Search

Pima Indians living in Arizona have a high prevalence of obesity, and we have previously shown that a relatively lower energy expenditure (EE) predicts weight and fat mass gain in this population. EE is a familial trait (heritability = 0.52); therefore, in the current study, we aimed to identify genetic variants that affect EE and thereby influence BMI and body fatness in Pima Indians. Genotypic data from 491,265 variants were analyzed for association with resting metabolic rate (RMR) and 24-h EE assessed in a whole-room calorimeter in 507 and 419 Pima Indians, respectively. Variants associated with both measures of EE were analyzed for association with maximum BMI and percent body fat (PFAT) in 5,870 and 912 Pima Indians, respectively. rs11014566 nominally associated with both measures of EE and both measures of adiposity in Pima Indians, where the G allele (frequency: Pima Indians = 0.60, Europeans <0.01) associated with lower 24-h EE (β = -33 kcal/day per copy), lower RMR (β = -31 kcal/day), higher BMI (β = +0.6 kg/m2), and higher PFAT (β = +0.9%). However, the association of rs11014566 with BMI did not directionally replicate when assessed in other ethnic groups. rs11014566 tags rs144895904, which affected promoter function in an in vitro luciferase assay. These variants map to GPR158, which is highly expressed in the brain and interacts with two other genes (RGS7 and CACNA1B) known to affect obesity in knockout mice. Our results suggest that common ethnic-specific variation in GPR158 may influence EE; however, its role in weight gain remains controversial, as it either had no association with BMI or associated with BMI but in the opposite direction in other ethnic groups. [ABSTRACT FROM AUTHOR]

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]

Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However, there was a strong interaction with BMI (P = 5.1 × 10(-7)) such that the diabetes association was stronger in leaner individuals. rs75493593 was also strongly associated with BMI in individuals with type 2 diabetes (P = 3.4 × 10(-15)) but not in individuals without diabetes (P = 0.77). Longitudinal analyses suggest that this is due, in part, to an association of the A allele with greater weight loss following diabetes onset (P = 0.02). Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with expression of the nearby RNASEK gene, suggesting that RNASEK expression may mediate the effect of genotype on diabetes. [ABSTRACT FROM AUTHOR]

Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the β-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population. [ABSTRACT FROM AUTHOR]

Insulin receptor substrate (IRS)-2 plays an important role in insulin signaling and its disruption results in diabetes in mice. In humans, the IRS-2 Gly1057Asp substitution was associated with lower risk of type 2 diabetes in lean individuals, but with a higher risk in obese individuals. To clarify the role of IRS-2 on the development of type 2 diabetes and obesity in Pima Indians, and particularly to investigate whether the effects of the Gly1057Asp polymorphism on metabolism are mediated by obesity, molecular scanning of the gene for mutations was performed and interaction of the polymorphism with obesity was tested. We identified the previously described Gly1057Asp mutation as well as a rare Asp819His mutation and four silent polymorphisms. The effect of the Gly1057Asp mutation on type 2 diabetes and obesity was tested in a large cohort of Pima Indians (n = 998). A subgroup of nondiabetic full-heritage Pima Indians (n = 233) had measurements of body composition, glucose tolerance, insulin action (M), endogenous glucose production (EGP; hyperinsulinemic clamp), acute insulin response (AIR, 25-g intravenous glucose tolerance test, n = 118 normal glucose-tolerant subjects), and percutaneous fat biopsy specimens from the periumbilical region (n = 160). A total of 132 nondiabetic subjects were included in longitudinal analyses. The frequency of the Asp1057 allele was 0.6. In cross-sectional analyses, subjects homozygous for the Asp1057 allele (Asp/Asp) had a higher prevalence of type 2 diabetes than heterozygote individuals and subjects homozygous for the Gly1057 allele (X/Gly, P = 0.04). There was no effect on BMI (P = 0.78) or gene-BMI interaction on the prevalence of type 2 diabetes (P = 0.57). In the nondiabetic subgroup, subjects with Asp/Asp had higher percent body fat (P = 0.01), BMI (P = 0.02), and waist circumference (P = 0.004), but there was no difference in metabolic characteristics (all P > 0.2). However, the relationship between percent body fat and fasting glucose, basal EGP, EGP during the clamp, AIR, and subcutaneous abdominal adipocyte size was significantly different in the Asp/Asp group (P for interaction = 0.02, 0.06, 0.0007, 0.08, and 0.006, respectively) compared with the X/Gly group, suggesting a more detrimental effect of Asp homozygosity on these traits with increasing percent body fat. In longitudinal analyses, among subjects in the upper tertile of change in percent body fat, those with Asp/Asp had a larger increase in fasting and postprandial glycemia and basal EGP and a larger decrease in M and AIR than subjects with X/Gly, independent of change in obesity (all P < 0.05). In conclusion, our findings suggest that the association of homozygosity for the Asp1057 allele in IRS-2 with type 2 diabetes in Pima Indians may be mediated by interaction of the polymorphism with obesity on several diabetes-related traits. [ABSTRACT FROM AUTHOR]

