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.
DNA methylation; Epigenetics; Gestational diabetes; Cardiometabolic; Intrauterine
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.
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.
diabetes; impaired glucose tolerance; menopause; oophorectomy; women
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.
RESEARCH DESIGN AND METHODS
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.
To estimate the prevalence of asthma among youth with types 1 and 2 diabetes and examine associations between asthma and glycemic control.
This was a cross-sectional analysis of data from the SEARCH for Diabetes in Youth study, which included youth diagnosed with type 1 (n = 1683) and type 2 (n = 311) diabetes from 2002 through 2005. Asthma status and medications were ascertained from medical records and self-administered questionnaires, and glycemic control was assessed from hemoglobin A1c measured at the study visit.
Prevalence of asthma among all youth with diabetes was 10.9% (95% confidence interval [CI]: 9.6%–12.3%). The prevalence was 10.0% (95% CI: 8.6%–11.4%) among youth with type 1 and 16.1% (95% CI: 12.0%–20.2%) among youth with type 2 diabetes and differed according to race/ethnicity. Among youth with type 1 diabetes, those with asthma had higher mean A1c levels than those without asthma, after adjustment for age, gender, race/ethnicity, and BMI (7.77% vs 7.49%; P = .034). Youth with asthma were more likely to have poor glycemic control, particularly those with type 1 diabetes whose asthma was not treated with pharmacotherapy, although this association was attenuated by adjustment for race/ethnicity.
Prevalence of asthma may be elevated among youth with diabetes relative to the general US population. Among youth with type 1 diabetes, asthma is associated with poor glycemic control, especially if asthma is untreated. Specific asthma medications may decrease systemic inflammation, which underlies the complex relationship between pulmonary function, BMI, and glycemic control among youth with diabetes.
asthma; diabetes mellitus; diabetes type 1; diabetes type 2; obesity
Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.
To describe demographic and clinical characteristics associated with self-reported receipt of tests and measurements recommended by the American Diabetes Association (ADA) for children and youths with diabetes.
The study included 1514 SEARCH for Diabetes in Youth study participants who completed a survey about diabetes care received. Quality-of-care measures were based on ADA guidelines for eye examinations and glycohemoglobin (hemoglobin A1c [HbA1c]), lipid level, microalbuminuria, and blood pressure measurements, and a composite variable of these 5 indicators was created. Multivariate logistic regression models were used to assess the association of selected demographic and clinical characteristics with the reported receipt of all recommended tests and measurements according to age and diabetes type subgroups.
Overall, 95% of the participants reported having their blood pressure checked at all or most visits, 88% had lipid levels measured, 83% had kidney function tested, 68% underwent HbA1c testing, and 66% underwent an eye examination, in accordance with ADA recommendations. Participants aged 18 years or older, particularly those with type 2 diabetes, tended to have fewer tests of all kinds performed. Age and family income emerged as important correlates of overall quality of care in multivariate models; older age and lower income were associated with not meeting guidelines.
Although there was relatively good adherence to ADA-recommended guidelines for most indicators, efforts are needed to improve rates of HbA1c testing and eye examinations, particularly among older youths.
quality of care; children and youths; diabetes mellitus
Previous studies have shown that summary measures of comorbid conditions are associated with decreased overall survival in breast cancer patients. However, less is known about associations between specific comorbid conditions on the survival of breast cancer patients.
The Surveillance, Epidemiology, and End Results–Medicare database was used to identify primary breast cancers diagnosed from 1992 to 2000 among women aged 66 years or older. Inpatient, outpatient, and physician visits within the Medicare system were searched to determine the presence of 13 comorbid conditions present at the time of diagnosis. Overall survival was estimated using age-specific Kaplan–Meier curves, and mortality was estimated using Cox proportional hazards models adjusted for age, race and/or ethnicity, tumor stage, cancer prognostic markers, and treatment. All statistical tests were two-sided.
