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1.  Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program 
To determine if the presence of diabetes autoantibodies predicts the development of diabetes among participants in the Diabetes Prevention Program.
A total of 3050 participants were randomized into three treatment groups: intensive lifestyle intervention, metformin and placebo. Glutamic acid decarboxylase (GAD) 65 autoantibodies and insulinoma-associated-2 autoantibodies were measured at baseline and participants were followed for 3.2 years for the development of diabetes.
The overall prevalence of GAD autoantibodies was 4.0%, and it varied across racial/ethnic groups from 2.4% among Asian-Pacific Islanders to 7.0% among non-Hispanic black people. There were no significant differences in BMI or metabolic variables (glucose, insulin, HbA1c, estimated insulin resistance, corrected insulin response) stratified by baseline GAD antibody status. GAD autoantibody positivity did not predict diabetes overall (adjusted hazard ratio 0.98; 95% CI 0.56–1.73) or in any of the three treatment groups. Insulinoma-associated-2 autoantibodies were positive in only one participant (0.033%).
These data suggest that ‘diabetes autoimmunity’, as reflected by GAD antibodies and insulinoma-associated-2 autoantibodies, in middle-aged individuals at risk for diabetes is not a clinically relevant risk factor for progression to diabetes.
PMCID: PMC4138247  PMID: 24646311
2.  Clinical evolution of beta cell function in youth with diabetes: the SEARCH for Diabetes in Youth study 
Diabetologia  2012;55(12):3359-3368.
Few studies have explored the epidemiology of beta cell loss in youth with diabetes. This report describes the evolution and major determinants of beta cell function, assessed by fasting C-peptide (FCP), in the SEARCH for Diabetes in Youth study.
Participants were 1,277 youth with diabetes (948 positive for diabetes autoantibodies [DAs] and 329 negative for DAs), diagnosed when aged <20 years, who were followed from a median of 8 months post diagnosis, for approximately 30 months. We modelled the relationship between rate of change in log FCP and determinants of interest using repeated measures general linear models.
Among DA-positive youth, there was a progressive decline in beta cell function of 4% per month, independent of demographics (age, sex, race/ethnicity), genetic susceptibility to autoimmunity (HLA risk), HbA1c and BMI z score, or presence of insulin resistance. Among DA-negative youth, there was marked heterogeneity in beta cell loss, reflecting an aetiologically mixed group. This group likely includes youths with undetected autoimmunity (whose decline is similar to that of DA-positive youth) and youth with non-autoimmune, insulin-resistant diabetes, with limited decline (~0.7% per month).
SEARCH provides unique estimates of beta cell function decline in a large sample of youth with diabetes, indicating that autoimmunity is the major contributor. These data contribute to a better understanding of clinical evolution of beta cell function in youth with diabetes, provide strong support for the aetiological classification of diabetes type and may inform tertiary prevention efforts targeted at high-risk groups.
PMCID: PMC4492685  PMID: 22990715
Beta cell function; Decline; Determinants; Epidemiology; Type 1 diabetes; Type 2 diabetes; Youth
3.  Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth 
Diabetologia  2010;54(3):535-539.
Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been associated with type 2 diabetes in adults. However, it is not known whether TCF7L2 variation increases the risk of early onset type 2 diabetes. Using a case–control design, we examined whether the reported variants [rs12255372 (T/G) and rs7903146 (T/C)] are associated with type 2 diabetes in SEARCH for Diabetes in Youth study participants.
Variants were genotyped in 694 non-Hispanic white (NHW) youth (86 cases, mean age 15.5 years, mean BMI 34.8; and 608 controls, mean age 14.4 years, mean BMI 22.3) and 545 African-American (AA) youth (154 cases, mean age 15.9, mean BMI 37; and 391 controls, mean age 14.8, mean BMI 23.8). Logistic regression adjusted for age, sex, BMI and West African ancestry.
The association of the risk T allele with case/control status was different in AA and NHW youth (p=0.025). Among AA youth, each copy of the T allele (rs7903146) was associated with a 1.97-fold (1.37, 2.82) increased odds for type 2 diabetes (p<0.0001), after adjustment for age, sex, BMI and African ancestry. No significant association was detected in NHW youth (adjusted OR, 1.14; 0.73, 1.79).
TCF7L2 variation is associated with an increased risk of early-onset type 2 diabetes among AA youth, and the association appears to be stronger in AA than NHW youth. This suggests potential different contributions of genetic and environmental factors to early-onset type 2 diabetes by race.