The KCNJ10 gene is located within a region on chromosome 1q linked to type 2 diabetes in the Pima Indians and six other populations. We therefore investigated this gene as a potential type 2 diabetes candidate gene in Pima Indians. KCNJ10 consists of two exons, spans approximately 33 kb, and we identified eight single-nucleotide polymorphisms (SNPs), including one (SNP2) in the coding region leading to a Glu359Lys substitution. Association studies were carried out in a case-control group composed of 149 affected and 150 unaffected Pimas, and the linkage analysis was performed in a linkage set of 1,338 Pimas. SNP1 in the promoter and SNP2 in the intron, which were in a complete linkage disequilibrium, and SNP5 in the 3' untranslated region showed association with diabetes in the case-control group (P = 0.02 and P = 0.01, respectively). When genotyped in the linkage set, only the KCNJ10-SNP1 variant showed a modest association with type 2 diabetes (P = 0.01). KCNJ10-SNP1 is in a strong linkage disquilibrium with SNP14 of the adjacent KCNJ9 locus, which we previously found to be associated with type 2 diabetes. After adjustment for KCNJ10-SNP1, the original linkage score at this locus was marginally reduced from 3.1 to 2.9. We conclude that these variants in KCNJ10 are unlikely to be the cause of linkage of type 2 diabetes with 1q in Pima Indians. [ABSTRACT FROM AUTHOR]

Objective: Physical activity and insulin sensitivity are related in epidemiological studies, but the consistency of this finding among populations that greatly differ in body size is uncertain. The present multiethnic epidemiological study examined whether physical activity was related to insulin concentrations in two populations at high risk for diabetes that greatly differ by location, ethnic group, and BMI.Research Design and Methods: The study populations consisted of 2,321 nondiabetic Pima Indian men and women aged 15-59 years from Arizona and 2,716 nondiabetic men and women aged 35-54 years from Mauritius. Insulin sensitivity was estimated by mean insulin concentration (average of the fasting and postload insulin), and total (i.e., leisure and occupational) physical activity was assessed by questionnaire.Results: Pima men and women who were more active had significantly (P < 0.05) lower mean insulin concentrations than those less active (BMI and age-adjusted means were 179 vs. 200 and 237 vs. 268 pmol/l). Similar findings were noted in Mauritian men and women (94 vs. 122 and 127 vs. 148 pmol/l). In both populations, activity remained significantly associated with mean insulin concentration controlled for age, BMI, waist-to-thigh or waist-to-hip ratio, and mean glucose concentrations.Conclusions: Physical activity was negatively associated with insulin concentrations both in the Pima Indians, who tend to be overweight, and in Mauritians, who are leaner. These findings suggest a beneficial role of activity on insulin sensitivity that is separate from any influence of activity on body composition. [ABSTRACT FROM AUTHOR]

Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone. [ABSTRACT FROM AUTHOR]

Examines the role of paternal inheritance in the association between type two diabetes and low birth weight of children in Arizona. Risks of diabetic fathers on offsprings; Comparison on the influences between maternal and paternal diabetes to children; Insulin mechanisms influencing birth weight.

Examines the relation between birth weight and the prevalence of diabetes in Pima Indians in Arizona. Nutritional factors reducing infant growth; Risk factors for the development of diabetes; Relationship between diabetes and obesity.

Background: In type 2 diabetes (T2DM), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimated glomerular filtration rate (eGFR) systematically underestimates the measured adjusted glomerular filtration rate (aGFR) when aGFR is high. We studied the extent to which glycemic variables associate with kidney function, and developed equations including these variables that estimate aGFR in people with T2DM.Methods: Diabetic Pima people had aGFR measured from iothalamate clearance divided by body surface area. eGFRs < 60 ml/min/1.73m2 were excluded. Multivariate linear regression identified variables correlated with kidney function. We constructed equations for approximating aGFR. Correlation analysis and 10-fold cross-validation were used to compare the CKD-EPI equation and the new approximating equations to the measured aGFR. Ability to detect hyperfiltration, defined as aGFR > 120 ml/min/1.73m2, was compared by analysis of receiver-operating (ROC) curves.Results: aGFR was measured 2798 times in 269 individuals. HbA1c, fasting plasma glucose (FPG), age, and serum creatinine (SCR) were significantly associated with aGFR. The best equations for approximating aGFR used HbA1c and FPG in addition to age and SCR. They approximate aGFR in this cohort of obese people with T2DM more precisely than the CKD-EPI equation. Analysis of ROC curves show that these equations detect hyperfiltration better than does the CKD-EPI equation.Conclusions: HbA1c, FPG, age, and SCR yielded the best equations for estimating aGFR in these subjects. The new equations identify hyperfiltration better than the CKD-EPI equation in this cohort and may inform clinical decisions regarding hyperfiltration in individuals with T2DM. [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]

