid and systolic blood pressure after multivariable-adjustments.
A positive association was observed between serum uric acid and systolic blood pressure in non-diabetic adults. In contrast, an inverse relationship was demonstrated after multivariable-adjustments in type 1 diabetes.
doi:10.1111/jch.12305
PMCID: PMC3989383  PMID: 24667019
Uric acid; hypertension; type 1 diabetes
11.  Assessing Age-Related Etiologic Heterogeneity in the Onset of Islet Autoimmunity 
BioMed Research International  2015;2015:708289.
Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW) ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA) levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.
doi:10.1155/2015/708289
PMCID: PMC4389824  PMID: 25883970
12.  Daycare Attendance, Breastfeeding, and the Development of Type 1 Diabetes: The Diabetes Autoimmunity Study in the Young 
BioMed Research International  2015;2015:203947.
Background. The hygiene hypothesis attributes the increased incidence of type 1 diabetes (T1D) to a decrease of immune system stimuli from infections. We evaluated this prospectively in the Diabetes Autoimmunity Study in the Young (DAISY) by examining daycare attendance during the first two years of life (as a proxy for infections) and the risk of T1D. Methods. DAISY is a prospective cohort of children at increased T1D risk. Analyses were limited to 1783 children with complete daycare and breastfeeding data from birth to 2 years of age; 58 children developed T1D. Daycare was defined as supervised time with at least one other child at least 3 times a week. Breastfeeding duration was evaluated as a modifier of the effect of daycare. Cox proportional hazards regression was used for analyses. Results. Attending daycare before the age of 2 years was not associated with T1D risk (HR: 0.89; CI: 0.54–1.47) after adjusting for HLA, first degree relative with T1D, ethnicity, and breastfeeding duration. Breastfeeding duration modified this association, where daycare attendance was associated with increased T1D risk in nonbreastfed children and a decreasing T1D risk with increasing breastfeeding duration (interaction P value = 0.02). Conclusions. These preliminary data suggest breastfeeding may modify the effect of daycare on T1D risk.
doi:10.1155/2015/203947
PMCID: PMC4389988  PMID: 25883944
13.  A method for reporting and classifying acute infectious diseases in a prospective study of young children: TEDDY 
BMC Pediatrics  2015;15:24.
Background
Early childhood environmental exposures, possibly infections, may be responsible for triggering islet autoimmunity and progression to type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) follows children with increased HLA-related genetic risk for future T1D. TEDDY asks parents to prospectively record the child’s infections using a diary book. The present paper shows how these large amounts of partially structured data were reduced into quantitative data-sets and further categorized into system-specific infectious disease episodes. The numbers and frequencies of acute infections and infectious episodes are shown.
Methods
Study subjects (n = 3463) included children who had attended study visits every three months from age 3 months to 4 years, without missing two or more consecutive visits during the follow-up. Parents recorded illnesses prospectively in a TEDDY Book at home. The data were entered into the study database during study visits using ICD-10 codes by a research nurse. TEDDY investigators grouped ICD-10 codes and fever reports into infectious disease entities and further arranged them into four main categories of infectious episodes: respiratory, gastrointestinal, other, and unknown febrile episodes. Incidence rate of infections was modeled as function of gender, HLA-DQ genetic risk group and study center using the Poisson regression.
Results
A total of 113,884 ICD-10 code reports for infectious diseases recorded in the database were reduced to 71,578 infectious episodes, including 74.0% respiratory, 13.1% gastrointestinal, 5.7% other infectious episodes and 7.2% febrile episodes. Respiratory and gastrointestinal infectious episodes were more frequent during winter. Infectious episode rates peaked at 6 months and began declining after 18 months of age. The overall infectious episode rate was 5.2 episodes per person-year and varied significantly by country of residence, sex and HLA genotype.
Conclusions
The data reduction and categorization process developed by TEDDY enables analysis of single infectious agents as well as larger arrays of infectious agents or clinical disease entities. The preliminary descriptive analyses of the incidence of infections among TEDDY participants younger than 4 years fits well with general knowledge of infectious disease epidemiology. This protocol can be used as a template in forthcoming time-dependent TEDDY analyses and in other epidemiological studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-015-0333-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12887-015-0333-8
PMCID: PMC4377063  PMID: 25884839
Childhood infections; Prospective study; Type 1 diabetes
14.  Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease 
Pediatric diabetes  2013;15(2):118-126.
