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Background Growth abnormalities in childhood have been related to later cardiometabolic risks, but little is known about these associations in populations at high risk of type 2 diabetes. Objectives We examined the associations of patterns of growth, including weight and height at ages 1–59 months, with cardiometabolic risk factors at ages 5–16 years. Methods We linked anthropometric data collected at ages 1–59 months to cardiometabolic data obtained from a longitudinal study in a southwestern American Indian population at high risk of diabetes. Analyses included 701 children with ≥1 follow-up examination at ages 5–16 years. We derived age- and sex-specific weight-for-height z -scores (WHZ) and height-for-age z -scores (HAZ) at ages 1–59 months. We selected the highest observed WHZ and the lowest observed HAZ at ages 1–59 months and analyzed associations of z -scores and categories of WHZ and HAZ with cardiometabolic outcomes at ages 5–16 years. We used linear mixed-effects models to account for repeated measures. Results Overweight/obesity (WHZ >2) at ages 1–59 months was significantly associated with increased BMI, fasting and 2-hour postload plasma glucose, fasting and 2-hour insulin, triglycerides, systolic blood pressure, diastolic blood pressure, and decreased HDL cholesterol at ages 5–16 years relative to normal weight (WHZ ≤1). For example, at ages 5–9 years, 2-hour glucose was 10.4 mg/dL higher (95% CI: 5.6–15.3 mg/dL) and fasting insulin was 4.29 μU/mL higher (95% CI: 2.96–5.71 μU/mL) in those with overweight/obesity in early childhood. Associations were attenuated and no longer significant when adjusted for concurrent BMI. A low height-for-age (HAZ < −2) at ages 1–59 months was associated with 5.37 mg/dL lower HDL (95% CI: 2.57–8.17 mg/dL) and 27.5 μU/mL higher 2-hour insulin (95% CI: 3.41–57.6 μU/mL) at ages 10–16 years relative to an HAZ ≥0. Conclusions In this American Indian population, findings suggest a strong contribution of overweight/obesity in early childhood to cardiometabolic risks in later childhood and adolescence, mediated through persistent overweight/obesity into later ages. Findings also suggest potential adverse effects of low height-for-age, which require confirmation. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2005.06.033 Byline: Aida Jimenez-Corona, Robert G. Nelson, Maurice L. Sievers, William C. Knowler, Robert L. Hanson, Peter H. Bennett Abstract: The association between electrocardiographic (ECG) abnormalities and deaths from cardiovascular diseases (CVD) and ischemic heart disease (IHD) has been reported in the general population, but there is little information regarding persons with type 2 diabetes. Author Affiliation: Diabetes Epidemiology and Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ Article History: Received 19 April 2005; Accepted 20 June 2005 Article Note: (footnote) An American Diabetes Association/Takeda Pharmaceuticals Mentor-based Minority Postdoctoral Fellowship Award supported Dr Aida Jimenez-Corona.

Background: Underlying blood pressure is that observed in the absence of antihypertensive treatment or, among those treated, the estimate of that which would be observed without treatment. This study aims to examine the relationships between diabetes or obesity and underlying systolic blood pressure adjusted for antihypertensive treatment by several methods.Methods: Data from two population studies were analyzed-an American Indian community in Arizona and the National Health and Nutrition Examination Surveys. Antihypertensive treatment was accounted for using: no adjustment; antihypertensive use as a covariate; blood pressure dichotomized into normotension and hypertension; addition of a fixed treatment effect; non-parametric algorithm; and censored normal regression.Results: The magnitude of association at each time point differed by adjustment method particularly where there was a difference in prevalence of antihypertensive use between people with and without diabetes or obesity. The common methods of ignoring antihypertensive treatment or including it as a covariate in a regression model underestimated the effects of diabetes and obesity on underlying blood pressure, compared to the recommended method of the censored normal regression.Conclusion: Proper accounting for antihypertensive treatment is needed in interpreting variables that affect blood pressure. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The aim of this study is to investigate the potential role of DNA methylation in mediating the increased risk of developing type 2 diabetes in offspring of mothers who had diabetes during pregnancy. Materials and Methods: Peripheral blood leukocytes were collected from non-diabetic Pima Indians who were either offspring of diabetic mothers (ODM; n=14) or offspring of nondiabetic mothers (ONDM; n=14). The two groups were matched for age, sex, age of mother, and fraction of Pima ethnicity. Differentially methylated regions were determined using a MeDIP-chip assay on an Affymetrix Human Tiling 2.0R Array. Data were analyzed using the model based analysis of tiling arrays (MAT) algorithm, and 4883 regions overlapping with putative promoters, were identified as differentially methylated, having met an empirically derived threshold (nominal p<0.0077). The list of genes with differentially methylated promoters was subjected to KEGG pathway analysis to determine canonical metabolic pathways enriched by these genes. Results: Pathway analysis of genes with differentially methylated promoters identified the top 3 enriched pathways as maturity onset diabetes of the young (MODY), type 2 diabetes, and Notch signaling. Several genes in these pathways are known to affect pancreatic development and insulin secretion. Conclusions: These findings support the hypothesis that epigenetic changes may increase the risk of type 2 diabetes via an effect on β-cell function in the offspring of mothers with diabetes during pregnancy. [Copyright &y& Elsevier]