Most genetic variants associated with adult height have been identified through large genome-wide association studies (GWASs) in European-ancestry cohorts. However, it is unclear how these variants influence linear growth during adolescence. This study uses anthropometric and genotypic data from a longitudinal study conducted in an American Indian community in Arizona between 1965-2007. Growth parameters (i.e. height, velocity, and timing of growth spurt) were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, in 787 participants with height measurements spanning the whole period of growth. Heritability estimates suggested that genetic factors could explain 25% to 71% of the variance of pubertal growth traits. We performed a GWAS of growth parameters, testing their associations with 5 077 595 imputed or directly genotyped variants. Six variants associated with height at peak velocity (P < 5 × 10-8, adjusted for sex, birth year and principal components). Implicated genes include NUDT3, previously associated with adult height, and PACSIN1. Two novel variants associated with duration of growth spurt (P < 5 × 10-8) in LOC105375344, an uncharacterized gene with unknown function. We finally examined the association of growth parameters with a polygenic score for height derived from 9557 single nucleotide polymorphisms (SNPs) identified in the GIANT meta-analysis for which genotypic data were available for the American Indian study population. Height polygenic score was correlated with the magnitude and velocity of height growth that occurred before and at the peak of the adolescent growth spurt, indicating overlapping genetic architecture, with no influence on the timing of adolescent growth., (Published by Oxford University Press 2024.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Aims/hypothesis: The aim of this work was to examine the associations of average weight and weight velocity in three growth periods from birth through adolescence with type 2 diabetes incidence., Methods: Child participants were selected from a 43 year longitudinal study of American Indians to represent three growth periods: pre-adolescence (birth to ~8 years); early adolescence (~8 to ~13 years); and late adolescence (~13 to ~18 years). Age-, sex- and height-standardised weight z score mean and weight z score velocity (change/year) were computed for each period. Participants were followed for up to 25 years from the end of each growth period until they developed diabetes. Associations of weight z score mean or weight z score velocity with diabetes incidence were determined with sex-, birth date- and maternal diabetes-adjusted Poisson regression models., Results: Among 2100 participants representing the pre-adolescence growth period, 1558 representing the early adolescence period and 1418 representing the late adolescence period, there were 290, 315 and 380 incident diabetes cases, respectively. During the first 10 years of follow-up, the diabetes incidence rate ratio (95% CI) was 1.72 (1.40, 2.11)/SD of log 10 weight z score mean in pre-adolescence, 2.09 (1.68, 2.60)/SD of log 10 weight z score mean in early adolescence and 1.85 (1.58, 2.17)/SD of log 10 weight z score mean in late adolescence. The diabetes incidence rate ratio (95% CI) was 1.79 (1.49, 2.17)/SD of log 10 weight z score velocity in pre-adolescence, 1.13 (0.91, 1.41)/SD of log 10 weight z score velocity in early adolescence and 1.29 (1.09, 1.51)/SD of log 10 weight z score velocity in late adolescence. There were strong correlations in the weight z score means and weak correlations in the weight z score velocities between successive periods., Conclusions/interpretation: Higher weight and accelerated weight gain in all growth periods associate with increased type 2 diabetes risk. Importantly, higher weight and greater weight velocity during pre-adolescence jointly associate with the highest type 2 diabetes risk. Graphical abstract.

Six rare functional coding mutations were previously identified in melanocortin 4 receptor (MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity. Fifty-six tag single-nucleotide polymorphisms (SNPs) were genotyped in 3,229 full-heritage Pima Indians, and nine of these SNPs which showed evidence for association were genotyped in additional 3,852 mixed-heritage American Indians. Associations of SNPs with maximum body mass index (BMI) in adulthood (n = 5,918), BMI z score in childhood (n = 5,350), percent body fat (n = 864), energy expenditure (n = 358) and ad libitum food intake (n = 178) were assessed. Conditional analyses demonstrated that SNPs, rs74861148 and rs483125, were independently associated with BMI in adulthood (β = 0.68 kg/m(2) per risk allele, p = 5 × 10(-5); β = 0.58 kg/m(2), p = 0.002, respectively) and BMI z score in childhood (β = 0.05, p = 0.02; β = 0.07, p = 0.01, respectively). One haplotype (frequency = 0.35) of the G allele at rs74861148 and the A allele at rs483125 provided the strongest evidence for association with adult BMI (β = 0.89 kg/m(2), p = 5.5 × 10(-7)), and was also associated with childhood BMI z score (β = 0.08, p = 0.001). In addition, a promoter SNP rs11872992 was nominally associated with adult BMI (β = 0.61 kg/m(2), p = 0.05) and childhood BMI z score (β = 0.11, p = 0.01), where the risk allele also modestly decreased transcription in vitro by 12 % (p = 0.005). This risk allele was further associated with increased percent body fat (β = 2.2 %, p = 0.002), increased food intake (β = 676 kcal/day, p = 0.007) and decreased energy expenditure (β = -53.4 kcal/day, p = 0.054). Common and rare variation in MC4R contributes to obesity in American Indians.