The study population included 64 034 patients with breast cancer diagnosed at a median age of 75 years. None of the selected comorbid conditions were identified in 37 306 (58%) of the 64 034 patients in the study population. Each of the 13 comorbid conditions examined was associated with decreased overall survival and increased mortality (from prior myocardial infarction, adjusted hazard ratio [HR] of death = 1.11, 95% CI = 1.03 to 1.19, P = .006; to liver disease, adjusted HR of death = 2.32, 95% CI = 1.97 to 2.73, P < .001). When patients of age 66–74 years were stratified by stage and individual comorbidity status, patients with each comorbid condition and a stage I tumor had similar or poorer overall survival compared with patients who had no comorbid conditions and stage II tumors.
In a US population of older breast cancer patients, 13 individual comorbid conditions were associated with decreased overall survival and increased mortality.
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.
RESEARCH DESIGN AND METHODS
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.
This paper resulted from a conference entitled “Lactation and Milk: Defining and refining the critical questions” held at the University of Colorado School of Medicine from January 18–20, 2012. The mission of the conference was to identify unresolved questions and set future goals for research into human milk composition, mammary development and lactation. We first outline the unanswered questions regarding the composition of human milk (Section I) and the mechanisms by which milk components affect neonatal development, growth and health and recommend models for future research. Emerging questions about how milk components affect cognitive development and behavioral phenotype of the offspring are presented in Section II. In Section III we outline the important unanswered questions about regulation of mammary gland development, the heritability of defects, the effects of maternal nutrition, disease, metabolic status, and therapeutic drugs upon the subsequent lactation. Questions surrounding breastfeeding practice are also highlighted. In Section IV we describe the specific nutritional challenges faced by three different populations, namely preterm infants, infants born to obese mothers who may or may not have gestational diabetes, and infants born to undernourished mothers. The recognition that multidisciplinary training is critical to advancing the field led us to formulate specific training recommendations in Section V. Our recommendations for research emphasis are summarized in Section VI. In sum, we present a roadmap for multidisciplinary research into all aspects of human lactation, milk and its role in infant nutrition for the next decade and beyond.
Lactation; Infant nutrition; Human milk; Breastfeeding; Mammary gland development; Human nutrition; Preterm birth; Obesity; Undernutrition; Lactational programming; Milk
To examine associations between exposure to maternal diabetes in utero and body mass index (BMI) growth trajectories from birth through 13 years of age among a diverse cohort of youth.
Mixed linear effects models were constructed to assess differences in BMI and BMI growth velocity from birth through 13 years of age for 95 subjects exposed to diabetes in utero and 409 unexposed subjects enrolled in a retrospective cohort study.
The overall BMI growth trajectory (adjusted for sex and race/ethnicity) was not significantly different for exposed and unexposed subjects from birth through 26 months of age (p=0.48). However, the overall growth trajectory from 27 months of age through 13 years differed by exposure status (p=0.008), adjusted for sex and race/ethnicity. The difference was primarily due to a significantly higher BMI growth velocity among exposed youth between 10–13 years, increasing by 4.56 kg/m2 compared to 3.51 kg/m2 in the unexposed (p=0.005). Control for demographic variables, socioeconomic factors and maternal pre-pregnancy BMI did not alter the observed associations.
Exposure to maternal diabetes in utero accelerates BMI growth in late childhood thus increasing long-term obesity risk.
Gestational diabetes; fetal overnutrition; fetal exposure to diabetes; childhood obesity; childhood BMI; growth trajectory
To evaluate whether breastfeeding attenuates increased childhood adiposity associated with exposure to diabetes in utero.
RESEARCH DESIGN AND METHODS
Retrospective cohort study of 89 children exposed to diabetes in utero and 379 unexposed youth with measured BMI, waist circumference, skinfolds, visceral (VAT) and subcutaneous (SAT) abdominal fat. A measure of breast milk–months was derived from maternal self-report and used to categorize breastfeeding status as low (<6) and adequate (≥6 breast milk–months). Multiple linear regression was used to model the relationship between exposure to diabetes in utero and offspring adiposity outcomes among youth stratified according to breastfeeding status.