PMCID: PMC3766323  PMID: 21109996
TCF7L2; Type 2 diabetes; Youth
4.  Is low birth weight associated with adiposity in contemporary U.S. youth? The Exploring Perinatal Outcomes among Children (EPOCH) Study 
Little is known about the relationship between low birth weight (BW), as a marker of under-nutrition in utero, and childhood body mass index (BMI) and adiposity parameters, including skinfold thickness, abdominal subcutaneous (SAT) and visceral adipose tissues (VAT) and intramyocellular accumulation of lipids (IMCL). The EPOCH Study (Exploring Perinatal Outcomes among Children) explored the association between BW and markers of adiposity in contemporary, multi-ethnic children from Colorado. A total of 442 youth age 6–13 years (50% male, mean age 10.5 years) had anthropometric measurements, abdominal SAT and VAT measured by magnetic resonance imaging and IMCL deposition in the soleus muscle measured by nuclear magnetic resonance spectroscopy. BW and gestational age were ascertained from an electronic perinatal database. A weak positive association between BW and current BMI (P=0.05) was seen, independent of demographic, perinatal, socio-economic and current lifestyle factors. When adjusted for current BMI, every one standard deviation decrease in BW (~500 g), was associated with a 8.8 cm2 increase in SAT, independent of potential confounders. In conclusion, in a contemporary cohort of youth, BW was positively, but weakly, associated with BMI and inversely, though weakly, associated with SAT, independent of current BMI. There were no significant associations between BW and waist circumference, skinfolds, VAT and IMCL. Our results provide some support to the hypothesis that under-nutrition in utero, as reflected by lower BW, is associated with lower overall childhood body size, but an increased propensity for abdominal adiposity, reflected in this young age-group, predominantly as subcutaneous fat.
PMCID: PMC3464921  PMID: 23050071
To evaluate the influence of breastfeeding on the body mass index (BMI) growth trajectory from birth through 13 years of age among offspring of diabetic pregnancies (ODP) and offspring of non-diabetic pregnancies (ONDP) participating in the EPOCH study.
There were 94 ODP and 399 ONDP who had multiple BMI measures obtained from birth throughout childhood. A measure of breast milk-months was derived from maternal self-report to categorize breastfeeding status as adequate (≥6 breast milk-months) or low (<6 breast milk-months). Mixed linear effects models were constructed to assess the impact of breastfeeding on the BMI growth curves during infancy (birth to 27 months) and childhood (27 months to 13 years).
ODP who were adequately breastfed had a slower BMI growth trajectory during childhood (p=0.047) and slower period-specific growth velocity with significant differences between 4 to 6 years of age (p=0.03) and 6 to 9 years of age (p=0.01) compared to ODP with low breastfeeding. A similar pattern was seen in the ONDP, with adequate breastfeeding associated with lower average BMI in infancy (p=0.03) and childhood (p=0.0002) and a slower growth trajectory in childhood (p=0.0002). Slower period-specific growth velocity was seen among the ONDP associated with adequate breastfeeding with significant differences between 12–26 months (p=0.02), 4–6 years (p=0.03), 6–9 years (p=0.0001) and 9–13 years of age (p<.0001).
Our study provides novel evidence that breastfeeding is associated with long-term effects on childhood BMI growth that extend beyond infancy into early and late childhood. Importantly, these effects are also present in the high-risk offspring, exposed to overnutrition during pregnancy. Breastfeeding in the early postnatal period may represent a critical opportunity to reduce the risk of childhood obesity.
PMCID: PMC3323752  PMID: 22290537
Breastfeeding; childhood obesity; fetal programming; fetal overnutrition; fetal exposure to diabetes; critical periods; gestational diabetes; BMI; childhood growth trajectories; early infant diet
6.  Association of insulin sensitivity to lipids across the lifespan in people with Type 1 diabetes 
Diabetic Medicine  2011;28(2):148-155.
Insulin resistance and dyslipidaemia both increase cardiovascular risk in Type 1 diabetes. However, little data exist on the associations of insulin resistance to lipids in Type 1 diabetes. Our objective was to explore the associations between insulin resistance (assessed by glucose infusion rate) and lipids in people with Type 1 diabetes and determine whether adiposity and/or average glycaemia influence these associations.
Hyperinsulinaemic–euglycaemic clamp studies were performed in 60 subjects with Type 1 diabetes aged 12–19 years (age 15 ± 2 years, 57% female, duration of diabetes 6.3 ± 3.8 years, HbA1c 8.6 ± 1.5%) and 40 subjects with Type 1 diabetes aged 27–61 years (age 45 ± 9 years, 53% female, duration of diabetes 23 ± 8 years, HbA1c 7.5 ± 0.9%). Multiple linear regression models were fit to examine the association between glucose infusion rate and fasting lipid levels with adjustment for possible confounders.
Lower glucose infusion rate was significantly associated with lower levels of HDL cholesterol in youths with Type 1 diabetes and with higher levels of triglycerides and higher triglyceride/HDL ratio in both youths and adults. The magnitude of the associations between glucose infusion rate and lipid levels translate into interquartile differences of 0.098 mmol/l for HDL cholesterol, 0.17 mmol/l for triglycerides and 1.06 for triglycerides/HDL in the adolescents and 0.20 mmol/l for triglycerides and 1.01 for triglycerides/HDL in the adults. The associations were attenuated and no longer statistically significant by adjustment for adiposity among adults, while adjustment for HbA1c had a small effect in youths and adults.
Lower insulin sensitivity is associated with a more atherogenic lipid profile in both youths and adults with Type 1 diabetes.