Objective
The Environmental Determinants of Diabetes in the Young (TEDDY) study is designed to identify environmental exposures triggering islet autoimmunity and type 1 diabetes (T1D) in genetically high-risk children. We describe the first 100 participants diagnosed with T1D, hypothesizing that 1) they are diagnosed at an early stage of disease, 2) a high proportion are diagnosed by an oral glucose tolerance test (OGTT) and 3) risk for early T1D is related to country, population, HLA-genotypes and immunological markers.
Methods
Autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2) and insulin (IAA) were analysed from 3 months of age in children with genetic risk. Symptoms and laboratory values at diagnosis were obtained and reviewed for ADA criteria.
Results
The first 100 children to develop T1D, 33 first-degree relatives (FDRs), with a median age 2.3 years (0.69–6.27), were diagnosed between 9/2005 and 11/2011. Although young, 36% had no symptoms and ketoacidosis was rare (8%). An OGTT diagnosed 9/30 (30%) children above 3 years of age but only 4/70 (5.7%) below the age of 3 years. FDRs had higher cumulative incidence than children from the general population (p<0.0001). Appearance of all three autoantibodies at seroconversion was associated with the most rapid development of T1D (HR=4.52, p<0.014), followed by the combination of GADA and IAA (HR=2.82, p=0.0001).
Conclusions
Close follow-up of children with genetic risk enables early detection of T1D. Risk factors for rapid development of diabetes in this young population were FDR status and initial positivity for GADA, IA-2, and IAA or a combination of GADA and IAA.
doi:10.1111/pedi.12066
PMCID: PMC3866211  PMID: 24034790
Type 1 diabetes; diagnosis; follow-up studies; autoantibodies; TEDDY study
15.  Risk of Pediatric Celiac Disease According to HLA Haplotype and Country 
BACKGROUND
The presence of HLA haplotype DR3–DQ2 or DR4–DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG).
METHODS
We studied 6403 children with HLA haplotype DR3–DQ2 or DR4–DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies.
RESULTS
The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3–DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3–DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4–DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25).
CONCLUSIONS
Children with the HLA haplotype DR3–DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)
doi:10.1056/NEJMoa1313977
PMCID: PMC4163840  PMID: 24988556
16.  GAD65 Autoantibodies Detected by Electrochemiluminescence Assay Identify High Risk for Type 1 Diabetes 
Diabetes  2013;62(12):4174-4178.
The identification of diabetes-relevant islet autoantibodies is essential for predicting and preventing type 1 diabetes (T1D). The aim of the current study was to evaluate a newly developed electrochemiluminescence (ECL)-GAD antibody (GADA) assay and compare its sensitivity and disease relevance with standard radioassay. The assay was validated with serum samples from 227 newly diagnosed diabetic children; 68 prediabetic children who were prospectively followed to T1D; 130 nondiabetic children with confirmed islet autoantibodies to insulin, GAD65, IA-2, and/or ZnT8 longitudinally followed for 12 ± 3.7 years; and 181 age-matched, healthy, antibody-negative children. The ECL-GADA assay had a sensitivity similar to that of the standard GADA radioassay in children newly diagnosed with T1D, prediabetic children, and high-risk children with multiple positive islet autoantibodies. On the other hand, only 9 of 39 nondiabetic children with only a single islet autoantibody (GADA only) by radioassay were positive for ECL-GADA. GADA not detectable by ECL assay is shown to be of low affinity and likely not predictive of future diabetes. In conclusion, the new ECL assay identifies disease-relevant GADA by radioassay. It may help to improve the prediction and correct diagnosis of T1D among subjects positive only for GADA and no other islet autoantibodies.
doi:10.2337/db13-0534
PMCID: PMC3837058  PMID: 23974918
17.  Early Diabetic Nephropathy 
Diabetes Care  2013;36(11):3678-3683.
OBJECTIVE
Diabetic nephropathy (DN) is a major cause of mortality in type 1 diabetes. Reduced insulin sensitivity is a well-documented component of type 1 diabetes. We hypothesized that baseline insulin sensitivity would predict development of DN over 6 years.