Adequate (vs. low) breastfeeding status was associated with significantly lower BMI, waist circumference, SAT, and VAT at ages 6–13 years. Among youth in the low breastfeeding category, exposure to diabetes in utero was associated with a 1.7 kg/m2 higher BMI (P = 0.03), 5.8 cm higher waist circumference (P = 0.008), 6.1 cm2 higher VAT (P = 0.06), 44.6 cm2 higher SAT (P = 0.03), and 0.11 higher ratio of subscapular-to-triceps skinfold ratio (P = 0.008). Among those with adequate breastfeeding in infancy, the effect of prenatal exposure to diabetes on childhood adiposity outcomes was not significant.
Adequate breastfeeding protects against childhood adiposity and reduces the increased adiposity levels associated with exposure to diabetes in utero. These data provide support for mothers with diabetes during pregnancy to breastfeed their infants in order to reduce the risk of childhood obesity.
European ecologic studies suggest higher socioeconomic status is associated with higher incidence of type 1 diabetes. Using data from a case-control study of diabetes among racially/ethnically diverse youth in the United States (U.S.), we aimed to evaluate the independent impact of neighborhood characteristics on type 1 diabetes risk. Data were available for 507 youth with type 1 diabetes and 208 healthy controls aged 10-22 years recruited in South Carolina and Colorado in 2003-2006. Home addresses were used to identify Census tracts of residence. Neighborhood-level variables were obtained from 2000 U.S. Census. Multivariate generalized linear mixed models were applied.
Controlling for individual risk factors (age, gender, race/ethnicity, infant feeding, birth weight, maternal age, number of household residents, parental education, income, state), higher neighborhood household income (p = 0.005), proportion of population in managerial jobs (p = 0.02), with at least high school education (p = 0.005), working outside the county (p = 0.04) and vehicle ownership (p = 0.03) were each independently associated with increased odds of type 1 diabetes. Conversely, higher percent minority population (p = 0.0003), income from social security (p = 0.002), proportion of crowded households (0.0497) and poverty (p = 0.008) were associated with a decreased odds.
Our study suggests that neighborhood characteristics related to greater affluence, occupation, and education are associated with higher type 1 diabetes risk. Further research is needed to understand mechanisms underlying the influence of neighborhood context.
Socioeconomic status; Type 1 diabetes; Risk factors; Youth
TCF7L2 variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses.
We examined the potential role of the TCF7L2 rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N = 2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults.
We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (P<0.001), higher baseline proinsulin∶insulin ratio (p<0.0001) and increased proinsulin∶insulin ratio over a median of 2.5 years of follow-up (P = 0.003). Effects were comparable across treatment arms.
The combination of a lack of impact of the TCF7L2 genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin∶insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production.
Many women who survive breast cancer die of causes unrelated to their cancer diagnosis. This study was undertaken to assess factors that are related to breast cancer mortality versus mortality from other causes and to describe the leading causes of death among older women diagnosed with breast cancer.
Women diagnosed with breast cancer at age 66 or older between 1992 and 2000 were identified in the Surveillance, Epidemiology and End Results-Medicare linked database and followed through the end of 2005.
A total of 63,566 women diagnosed with breast cancer met the inclusion criteria and were followed for a median of approximately nine years. Almost one-half (48.7%) were alive at the end of follow-up. Ages and comorbidities at the time of diagnosis had the largest effects on mortality from other causes, while tumor stage, tumor grade, estrogen receptor status, age and comorbidities at the time of diagnosis all had effects on breast cancer-specific mortality. Fully adjusted relative hazards of the effects of comorbidities on breast cancer-specific mortality were 1.24 (95% confidence interval (95% CI) 1.13 to 1.26) for cardiovascular disease, 1.13 (95% CI 1.13 to 1.26) for previous cancer, 1.13 (95% CI 1.05 to 1.22) for chronic obstructive pulmonary disease and 1.10 (95% CI 1.03 to 1.16) for diabetes. Among the total study population, cardiovascular disease was the primary cause of death in the study population (15.9% (95% CI 15.6 to 16.2)), followed closely by breast cancer (15.1% (95% CI 14.8 to 15.4)).