PMCID: PMC3395467  PMID: 21219421
insulin resistance; insulin sensitivity; lipids; Type 1 diabetes
7.  Association of exposure to diabetes in utero with adiposity and fat distribution in a multiethnic population of youth: the Exploring Perinatal Outcomes among Children (EPOCH) Study 
Diabetologia  2010;54(1):87-92.
To evaluate whether exposure to maternal gestational diabetes (GDM) is associated with adiposity and fat distribution in a multiethnic population of children.
Retrospective cohort study of 82 children exposed to maternal GDM and 379 unexposed youths 6–13 years of age with measured BMI, waist circumference, skinfold thickness, and visceral and subcutaneous abdominal fat.
Exposure to maternal GDM was associated with higher BMI (p=0.02), larger waist circumference (p=0.004), more subcutaneous abdominal fat (p=0.01) and increased subscapular to triceps skinfold thickness ratio (p=0.01) in models adjusted for age, sex, race/ethnicity and Tanner stage. Adjustment for socioeconomic factors, birthweight and gestational age, maternal smoking during pregnancy and current diet and physical activity did not influence associations; however, adjustment for maternal pre-pregnancy BMI attenuated all associations.
Exposure to maternal GDM is associated with increased overall and abdominal adiposity, and a more central fat distribution pattern in 6- to 13-year-old youths from a multi-ethnic population, providing further support for the fetal overnutrition hypothesis.
PMCID: PMC3027214  PMID: 20953862
Childhood obesity; Fat distribution; Fetal exposure to diabetes; Fetal overnutrition; Gestational diabetes; Subcutaneous fat; Visceral fat
8.  Association of a Common G6PC2 Variant with Fasting Plasma Glucose Levels in Non-Diabetic Individuals 
Fasting plasma glucose (FPG) levels correlate with cardiovascular disease and mortality in both diabetic and non-diabetic subjects. G6PC2 encodes a pancreatic islet-specific glucose-6-phosphatase-related protein and G6pc2-null mice were reported to exhibit decreased blood glucose levels. Two recent genome-wide association studies have implicated a role for G6PC2 in regulation of FPGlevels in the general European population and reported the strongest association with the rs560887 SNP. The purpose of this study was to replicate this association in our independent epidemiological samples.
DNA samples from non-Hispanic white Americans (NHWs; n = 623), Hispanic Americans (n = 410) and black Africans (n = 787) were genotyped for rs560887 using TaqMan allelic discrimination.
While no minor allele A of rs560887 was observed among blacks, its frequency was 33% in NHWs and 17.5% in Hispanics. The rs560887 minor allele was associated with reduced FPG levels in non-diabetic NHWs (p = 0.002 under an additive model). A similar trend of association was observed in non-diabetic Hispanics (p = 0.076 under a dominant model), which was more pronounced in normoglycemic subjects (p = 0.036).
Our results independently confirm the robust association of G6PC2/rs560887 with FPG levels in non-diabetic NHWs. The observed evidence for association in Hispanics warrants further studies in larger samples.
PMCID: PMC2855271  PMID: 20029179
Blood glucose; Plasma glucose; Fasting plasma glucose; G6PC2; Single nucleotide polymorphism; Polymorphism; rs560887
10.  Asthma in schoolchildren. Demographic associations and peak expiratory flow rates compared in children with bronchitis. 
The frequency of asthma in 10 971 school-children between the ages of 5 and 14 years was reported by their parents to be 3-8%. Of these, 20-7% were said to have had bronchitis, 5-9% pneumonia, and 4-7% eczema. Asthma was reported more commonly in boys than girls and was greatest in children of social classes I and II. One-third of the children were reported to have their first attack before the age of 2 years. Few (18%) first attacks started after the age of 5 years. There was no evidence that bronchitis predisposed to the later development of asthma, or vice versa. Within each age-sex group children with a history of asthma had lower peak expiratory flow rates than children who gave no such history. These diffences in PEFR were greater than for children with a history of bronchitis.
PMCID: PMC478920  PMID: 1220834
11.  Hypertension among rural Hispanics and non-Hispanic whites: the San Luis Valley Diabetes Study. 
Public Health Reports  1996;111(Suppl 2):27-29.
IN THE SAN LUIS VALLEY DIABETES STUDY (SLVDS) researchers studied hypertension morbidity and risk factors in 1788 Hispanics and non-Hispanic whites (NHW) from the rural San Luis Valley in Colorado. Hypertension was defined by The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V) criteria. In this population-based study, the prevalence, incidence, and risk factors for hypertension did not differ significantly between non-diabetic Hispanics and NHW participants. Hypertension risk increased with age, heart rate, serum triglycerides, insulin area, and obesity (in young participants). Compared with the prevalence rates in non-diabetic participants, the rates were significantly higher in people with diabetes and increased with the duration of diabetes and central obesity. The risk of hypertension in diabetic Hispanics appeared to be somewhat lower than that in NHW diabetics.
PMCID: PMC1381658  PMID: 8898767

Results 1-11 (11)