RESEARCH DESIGN AND METHODS
We assessed the relationship between insulin sensitivity at baseline and development of early phenotypes of DN—microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (glomerular filtration rate [GFR] loss >3 mL/min/1.73 m2 per year)—with three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations over 6 years. Subjects with diabetes (n = 449) and without diabetes (n = 565) in the Coronary Artery Calcification in Type 1 Diabetes study had an estimated insulin sensitivity index (ISI) at baseline and 6-year follow-up.
RESULTS
The ISI was lower in subjects with diabetes than in those without diabetes (P < 0.0001). A higher ISI at baseline predicted a lower odds of developing an ACR ≥30 mg/g (odds ratio 0.65 [95% CI 0.49–0.85], P = 0.003) univariately and after adjusting for HbA1c (0.69 [0.51–0.93], P = 0.01). A higher ISI at baseline conferred protection from a rapid decline of GFR as assessed by CKD-EPI cystatin C (0.77 [0.64–0.92], P = 0.004) and remained significant after adjusting for HbA1c and age (0.80 [0.67–0.97], P = 0.02). We found no relation between ISI and rapid GFR decline estimated by CKD-EPI creatinine (P = 0.38) or CKD-EPI combined cystatin C and creatinine (P = 0.50).
CONCLUSIONS
Over 6 years, a higher ISI independently predicts a lower odds of developing microalbuminuria and rapid GFR decline as estimated with cystatin C, suggesting a relationship between insulin sensitivity and early phenotypes of DN.
doi:10.2337/dc13-0631
PMCID: PMC3816872  PMID: 24026551
18.  Insulin Sensitivity and Insulin Clearance are Heritable and Have Strong Genetic Correlation in Mexican Americans 
Obesity (Silver Spring, Md.)  2014;22(4):1157-1164.
Objective
We describe the GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI).
Design and Methods
GUARDIAN is comprised of seven cohorts, consisting of 4336 Mexican-American individuals in 1346 pedigrees. Insulin sensitivity (SI), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3925 individuals) using variance components.
Results
Across studies, age and gender-adjusted heritability of insulin sensitivity (SI, M, M/I) ranged from 0.23–0.48 and of MCRI from 0.35–0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and −0.57 to −0.59 for AIRg and MCRI (all P<0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P<0.0001); and −0.16 to −0.36 for AIRg and MCRI (P <0.0001−0.06).
Conclusions
These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.
doi:10.1002/oby.20639
PMCID: PMC3968231  PMID: 24124113
insulin sensitivity; insulin clearance; heritability; genetic correlation; environmental correlation
19.  Methods, Quality Control and Specimen Management in an International Multi-Center Investigation of Type 1 Diabetes: TEDDY 
The Environmental Determinants of Diabetes in the Young (TEDDY) is a multi-center, international prospective study (n = 8,677) designed to identify environmental triggers of type 1 diabetes (T1D) in genetically at-risk children from age 3 months until 15 years. The study is conducted through six primary clinical centers located in four countries. As of May 2012, over three million biological samples and 250 million total data points have been collected which will be analyzed to assess autoimmunity status, presence of inflammatory biomarkers, genetic factors, exposure to infectious agents, dietary biomarkers, and other potentially important environmental exposures in relation to autoimmunity and progression to T1D. The vast array and quantity of longitudinal samples collected in the TEDDY study present a series of challenges in terms of quality control procedures and data validity. To address this, pilot studies have been conducted to standardize and enhance both biospecimen collection and sample obtainment in terms of autoantibody collection, stool sample preservation, RNA, biomarker stability, metabolic biomarkers, and T-cell viability. This paper details the procedures utilized to standardize both data harmonization and management when handling a large quantity of longitudinal samples obtained from multiple locations. In addition, we provide a description of the available specimens that serve as an invaluable repository for the elucidation of determinants in T1D focusing on autoantibody concordance and harmonization, transglutaminase autoantibody (tGA), inflammatory biomarkers (T-cells), genetic proficiency testing, RNA lab internal quality control testing, infectious agents (monitoring cross contamination, virus preservation, and nasal swab collection validity), and HbA1c testing.
doi:10.1002/dmrr.2427
PMCID: PMC3992860  PMID: 23674484
quality control; data integrity; stool sample preservation; RNA; biomarker stability; metabolic biomarkers; T-cell viability
20.  Impaired Renal Function Further Increases Odds of 6-Year Coronary Artery Calcification Progression in Adults With Type 1 Diabetes 
Diabetes Care  2013;36(9):2607-2614.