Background: We compared values of baseline serum cystatin C (SCysC), serum creatinine (SCr), and measured glomerular filtration rate (mGFR) for predicting end-stage renal disease (ESRD) in patients with type 2 diabetes and elevated albuminuria., Study Design: Observational longitudinal study., Setting & Participants: Pima Indians with type 2 diabetes and elevated albumin-creatinine ratio (ACR ≥30 mg/g)., Predictors: Baseline SCysC, SCr, and mGFR., Outcomes & Measurements: Individuals were followed up from their first examination with diabetes and ACR ≥30 mg/g until December 2010, onset of ESRD, or death, whichever came first. Incidence rates adjusted for age and sex were computed by Mantel-Haenszel stratification. The abilities of SCysC, SCr, and mGFR values to predict ESRD were compared with receiver operating characteristic curves., Results: Of 234 Pima Indians with a mean age of 42.8 years who were followed up for a median of 10.7 (range, 0.6-21.3) years, 68 (29%) developed ESRD. The incidence of ESRD was significantly higher in patients in the lowest versus highest tertile of 1/SCysC (incidence rate ratio, 2.43; 95% CI, 1.31-4.50). By contrast, mGFR and 1/SCr had J-shaped associations with ESRD. In unadjusted analyses, 1/SCysC had the highest area under the receiver operating characteristic curve (AUROC; 0.719 ± 0.035) and mGFR had the lowest (0.585 ± 0.042; P < 0.001); the AUROC for 1/SCr was intermediate (0.672 ± 0.040; P = 0.1 and P = 0.03 vs 1/SCysC and mGFR, respectively). In analyses adjusted for age, sex, diabetes duration, height, weight, hemoglobin A1c level, and ACR, 1/SCysC had the highest AUROC (0.845 ± 0.026). Models with mGFR or 1/SCr alone had similar AUROCs (P = 0.9) and both were lower than the model with 1/SCysC alone (P = 0.02 and P = 0.03, respectively)., Limitations: The predictive values of the filtration markers are limited to the extent that their precision is based on a single measurement., Conclusions: SCysC level was a better predictor of ESRD than mGFR or SCr level in Pima Indians with type 2 diabetes and elevated albuminuria., (Published by Elsevier Inc.)

Genetic variation in SIRT1 affects obesity-related phenotypes in several populations. The purpose of this study was to determine whether variation in SIRT1 affects susceptibility to obesity or type 2 diabetes in Pima Indians, a population with very high prevalence and incidence rates of these diseases. Genotypic data from single nucleotide polymorphisms (SNPs) identified by sequencing regions of SIRT1 combined with SNPs in/near SIRT1 from a prior genome-wide association study determined that 4 tag SNPs (rs7895833, rs10509291, rs7896005, and rs4746720) could capture information across this gene and its adjacent 5' region. The tag SNPs were genotyped in a population-based sample of 3501 Pima Indians (44% had diabetes, 58% female) for association with type 2 diabetes and BMI. Metabolic trait data and adipose biopsies were available on a subset of these subjects. Two tag SNPs, rs10509291 and rs7896005, were nominally associated with type 2 diabetes (P=0.01, OR=1.25 95%CI 1.05-1.48, and P=0.02, OR=1.17 95%CI 1.02-1.34, respectively; additive P values adjusted for age, sex, birth year, and family membership), but not BMI (adjusted P values 0.52 and 0.45, respectively). Among metabolically characterized subjects with normal glucose tolerance (N=243), those carrying the diabetes risk allele (T) for rs10509291 and (G) for rs7896005 had a reduced acute insulin response (AIR) to an intravenous glucose bolus (adjusted P=0.045 and 0.035, respectively). SIRT1 expression in adipose biopsies was negatively correlated with BMI (adjusted P=0.00001). We conclude that variation in SIRT1 is nominally associated with reduced AIR and increased risk for type 2 diabetes. SIRT1 expression in adipose is correlated with BMI, but it remains unknown whether this is a cause or consequence of obesity., (Published by Elsevier Inc.)

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 > or =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., (Published by Elsevier Ireland Ltd.)

Objective: To examine the prognostic significance of elevated albuminuria in youth with type 2 diabetes., Patients and Methods: Cross-sectional and prospective studies were conducted on Pima Indian youth aged 5 to 19 years at baseline who were examined between July 1, 1982, and December 31, 2007. Prevalence and sequential changes in the level of microalbuminuria (30 < or = albumin-to-creatinine ratio [ACR] < 300 mg/g) and macroalbuminuria (ACR > or = 300 mg/g) and incidence of macroalbuminuria were computed according to the presence or absence of type 2 diabetes., Results: The prevalence of microalbuminuria and macroalbuminuria was 6.5% and 0.6% in the 3856 nondiabetic youth and 18.5% and 2.9% in the 103 youth with diabetes, respectively. One hundred forty-one of 187 (75.4%) nondiabetic youth, but only 1 of 14 (7.1%) diabetic youth with an elevated ACR (> or =30 mg/g) regressed to an undetectable or normal ACR (<30 mg/g) on subsequent examination. In a subset of 2666 youth with a median follow-up of 8.1 years, 36 nondiabetic and 30 diabetic youth with baseline ACRs of <300 mg/g developed macroalbuminuria. For a given ACR, the incidence of macroalbuminuria was 15.9-fold (95% confidence interval: 11.1-22.6) higher in the diabetic than in the nondiabetic youth., Conclusions: Elevated albuminuria is infrequent and largely transient in nondiabetic youth, but it is relatively frequent and largely persistent in those with diabetes. Microalbuminuria in youth with type 2 diabetes strongly predicts progression to macroalbuminuria, which supports annual screening for albuminuria.

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.