Comorbid conditions contribute importantly to both total mortality and breast cancer-specific mortality among breast cancer survivors. Attention to reducing the risk of cardiovascular disease should be a priority for the long-term care of women following the diagnosis and treatment of breast cancer.
We evaluated geographic variation of Type 1 and Type 2 diabetes mellitus (T1DM, T2DM) in four regions of the United States.
Data on 807 incident T1DM cases diabetes and 313 T2DM cases occurring in 2002-03 in South Carolina (SC) and Colorado (CO), 5 counties in Washington (WA), and an 8 county region around Cincinnati, Ohio (OH) among youth aged 10 through 19 years were obtained from the SEARCH for Diabetes in Youth Study. Geographic patterns were evaluated in a Bayesian framework.
Incidence rates differed between the study regions, even within race/ethnic groups. Significant small area variation within study region was observed for T1DM and for T2DM. Evidence for joint spatial correlation between T1DM and T2DM was present at the county level for SC (rSC= 0.31) and CO non-Hispanic whites (rCO= 0.40) and CO Hispanics (rCO= 0.72). At the tract level no evidence for meaningful joint spatial correlation was observed (rSC= -0.02; rCO= -0.02; rOH= 0.03; rWA= 0.09).
Our study provides evidence for the presence of both regional and small-area, localized variation in type 1 and type 2 incidence among youth aged 10-19 years in the United States.
Diabetes mellitus; youth; spatial epidemiology; Bayesian methods
Arterial stiffness occurs early in the atherosclerotic process; however, few data are available concerning risk factors for arterial stiffness in youth with diabetes. We identified factors associated with arterial stiffness in youth with diabetes and assessed the effects of these factors on the relationship between arterial stiffness and diabetes type (type 1 vs. type 2).
RESEARCH DESIGN AND METHODS
A subset of patients from the SEARCH for Diabetes in Youth study with type 1 (n = 535) and type 2 diabetes (n = 60), aged 10–23 years (52% male; 82% non-Hispanic white; diabetes duration 65 ± 49 months) had arterial stiffness, anthropometrics, blood pressure, fasting lipids, and A1C measured. Arterial stiffness was measured by brachial distensibility (brachD), pulse wave velocity (PWV), and augmentation index adjusted to heart rate of 75 beats/min (AI75).
Youth with type 2 diabetes had worse brachD (5.2 ± 0.9 vs. 6.1 ± 1.2%/mmHg), PWV (6.4 ± 1.3 vs. 5.3 ± 0.8 m/s), and AI75 (6.4 ± 9.9 vs. 2.2 ± 10.2%) than those with type 1 diabetes (P < 0.01 for each). These differences were largely mediated through increased central adiposity and higher blood pressure in youth with type 2 diabetes. We also found a pattern of association of arterial stiffness measures with waist circumference and blood pressure, independent of diabetes type.
Youth with type 2 diabetes have worse arterial stiffness than similar youth with type 1 diabetes. Increased central adiposity and blood pressure are associated with measures of arterial stiffness, independent of diabetes type. Whether these findings indicate that youth with type 2 diabetes will be at higher risk for future complications requires longitudinal studies.
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.
Breastfeeding duration; Infant weight gain; Diabetes exposure in utero; Birth size; Mediator
Seasonal environment at birth may influence diabetes incidence in later life. We sought evidence for this effect in a large sample of diabetic youth residing in the U.S.
RESEARCH DESIGN AND METHODS
We compared the distribution of birth months within the SEARCH for Diabetes in Youth Study (SEARCH study) with the monthly distributions in U.S. births tabulated by race for years 1982–2005. SEARCH study participants (9,737 youth with type 1 diabetes and 1,749 with type 2 diabetes) were identified by six collaborating U.S. centers.
Among type 1 diabetic youth, the percentage of observed to expected births differed across the months (P = 0.0092; decreased in October–February and increased in March–July). Their smoothed birth-month estimates demonstrated a deficit in November–February births and an excess in April–July births (smoothed May versus January relative risk [RR] = 1.06 [95% CI 1.02–1.11]). Stratifications by sex or by three racial groups showed similar patterns relating type 1 diabetes to month of birth. Stratification by geographic regions showed a peak-to-nadir RR of 1.10 [1.04–1.16] in study regions from the northern latitudes (Colorado, western Washington State, and southern Ohio) but no birth-month effect (P > 0.9) in study regions from more southern locations. Among type 2 diabetic youth, associations with birth month were inconclusive.