OBJECTIVE
To determine whether baseline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) independently predict coronary artery calcification (CAC) progression, and to determine how eGFR changes over 6 years in adults with type 1 diabetes compared with nondiabetic adults.
RESEARCH DESIGN AND METHODS
The Coronary Artery Calcification in Type 1 Diabetes study participants (n = 1,066) with complete data for eGFR assessment at baseline and 6 years were included. Three Chronic Kidney Disease Epidemiology Collaboration equations (serum creatinine, cystatin C, and both) were used to estimate eGFR. The association of baseline ACR and eGFR with CAC progression was analyzed using multiple logistic regression.
RESULTS
Increasing categorical baseline ACR (<10, 10–30, and >30 µg/mg) predicted CAC progression in participants with type 1 diabetes (odds ratio [OR], 2.15; 95% CI, 1.50–3.09; 7.19 [3.90–13.26]; and 18.09 [8.48–38.62]), respectively, compared with nondiabetic subjects. Baseline eGFR <60 mL/min/1.73 m2 also predicted CAC progression (OR, 5–7, compared with nondiabetic participants). ORs for CAC progression were higher in women than in men when using the cystatin C–based Chronic Kidney Disease Epidemiology Collaboration equations. Participants with type 1 diabetes had greater eGFR decreases over 6 years than nondiabetic participants using cystatin C–based equations.
CONCLUSIONS
Although increasing ACR or decreasing eGFR predicts CAC progression, coronary atherosclerosis progresses faster in people with type 1 diabetes even in the absence of diabetic kidney disease. These findings emphasize the interaction between kidney disease and cardiovascular disease in type 1 diabetes and highlight the public health importance of lowering cardiorenal risk in people with type 1 diabetes.
doi:10.2337/dc12-2538
PMCID: PMC3747879  PMID: 23835686
21.  Prospective Association Between Inflammatory Markers and Progression of Coronary Artery Calcification in Adults With and Without Type 1 Diabetes 
Diabetes Care  2013;36(7):1967-1973.
OBJECTIVE
The role of inflammation in the increased risk of cardiovascular disease in type 1 diabetes is unclear. We examined the association of inflammation and progression of coronary artery calcification (CAC)—a marker of subclinical atherosclerosis—in adults with and without type 1 diabetes.
RESEARCH DESIGN AND METHODS
A nested case-control study was performed within the prospective cohort of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. Participants underwent two CAC measurements ∼2.5 years apart. Case subjects (n = 204) were those with significant progression of CAC. Control subjects (n = 258) were frequency-matched to case subjects on diabetes status, sex, age, and baseline CAC status. Inflammatory marker assessments were performed on stored blood samples from baseline. A principal components analysis (PCA) was performed and a composite score derived from that analysis. The composite score was constructed by assigning a value of 1 for each PCA component where at least one of the markers exceeded the 75th percentile (range 0–4). Conditional logistic regression was used for the matching strategy.
RESULTS
The first two components of the PCA were modestly (odds ratio 1.38 [95% CI 1.08–1.77] and 1.27 [1.02–1.59], respectively) associated with CAC progression after adjustment for other risk factors. The composite score was more strongly associated with CAC progression for those with elevated markers in three or four of the principal components compared with those with none.
CONCLUSIONS
Measures of inflammation were associated with progression of CAC in a population of adults with and without type 1 diabetes.
doi:10.2337/dc12-1874
PMCID: PMC3687315  PMID: 23340891
22.  The Next Big Idea 
Diabetes Technology & Therapeutics  2013;15(Suppl 2):S2-29-S2-36.
Abstract
George S. Eisenbarth will remain in our memories as a brilliant scientist and great collaborator. His quest to discover the cause and prevention of type 1 (autoimmune) diabetes started from building predictive models based on immunogenetic markers. Despite his tremendous contributions to our understanding of the natural history of pre-type 1 diabetes and potential mechanisms, George left us with several big questions to answer before his quest is completed.
doi:10.1089/dia.2013.0141
PMCID: PMC3676661  PMID: 23786296
23.  Infant Exposures and Development of Type 1 Diabetes Mellitus 
JAMA pediatrics  2013;167(9):808-815.