Objective: Haploinsufficiency of SIM1 is a cause of rare monogenic obesity. To assess the role of SIM1 in polygenic obesity, this gene was analyzed in the Pima Indian population, which has a high prevalence of obesity., Research Design and Methods: SIM1 was sequenced in 96 individuals. Variants (n = 46) were genotyped in a population-based sample of 3,250 full-heritage Pima Indians and in a separate replication sample of 2,944 predominately non-full-heritage subjects from the same community., Results: Variants spanning the upstream region of SIM1 through intron 8 were associated with BMI in the full-heritage Pima Indians, where the strongest associations (P approximately 10(-4) to 10(-6)) were with common variants (risk allele frequency 0.61-0.67). The difference in mean BMI between individuals homozygous for the major allele compared with homozygotes for the minor allele was approximately 2.2 kg/m(2) (P = 2 x 10(-5) for rs3213541). These associations replicated in the separate sample of subjects from the same community (P = 5 x 10(-3) for rs3213541). The strongest associations (P = 4 x 10(-7), controlled for age, sex, birth year, and heritage) were seen in the combined sample (n = 6,194). The risk allele for obesity was more common in full-heritage Pimas than in the mixed-heritage subjects. Two variants (rs3734353 and rs3213541) were also genotyped in 1,275 severely obese and 1,395 lean control subjects of French European ancestry. The Pima risk alleles were the minor alleles in the European samples, and these variants did not display any significant association (P > 0.05)., Conclusions: Common variation in SIM1 is associated with BMI on a population level in Pima Indians where the risk allele is the major allele.

Diabetes affects American Indians disproportionately compared with other racial/ethnic groups in the United States and is almost exclusively type 2 diabetes. Much of our knowledge about diabetes in American Indians comes from studies in a few tribes. The most extensively studied American Indians are the Pima Indians from the Gila River Indian Community in Arizona, who participated in a longitudinal study of diabetes and its complications between 1965 and 2007. They have one of the highest reported incidence and prevalence of type 2 diabetes in the world, and kidney disease attributable to diabetes is a major cause of morbidity and mortality. In this article, we examine the course, determinants, and trends of diabetic kidney disease in American Indians, with special emphasis on studies conducted in the Pima Indians. We also review therapeutic strategies for managing diabetic kidney disease.

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.

Objective: A prior genome-wide association (GWA) study in Pima Indians identified variants within PCLO that were associated with early-onset type 2 diabetes. PCLO encodes a presynaptic cytomatrix protein that functions as a Ca(2+) sensor that may be involved in insulin secretion and/or insulin action. Therefore, PCLO was analyzed as a candidate gene for type 2 diabetes., Research Design and Methods: Sequencing of PCLO identified four nonsynonymous variants and a 10-amino acid insertion. These variants, together with 100 additional variants identified by sequencing or chosen from databases, were genotyped for association analysis in the same 895 subjects analyzed in the prior GWA study (300 case subjects with diabetes onset at aged <25 years, 334 nondiabetic control subjects aged >45 years, and 261 discordant siblings of the case or control subjects for within-family analyses), as well as 415 nondiabetic Pima Indians who had been metabolically phenotyped for predictors of diabetes. Selected variants were further genotyped in a population-based sample of 3,501 Pima Indians., Results: Four variants were modestly associated with early-onset type 2 diabetes in both general and within-family analyses (P = 0.004-0.04, recessive model), where the diabetes risk allele was also nominally associated with a lower insulin-mediated glucose disposal rate (P = 0.009-0.14, recessive model) in nondiabetic Pima Indians. However, their association with diabetes in the population-based sample was weaker (P = 0.02-0.20, recessive model)., Conclusions: Variation within PCLO may have a modest effect on early-onset type 2 diabetes, possibly as a result of reduced insulin action, but has minimal, if any, impact on population-based risk for type 2 diabetes.

Objective: To evaluate whether impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are associated with increased risk of mortality and prevalent ischemic heart disease (IHD) and to analyze if the increased risk of death is dependent on subsequent development of diabetes in Pima Indians., Research Design and Methods: A total of 2,993 Pima Indians aged >or=35 years were included. Prevalent IHD, defined by major ischemic electrocardiogram changes, was evaluated according to the following glucose/diabetes categories: normal glucose regulation (NGR), IFG and/or IGT, and diabetic groups by duration. During a median follow-up of 10.4 years, 780 subjects died from natural causes and 156 of these died from IHD. Mortality was analyzed according to the same glucose/diabetes categories at baseline and then as time-dependent variables., Results: Only subjects with diabetes >or=15 years of duration have a higher prevalence of IHD (odds ratio 1.9 [95% CI 1.4-2.5]) relative to NGR. In baseline and time-dependent models, age- and sex-adjusted death rates from natural causes and from IHD were similar among the nondiabetic groups. Among diabetic subjects, natural mortality was higher in those with >or=15 years diabetes duration (death rate ratio [DRR] relative to NGR = 2.6 [95% CI 2.1-3.3]). IHD mortality was higher in subjects with long diabetes duration (DRR for diabetes 10-15 years = 3.8 [1.5-9.5]; DRR for diabetes >or=15 years = 8.6 [3.8-19.4]) in the time-dependent model., Conclusions: Natural and IHD mortality are not increased in Pima Indians with IFG and/or IGT. Only after the onset of diabetes do the rates of these events increase relative to NGR.