Background: To determine whether historic albuminuria measurements provide additional predictive value for diabetic end-stage renal disease (ESRD) and natural mortality over the most recent measurement, ie, whether "regression" from high albuminuria has a different prognosis than stability at the lower level.Study Design: Observational longitudinal study.Setting& Participants: Pima Indians 15 years or older with type 2 diabetes and at least 2 consecutive measurements of urinary albumin-creatinine ratio (ACR) within 6 years.Predictors: Sequential measurements of urinary ACR.Outcomes& Measurements: Proportional hazards analyses were used to estimate the risk of ESRD and natural death associated with the first and second ACR measurement. The ability of these highly correlated variables to predict outcome was compared with receiver operating characteristic curves calculated by means of the generalized c statistic.Results: In 983 subjects, 136 developed ESRD and 180 died of natural causes during a maximum follow-up of 12.6 years. Each doubling in the second ACR was associated with a 1.71-fold greater incidence of ESRD (95% confidence interval, 1.54 to 1.89) and 1.16-fold greater natural mortality (95% confidence interval, 1.07 to 1.27) adjusted for age, sex, diabetes duration, and antihypertensive medication. The addition of the first ACR measurement to the model did not add to the predictive value for ESRD or mortality. In pairwise comparisons of c statistics, the second ACR was a significantly better predictor of ESRD than the first ACR.Limitations: The predictive value of ACR measurements is decreased to the extent that its precision is based on a single measure.Conclusion: The predictive power of the latest ACR for ESRD and natural mortality in patients with diabetes is not enhanced by knowledge of the preceding ACR. Therefore, ACR changes over time, ie, regression or progression, add minimal predictive value beyond the latest measurement in the series. [ABSTRACT FROM AUTHOR]

Background: Greater central adiposity is related to the risk of diabetes. Objective: We aimed to test the hypothesis that central adiposity measured by computed tomography (CT) is a better predictor of the risk of diabetes than is body mass index (BMI), waist circumference (WC), waist/hip ratio (WHR), or waist/height ratio. Design: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured at the L2-3 and L4-5 disc spaces in 1106 of the 3234 participants in the Diabetes Prevention Program. Sex-specific proportional hazards models were used to evaluate the association between VAT and SAT at both cuts, BMI, and other measures of central adiposity as predictors of the development of diabetes. Results: Men had more VAT than did women. White subjects had more VAT at both cuts than did other ethnic groups. The ratio of VATtoSATwas lowest in African Americans of both sexes.Among men in the placebo group, VAT at both cuts, WC, BMI, waist/height ratio, and WHRpredicted diabetes (hazard ratio: 1.79 -1.44 per 1SD of variable). Among women in the lifestyle group, VAT at both cuts predicted diabetes as well as did BMI, and L2-3 was a significantly better predictor than was WCorWHR.SAT did not predict diabetes. None of the body fat measurements predicted diabetes in the metformin group. Conclusions: In the placebo and lifestyle groups, VAT at both cuts, WHR, andWCpredicted diabetes. No measure predicted diabetes in the metformin group. CT provided no important advantage over these simple measures. SAT did not predict diabetes. [ABSTRACT FROM AUTHOR]