IMPORTANCE
The incidence of type 1 diabetes mellitus (T1DM) is increasing worldwide, with the most rapid increase among children younger than 5 years of age.
OBJECTIVE
To examine the associations between perinatal and infant exposures, especially early infant diet, and the development of T1DM.
DESIGN
The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal, observational study.
SETTING
Newborn screening for human leukocyte antigen (HLA) was done at St. Joseph’s Hospital in Denver, Colorado. First-degree relatives of individuals with T1DM were recruited from the Denver metropolitan area.
PARTICIPANTS
A total of 1835 children at increased genetic risk for T1DM followed up from birth with complete prospective assessment of infant diet. Fifty-three children developed T1DM.
EXPOSURES
Early (<4 months of age) and late (≥6 months of age) first exposure to solid foods compared with first exposures at 4 to 5 months of age (referent).
MAIN OUTCOME AND MEASURE
Risk for T1DM diagnosed by a physician.
RESULTS
Both early and late first exposure to any solid food predicted development of T1DM (hazard ratio [HR], 1.91; 95% CI, 1.04–3.51, and HR, 3.02; 95% CI, 1.26–7.24, respectively), adjusting for the HLA-DR genotype, first-degree relative with T1DM, maternal education, and delivery type. Specifically, early exposure to fruit and late exposure to rice/oat predicted T1DM (HR, 2.23; 95% CI, 1.14–4.39, and HR, 2.88; 95% CI, 1.36–6.11, respectively), while breastfeeding at the time of introduction to wheat/barley conferred protection (HR, 0.47; 95% CI, 0.26–0.86). Complicated vaginal delivery was also a predictor of T1DM (HR, 1.93; 95% CI, 1.03–3.61).
CONCLUSIONS AND RELEVANCE
These results suggest the safest age to introduce solid foods in children at increased genetic risk for T1DM is between 4 and 5 months of age. Breastfeeding while introducing new foods may reduce T1DM risk.
doi:10.1001/jamapediatrics.2013.317
PMCID: PMC4038357  PMID: 23836309
24.  The effect of insurance status and parental education on glycemic control and cardiovascular disease risk profile in youth with Type 1 Diabetes 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/2251-6581-13-59
PMCID: PMC4064822  PMID: 24955334
Type 1 diabetes; Socioeconomic status; Parental education; Hemoglobin A1c; Cardiovascular disease
25.  Components of metabolic syndrome and 5-year change in insulin clearance - The Insulin Resistance Atherosclerosis Study (IRAS) 
Diabetes, obesity & metabolism  2013;15(5):10.1111/dom.12049.
Aims
Cross-sectional evidence indicates that abdominal adiposity, hypertension, dyslipidemia and glycemia are associated with reduced metabolic clearance of insulin (MCRI). Little is known about the progression of MCRI and whether components of metabolic syndrome are associated with the change in MCRI. In this study, we examined the association between components of metabolic syndrome and the 5-year change of MCRI.
Methods and Materials
At baseline and 5-year follow-up, we measured fasting plasma triglycerides (TG), high density lipoprotein (HDL)-cholesterol, blood pressure (BP), waist circumference (WC) and fasting blood glucose (FBG) in 784 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. MCRI, insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests.
Results
We observed a 29% decline of MCRI at follow-up. TG, systolic BP and WC at baseline were inversely associated with a decline of MCRI regression models adjusted for age, sex, ethnicity, smoking, alcohol consumption, energy expenditure, family history of diabetes, BMI, SI and AIR (β= −0.057 [95% CI −0.11, −0.0084] for TG, β= −0.0019 [95% CI −0.0035, −0.00023] for systolic BP, β= −0.0084 [95% CI −0.013, −0.0039] for WC; all p<0.05). Higher HDL-cholesterol at baseline was associated with an increase in MCRI (multivariable-adjusted β= 0.0029 [95% CI 0.0010, 0.0048], p=0.002). FBG at baseline was not associated with MCRI at follow-up (multivariable-adjusted β= 0.0014 [95% CI −0.0026, 0.0029]).
Conclusions
MCRI declined progressively over 5 years in a non-diabetic cohort. Components of metabolic syndrome at baseline were associated with a significant change in MCRI.
doi:10.1111/dom.12049
PMCID: PMC3810428  PMID: 23216702

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