Objective: Optimal prevention of young-onset type 2 diabetes requires identification of the early-life modifiable risk factors. We aimed to do this using longitudinal data in 1,604 5- to 19-year-old initially nondiabetic American Indians., Research Design and Methods: For type 2 diabetes prediction, we derived an optimally weighted, continuously distributed, standardized multivariate score (zMS) comprising commonly measured metabolic, anthropometric, and vascular traits (i.e., fasting and 2-h glucose, A1C, BMI, waist circumference, fasting insulin, HDL cholesterol, triglycerides, and blood pressures) and compared the predictive power for each feature against zMS., Results: In separate Cox proportional hazard models, adjusted for age, sex, and ethnicity, zMS and each of its component risk factors were associated with incident type 2 diabetes. Stepwise proportional hazards models selected fasting glucose, 2-h glucose, HDL cholesterol, and BMI as independent diabetes predictors; individually, these were weaker predictors than zMS (P < 0.01). However, a parsimonious summary score combining only these variables had predictive power similar to that of zMS (P = 0.33). Although intrauterine diabetes exposure or parental history of young-onset diabetes increased a child's absolute risk of developing diabetes, the magnitude of the diabetes-risk relationships for zMS and the parsimonious score were similar irrespective of familial risk factors., Conclusions: We have determined the relative value of the features of the metabolic syndrome in childhood for the prediction of subsequent type 2 diabetes. Our findings suggest that strategies targeting obesity, dysregulated glucose homeostasis, and low HDL cholesterol during childhood and adolescence may have the most success in preventing diabetes.

Objective: The transcription factor 7-like 2 (TCF7L2) gene was initially reported to be associated with type 2 diabetes in Icelandic, Danish, and U.S. populations. We investigated whether TCF7L2 also has a role in type 2 diabetes susceptibility in Pima Indians., Research Design and Methods: The six variants reported to be associated with type 2 diabetes in the Icelandic study were genotyped in a population-based sample of 3,501 Pima Indians (1,561 subjects had type 2 diabetes, and 1,940 did not have diabetes). In addition, the coding and promoter regions of TCF7L2 were sequenced in 24 Pima subjects. The one variant identified by sequencing, 35 additional database variants positioned in introns, and the six variants reported in the Icelandic study were genotyped in Pima families to determine the haplotype structure of TCF7L2 among Pima Indians. Fourteen representative variants were selected and genotyped in 3,501 Pima Indians., Results: The six variants initially reported to be associated with type 2 diabetes were less common in Pima Indians compared with samples of European origin, and none were associated with type 2 diabetes. One representative variant, rs1225404, was nominally associated with type 2 diabetes in a general model (additive P = 0.03, dominant P = 0.005) but not in a within-family analysis (additive P = 0.2, dominant P = 0.07). However, several variants were associated with BMI; in particular, rs12255372 was associated in both general and within-family analyses (both P = 0.0007). Modest associations were also found with traits predictive for type 2 diabetes., Conclusions: Variation within TCF7L2 does not confer major risk for type 2 diabetes among the Pima Indian population.

Objective: To identify genetic variants in linkage disequilibrium with those conferring diabetes susceptibility, a genome-wide association study for young-onset diabetes was conducted in an American-Indian population., Research Design and Methods: Data come from 300 case subjects with type 2 diabetes with age of onset <25 years and 334 nondiabetic control subjects aged >or=45 years. To provide for tests of within-family association, 121 nondiabetic siblings of case subjects were included along with 140 diabetic siblings of control subjects (172 sibships). Individuals were genotyped on the Affymetrix 100K array, resulting in 80,044 usable single nucleotide polymorphisms (SNPs). SNPs were analyzed for within-family association and for general association in case and control subjects, and these tests were combined by Fisher's method, with priority given to the within-family test., Results: There were more SNPs with low P values than expected theoretically under the global null hypothesis of no association, and 128 SNPs had evidence for association at P < 0.001. The association of these SNPs with diabetes was further investigated in 1,207 diabetic and 1,627 nondiabetic individuals from the population study who were not included in the genome-wide study. SNPs from 10 genomic regions showed evidence for replication at P < 0.05. These included SNPs on chromosome 3 near ZNF659, chromosome 11 near FANCF, chromosome 11 near ZBTB15, and chromosome 12 near SENP1., Conclusions: These studies suggest several regions where marker alleles are potentially in linkage disequilibrium with variants that confer susceptibility to young-onset type 2 diabetes in American Indians.