Background: Understanding the factors that contribute to physical inactivity in children is important because sedentary behavior strongly relates to metabolic disorders such as obesity and diabetes. Objective: We aimed to quantify the genetic and environmental influences on physical activity energy expenditure (PAEE) in 100 sex-concordant dizygotic (n = 38) and monozygotic (n = 62) twin pairs aged 4-10 y. Design: Resting metabolic rate (RMR) was assessed by using respiratory gas exchange, total energy expenditure (TEE) by using doubly labeled water, and body composition by using dual-energy X-ray absorptiometry. Structural equation modeling was used to partition the phenotypic variance into additive genetic (a2) and common (c2) and unshared (e2) environmental components. Results: Because PAEE [TEE-(RMR+0.1×TEE)] depends on body weight, which is highly heritable, we tested several models: 1) after adjustment for age, sex, ethnicity, study date, season, and weight, a2 explained none of the phenotypic variance in PAEE (95% CI: 0%, 38%), whereas c2 and e2 accounted for69%(33%, 77%;P= 0.001) and 31% (23%, 39%; P < 0.001) of the variance, respectively; 2) after adjustment for the cofactors in model 1, a2 explained 19% of the phenotypic variance in TEE (0%, 60%; P = 0.13), whereas c2 and e2 accounted for 59% (16%, 79%; P = 0.007) and 23% (17%, 31%; P < 0.0001) of the variance, respectively; 3) in models adjusted as above (excluding weight), a2 explained no variance in physical activity level (TEE/RMR) (0%, 32%; P = 0.50), whereas c2 and e2 explained 65% (34%, 60%; P = 0.001) and 35% (28%, 45%; P < 0.0001) of the variance, respectively. Conclusions: Our data suggest that the familial resemblance in physical activity in these children is explained predominantly by shared environmental factors and not by genetic variability. [ABSTRACT FROM AUTHOR]

Background: In Caucasians, lower triglycerides (TG), total or LDL cholesterol and high HDL cholesterol are generally associated with lower mortality. However, low cholesterol is associated with higher mortality in some Asian populations. This study examines the relationship between serum lipids and mortality in American Indians.Methods: 2125 American Indians aged ≥40years were examined biennially between 1993 and 2007. Vital status was determined through 2011. Mortality rates, adjusted for age, sex and diabetes, were calculated using Poisson regression.Results: The median baseline age was 46years and 61% were women. Over a median follow-up of 10.1years, 522 deaths occurred. Relationships between baseline lipids, except for HDL cholesterol, and all-cause mortality were negative and linear in persons without diabetes and U-shaped in persons with diabetes. For HDL cholesterol, the relationship was U-shaped in the total cohort. Cardiovascular mortality was positively associated with total, LDL and non-HDL cholesterol whereas lower lipid concentrations were adversely associated with mortality from liver disease or external causes, except for HDL cholesterol, where associations were positive.Conclusion: The common belief that low cholesterol and TG are beneficial for health is not universally observed; evidence suggests increased mortality at both ends of the cholesterol and TG distributions. [ABSTRACT FROM AUTHOR]

Objective: Gypsies (or Roma) recently experienced a transition from a traditional to a Westernized lifestyle. Although mortality in this population is 4-fold higher compared with non-Gypsies, very limited information is available on their morbidity especially with regard to non-communicable diseases. Our aim was to determine the prevalence of type 2 diabetes mellitus (T2DM), metabolic syndrome and cardiovascular diseases in Gypsies and non-Gypsies living in the same region of southern Slovakia. Materials and methods: We examined 156 Gypsies and 501 non-Gypsies who participated in a population survey. Age- and sex-standardized prevalence rates were computed for each of the following: T2DM, obesity, hyperlipidemia, hypertension, hyperinsulinemia, elevated albumin/creatinine ratio (ACR), metabolic syndrome and cardiovascular disease. Results: Age–sex standardized prevalence of T2DM was 30% (95% CI=22–39) in Gypsies and 10% (8–13, P=0.0001 for comparison of ethnic groups) in non-Gypsies. Corresponding prevalence of the other variables are: 65% (56–74) and 30% (26–34, P=0.0001) for obesity, 69% (61–76) and 59% (54–63, P=0.04) for hypercholesterolemia, 66% (59–74) and 39% (35–43, P=0.009) for hypertriglyceridemia, 49% (42–56) and 43% (39–47, P=0.1) for hypertension, 33% (26–50) and 8% (2–14, P=0.002) for hyperinsulinemia, 16% (9–22) and 5% (3–7, P=0.0001) for elevated ACR, 20% (12–27) and 4% (3–6, P=0.0001) for metabolic syndrome and 35% (28–43) and 26% (22–29, P=0.004) for cardiovascular disease. Conclusions: Compared with non-Gypsies, Gypsies had a much higher prevalence of T2DM, metabolic syndrome and cardiovascular disease, which may contribute to their higher mortality. [Copyright &y& Elsevier]

Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23. Background. Diabetic nephropathy is the major cause of end-stage renal failure in patients with diabetes mellitus types 1 and 2. Epidemiological studies have suggested a genetic susceptibility to diabetic nephropathy. The aim of this study was to localize the gene(s) responsible for susceptibility to diabetic nephropathy. Methods. A genetic linkage analysis was performed in 18 large Turkish families with type 2 diabetes mellitus and diabetic nephropathy. The result was checked in 101 affected sibling pairs of Pima Indians. Results. A highly significant LOD score of 6.1 on chromosome 18q22.3-23 between the markers D18S469 and D18S58 was obtained in multipoint analysis. There was no indication for locus heterogeneity. In Pima Indians, linkage to the markers D18S469 and D18S58 was confirmed (P = 0.033), using the affected sib-pair method. The genetic model that fit best was a dominant mode of inheritance with an almost complete penetration in the Turkish population. Conclusions. There is strong evidence for the localization of a gene responsible for diabetic nephropathy in Turkish type 2 diabetes mellitus patients. This locus maps to chromosome 18q22.3-23, between D18S43 and D18S50, an interval of 8.5 cM. [ABSTRACT FROM AUTHOR]

While the samples and data from the Pima Indians of the Gila River Indian Community have been included in many international HLA workshops and conferences and have been the focus of numerous population reports and the source of novel alleles at the classical HLA loci, they have not been studied for the non-classical loci. In order to expand our HLA -disease association studies, we typed over 300 whole genome sequences from full Pima heritage members, controlled for first degree relationship, and employed recently developed computer algorithms to resolve HLA alleles. Both classical— HLA-A, -B , and - C — and non-classical— HLA-E, -F, -G, -J, -L, -W, -Y, -DPA2, -DPB2, -DMA, -DMB, -DOA, -DRB2, -DRB9 , TAP1 — loci were typed at the 4-field level of resolution. We present allele and selected haplotype frequencies, test the genotype distributions for population structure, discuss the issues that are created for tests of Hardy-Weinberg equilibrium over the four sample spaces of high resolution HLA typing, and address the implications for the evolution of non-classical pseudogenes that are no longer expressed in a phenotype subject to natural selection. [ABSTRACT FROM AUTHOR]

The Pima Indians of the Gila River Indian Community in Arizona have participated in a long-range study of type 2 diabetes mellitus since 1965 and have been the subject of HLA typing and population studies since the early days of serological assays. These data have been in numerous HLA workshops and conferences and have been the source of at least five novel alleles at the classical HLA loci. In recent time nearly the entire study group was subject to next generation sequencing by whole genome or exome technologies, which has allowed us to HLA type over 3000 full heritage persons with recently developed computer algorithms. We present here the results for the classical HLA Loci: HLA-A , B, C, DRA, DRB1, DRB3, DRB4, DRB5, DPA1, DPB1, DQA1, and DQB1 to the third field of resolution for synonymous alleles and type the likely four field resolution alleles from the subset of whole genome sequences. Allele frequencies, and haplotype frequencies at up to five loci, are presented as well as measures of population structure and heterozygosity. We define a core set of HLA variation that approximates the distribution for the Paleo-Indians and impute nine-locus, 4-field haplotypes that are expected to be common in full heritage peoples. [ABSTRACT FROM AUTHOR]