Spring births were associated with increased likelihood of type 1 diabetes but possibly not in all U.S. regions. Causal mechanisms may involve factors dependent on geographic latitude such as solar irradiance, but it is unknown whether they influence prenatal or early postnatal development.
To determine the extent of β-cell function in youth with diabetes and GAD65 and/or IA2 autoantibodies.
RESEARCH DESIGN AND METHODS
Fasting C-peptide levels from 2,789 GAD65- and/or IA2 autoantibody-positive youth aged 1–23 years from the SEARCH for Diabetes in Youth study were used. Preserved β-cell function was defined on the basis of cut points derived from the Diabetes Control and Complications Trial (DCCT) (fasting C-peptide ≥0.23 ng/ml) and from the U.S. adolescent population of the National Health and Nutrition Examination Survey (NHANES) 5th percentile for fasting C-peptide (≥1.0 ng/ml). We compared the clinical characteristics between those with and without preserved β-cell function.
Within the first year of diagnosis, 82.9% of youth had a fasting C-peptide ≥0.23 ng/ml and 31.2% had values ≥1.0 ng/ml. Among those with ≥5 years of diabetes duration, 10.7% had preserved β-cell function based on the DCCT cutoff and 1.0% were above the 5th percentile of the NHANES population.
Within the 1st year of diagnosis, four of five youth with autoantibody-positive diabetes have clinically significant amounts of residual β-cell function and about one-third have fasting C-peptide levels above the 5th percentile of a healthy adolescent population. Even 5 years after diagnosis, 1 of 10 has fasting C-peptide above a clinically significant threshold. These findings have implications for clinical classification of youth with diabetes as well as clinical trials aimed to preserve β-cell function after diabetes onset.
We tested the association of adiponectin/leptin ratio (ALR) with diabetes type after adjusting for multiple factors in 1,156 youth with newly diagnosed diabetes in the SEARCH study. Although ALR is associated with diabetes type in youth, it is due to differences in adiponectin, but not leptin levels.
adiponectin; leptin; adiponectin/leptin ratio; type 1 diabetes; type 2 diabetes; pediatrics; youth
The extent to which cardiovascular disease (CVD) risk factors cluster in youth with a diagnosis of type 1 (T1DM) or type 2 diabetes mellitus (T2DM) is unclear. Therefore, we aimed to evaluate potential clustering of traditional CVD risk factors that may reflect an unmeasured but unifying single pathology that may explain the phenomenon of the metabolic syndrome in these youths.
Youths who participated in the SEARCH for Diabetes in Youth study with diabetes diagnosed <20 years, with current age >10 years (maximum current age, 22 years) were included. Confirmatory factor analysis (CFA) was performed to determine statistical associations among CVD risk factors, including obesity, blood pressure, triglycerides, and high-density lipoprotein cholesterol (HDL-C). Diabetes type was defined by diabetes autoantibodies (DAA) and fasting C-peptide (FCP); type 1 (T1DM, DAA positive, and FCP <0.8 ng/mL, n = 1198) and type 2 (T2DM, DAA negative, and FCP >2.9 ng/mL, n = 95). For T1DM, the sample was split randomly and analyses were conducted separately in each split sample.
Among five prespecified data structures ranging from a single underlying factor to a hierarchical structure of factors, the worst-fitting model for both of the T1DM split samples was the single-factor structure and the best-fitting model was a three-correlated-factor structure. The three correlated factors identified were obesity, lipids, and blood pressure. Results were very similar for youths with T2DM.
There is little evidence that a single factor underlies the CVD risk factor pattern in youths with diabetes. The concept of the metabolic syndrome provides a useful description of clinical characteristics but does not efficiently capture a single target for etiologic research among youths with diabetes.