Objective: Linkage to type 2 diabetes has been reported on chromosome 1q21-25 in Pima Indians. Fine mapping identified single nucleotide polymorphisms (SNPs) near the CACNA1E gene associated with this disease. CACNA1E encodes the voltage-dependent calcium channel Ca(v)2.3 Ca(2+), and mice lacking this channel exhibit impaired glucose tolerance and insulin secretion. Therefore, CACNA1E was investigated as a positional candidate gene., Research Design and Methods: CACNA1E was sequenced, and 28 SNPs were genotyped in the same group of Pima subjects who had been analyzed in the linkage study. Allele-specific expression was used to functionally evaluate a variant in the 3' untranslated region (UTR)., Results: A novel G/A variant in the 3'-UTR was associated with young-onset type 2 diabetes (odds ratio 2.09 per copy of the G-allele [95% CI 1.31-3.33], adjusted P = 0.001) and had an effect on the evidence for linkage at chromosome 1q21-25 (P = 0.004). Among 372 nondiabetic Pima subjects who had undergone metabolic testing, the risk allele was associated with reduced insulin action including increased fasting, 30, 60, and 120 min plasma glucose concentrations and increased fasting plasma insulin during an oral glucose tolerance test (all P < 0.01), as well as a decreased rate of insulin-stimulated glucose disposal at both physiologically and maximally stimulated insulin concentrations (both P < 0.002). Functional analysis of this variant showed that the nonrisk allele had a 2.3-fold higher expression compared with the risk allele., Conclusions: A functional variant in CACNA1E contributes to type 2 diabetes susceptibility by affecting insulin action. This variant partially explains the linkage to type 2 diabetes on chromosome 1q21-25 in Pima Indians.

A prior genome-wide linkage scan in Pima Indians indicated a young-onset (aged <45 years) type 2 diabetes susceptibility locus on chromosome 1q21-q23. ARHGEF11, which encodes the Rho guanine nucleotide exchange factor 11, was analyzed as a positional candidate gene for this linkage because this protein may stimulate Rho-dependent signals, such as the insulin signaling cascade. The ARHGEF11 gene, and two adjacent genes NTRK1 and INSRR, were sequenced in 24 Pima Indians who were not first-degree relatives. Sequencing of the coding regions, 5' and 3' untranslated regions and putative promoter regions of these genes, identified 28 variants in ARHGEF11, 11 variants in NTRK1, and 8 variants in INSSR. These 47 variants, as well as 84 additional public database variants within/between these genes, were genotyped for association analysis in the same group of Pima Indians who had participated in the linkage study (n = 1,228). An R1467H in ARHGEF11, and several additional noncoding variants that were in high linkage disequilibrium with this variant, were nominally associated with young-onset type 2 diabetes (P = 0.01; odds ratio 3.39) after adjusting for sex, family membership, and Pima heritage. The risk allele H had a frequency of 0.10. In a subgroup of 262 nondiabetic, full-heritage Pima Indians who had undergone detailed metabolic testing, the risk allele H also was associated with a lower mean insulin-mediated glucose disposal rate and a lower mean nonoxidative glucose storage rate after adjusting for age, sex, nuclear family membership, and percentage of body fat (P < or = 0.01). These findings suggest that variation within ARHGEF11 nominally increases risk of type 2 diabetes, possibly as a result of increased insulin resistance.

Hyperglycemia and long duration of diabetes are widely recognized risk factors for diabetic retinopathy, but inherited susceptibility may also play a role because retinopathy aggregates in families. A genome-wide linkage analysis was conducted in 211 sibships in which > or =2 siblings had diabetes and retinal photographs were available from a longitudinal study. These sibships were a subset of 322 sibships who had participated in a previous linkage study of diabetes and related traits; they comprised 607 diabetic individuals in 725 sibpairs. Retinal photographs were graded for presence and severity of diabetic retinopathy according to a modification of the Airlie House classification system. The grade for the worse eye was adjusted for age, sex, and diabetes duration and analyzed as a quantitative trait. Heritability of diabetic retinopathy in this group was 18% (95% CI 2-36). A genome-wide linkage analysis using variance components modeling found evidence of linkage on chromosome 1p. Using single-point analysis, the peak logarithm of odds (LOD) was 3.1 for marker D1S3669 (34.2 cM), whereas with multipoint analysis the peak LOD was 2.58 at 35 cM. No other areas of suggestive linkage were found. We propose that an area on chromosome 1 may harbor a gene or genes conferring susceptibility to diabetic retinopathy.

To identify genetic variants contributing to end-stage renal disease (ESRD) in type 2 diabetes, we performed a genome-wide analysis of 115,352 single nucleotide polymorphisms (SNPs) in pools of 105 unrelated case subjects with ESRD and 102 unrelated control subjects who have had type 2 diabetes for > or =10 years without macroalbuminuria. Using a sliding window statistic of ranked SNPs, we identified a 200-kb region on 8q24 harboring three SNPs showing substantial differences in allelic frequency between case and control pools. These SNPs were genotyped in individuals comprising each pool, and strong evidence for association was found with rs2720709 (P = 0.000021; odds ratio 2.57 [95% CI 1.66-3.96]), which is located in the plasmacytoma variant translocation gene PVT1. We sequenced all exons, exon-intron boundaries, and the promoter of PVT1 and identified 47 variants, 11 of which represented nonredundant markers with minor allele frequency > or =0.05. We subsequently genotyped these 11 variants and an additional 87 SNPs identified through public databases in 319-kb flanking rs2720709 ( approximately 1 SNP/3.5 kb); 23 markers were associated with ESRD at P < 0.01. The strongest evidence for association was found for rs2648875 (P = 0.0000018; 2.97 [1.90-4.65]), which maps to intron 8 of PVT1. Together, these results suggest that PVT1 may contribute to ESRD susceptibility in diabetes.