Abstract: Pima Indians from the Gila River Indian Community in Arizona have a high incidence rate of type 2 diabetes, and kidney disease attributable to diabetes is a major cause of morbidity and mortality in this population. Since 1965, each member of the population at least 5 years of age is invited to participate in a research examination every other year. During the past 43 years, the overall incidence of diabetes in the Pima Indians has not changed, but the incidence of diabetes among those less than 15 years of age has increased nearly 6-fold, as an increasing prevalence and degree of obesity in the youth have shifted the onset of diabetes to younger ages. The rising frequency of diabetes in the youth has led, in turn, to the emergence in mid-life of the major complications of diabetes, including kidney disease. On the other hand, the introduction and widespread use of medicines to control blood pressure, reduce hyperglycemia, and block the renin–angiotensin system (RAS) have lead to improvements in the average blood pressure and glycosylated hemoglobin levels in the diabetic population. These countervailing forces have influenced the course of diabetic nephropathy in a generally favorable direction in the past few years, as evidenced by the decline in the overall incidence of end-stage kidney disease since 1990. A continued increase in the incidence of type 2 diabetes in youth, however, threatens to reverse this trend. [Copyright &y& Elsevier]

Abstract: Objectives: Understanding why prolonged Bazett-corrected QT interval (QTc) is a risk factor for mortality is difficult, because QTc is positively correlated with heart rate. To optimally distinguish the effects of QT interval and heart rate on mortality, QT interval and heart rate were modeled separately and jointly in Pima Indians. Methods: The effects of QT and heart rate on all-cause and cause-specific mortality were assessed in the overall study population and according to the presence or absence of diabetes using multivariable time-dependent proportional hazards models. Results: Among 1488 nondiabetic and 990 diabetic subjects ≥25 years old, 81 nondiabetic and 149 diabetic subjects died during a median follow-up of 7.3 years. When included in the same regression model, QT and heart rate each predicted all-cause mortality [hazard ratios per standard deviation (SD) (95% confidence interval)=1.31 (1.10–1.57) and 1.57 (1.32–1.87) respectively]. In nondiabetic subjects, hazard ratios for all-cause mortality were 1.54 (1.19–1.99) for QT and 1.86 (1.46–2.37) for heart rate. In diabetic subjects, hazard ratios for all-cause mortality were lower, 1.27 (1.00–1.62) for QT and 1.41 (1.12–1.78) for heart rate. In the overall study population, neither QT nor heart rate significantly predicted cardiovascular disease (CVD) mortality [hazard ratios=1.13 (0.77–1.64) and 1.46 (0.98–2.19)] when adjusted for each other. Heart rate unadjusted for QT, however, predicted CVD mortality [hazard ratio=1.34 (1.00–1.79)] in a separate model. Conclusions: QT prolongation and high heart rate both predict all-cause mortality in Pima Indians, but heart rate was consistently the stronger predictor of the two. [Copyright &y& Elsevier]

Background: A limited body of evidence, mostly based on self-report, is available regarding physical activity levels among American-Indian adults.Purpose: This study aims to examine physical activity levels objectively using pedometers among a large cohort of American-Indian adult participants in the Strong Heart Family Study (SHFS).Methods: Physical activity levels in 2604 American-Indian adults, aged 18-91 years, from 13 American-Indian communities were assessed using Accusplit AE120 pedometers over a period of 7 days during 2001-2003. Anthropometric measurements were also assessed. All data analyses were conducted in 2008. Age-adjusted Pearson correlations were used to examine the relationship between average steps per day and age and anthropometric variables. Subjects were placed in age and BMI categories (according to National Heart, Lung, and Blood Institute cut points) to examine trends in physical activity with increasing age and BMI.Results: Daily pedometer steps ranged from 1001 to 38,755. Mean step counts by age group for men were 5384 (aged 18-29 years); 5120 (aged 30-39 years); 5040 (aged 40-49 years); 4561(aged 50-59 years); 4321 (aged 60-69 years); and 3768 (aged >or=70 years) and for women, 5038 (aged 18-29 years); 5112 (aged 30-39 years); 5054 (aged 40-49 years); 4582 (aged 50-59 years); 3653 (aged 60-69 years); and 3770 (aged >or=70 years). A significant linear trend in physical activity was noted with increasing age (p=0.002 for men, p<0.0001 for women) and with increasing BMI (p=0.05 for men, p=0.04 for women).Conclusions: Objectively measured data suggest that inactivity is a problem among American-Indian adults and that a majority of American-Indian adults in the SHFS may not be meeting the minimum physical activity public health recommendations. Efforts to increase physical activity levels in this population are warranted. [ABSTRACT FROM AUTHOR]