Objective: To assess the role of homocysteine as a risk factor for mortality in diabetic subjects., Methods: Homocysteine, vitamin B(12), and folate concentrations were measured in stored sera of 396 diabetic Pima Indians aged > or = 40 years when examined between 1982 and 1985. Vital status was assessed through 2001., Results and Conclusions: Over a median follow-up of 15.7 years, there were 221 deaths-76 were due to cardiovascular disease (CVD), 36 to diabetes/nephropathy and 34 to infections. Homocysteine was positively associated with mortality from all causes (hazard rate ratio (HRR) for highest versus lowest tertile of homocysteine = 1.70, 95% confidence interval (CI) 1.18-2.46), from diabetes/nephropathy (HRR = 2.39, 95% CI 0.94-6.11) and from infectious diseases (HRR = 3.39, 95% CI 1.19-9.70), but not from CVD (HRR = 1.16, 95% CI 0.62-2.17) after adjustment for age, sex and diabetes duration. Homocysteine correlated with serum creatinine (r = 0.50), and the relationships with mortality rates were not significant after adjustment for creatinine. Vitamin B(12) was positively associated with all-cause mortality (HRR for 100 pg/mL difference adjusted for age, sex and diabetes duration = 1.15, 95% CI 1.08-1.22) and death from diabetes/nephropathy (HRR = 1.27, 95% CI 1.10-1.46). The association between homocysteine and mortality in type 2 diabetes is not causal, but is confounded by renal disease in Pima Indians., ((c) 2007 John Wiley & Sons, Ltd.)

Diminished insulin sensitivity is a characteristic feature of type 2 diabetes. Inhibition of insulin action, resulting in reduced skeletal muscle glucose uptake, is mediated in part through stimulation of RhoA activity. One regulator of RhoA activity is leukemia-associated Rho guanine nucleotide exchange factor (LARG). The LARG gene maps to a region on chromosome 11q23-24 that shows genetic linkage to BMI and type 2 diabetes in Pima Indians. Because of its role in RhoA activation, the LARG gene was analyzed as a positional candidate gene for this linkage. Sequencing of the LARG gene and genotyping of variants identified several polymorphisms that were associated with in vivo rates of insulin-mediated glucose uptake, at both physiological and maximally stimulating insulin concentrations, among 322 nondiabetic Pima Indians who had undergone a hyperinsulinemic-euglycemic clamp. The strongest association with rate of glucose uptake was found with a Tyr1306Cys polymorphism (P < 0.0001, adjusted for age, sex, percent body fat, and nuclear family membership). In transient transfection studies in NIH3T3 cells, the LARG(Cys1306) protein had reduced activity compared with LARG(Tyr1306) protein (P < 0.05). We propose that the Tyr1306Cys substitution in LARG, through its differential activation of RhoA, increases insulin sensitivity in nondiabetic Pima Indians.

Peptide YY (PYY) and Y2 receptor (Y2R) may be important in the central regulation of body weight and food intake. To determine whether genetic variation in PYY and/or Y2R may contribute to morbid obesity in humans, these genes were sequenced in 83 extremely obese Pima Indians (BMI > or = 50 kg/m2). Sequencing of PYY identified three single nucleotide polymorphisms (SNPs) in the untranslated region. Sequencing of the Y2R coding region identified one missense (Ala172Thr) substitution and two silent substitutions. Eight additional SNPs in the 5' untranslated region of Y2R were identified from public databases. These SNPs were genotyped in 489 full-heritage adult Pimas (362 severely obese and 127 nondiabetic, nonobese subjects), who are not first-degree relatives, for association analysis. The PYY variants were not associated with obesity, whereas four variants from two haplotype blocks in Y2R were marginally associated (P = 0.054-0.067) with obesity. However, if the analysis was restricted to men (n = 167, 100 obese and 67 lean), the PYY variants and two SNPs in Y2R that were in complete linkage disequilibrium were significantly associated with severe obesity (P = 0.001 and P = 0.002, respectively). Our data suggest that the PYY-Y2R pathway may influence body weight through a sex-specific mechanism, but this finding requires confirmation in other populations.

Objective: Periodontal disease may contribute to the increased mortality associated with diabetes., Research Design and Methods: In a prospective longitudinal study of 628 subjects aged > or =35 years, we examined the effect of periodontal disease on overall and cardiovascular disease mortality in Pima Indians with type 2 diabetes. Periodontal abnormality was classified as no or mild, moderate, and severe, based on panoramic radiographs and clinical dental examinations., Results: During a median follow-up of 11 years (range 0.3-16), 204 subjects died. The age- and sex-adjusted death rates for all natural causes expressed as the number of deaths per 1,000 person-years of follow-up were 3.7 (95% CI 0.7-6.6) for no or mild periodontal disease, 19.6 (10.7-28.5) for moderate periodontal disease, and 28.4 (22.3-34.6) for severe periodontal disease. Periodontal disease predicted deaths from ischemic heart disease (IHD) (P trend = 0.04) and diabetic nephropathy (P trend < 0.01). Death rates from other causes were not associated with periodontal disease. After adjustment for age, sex, duration of diabetes, HbA1c, macroalbuminuria, BMI, serum cholesterol concentration, hypertension, electrocardiographic abnormalities, and current smoking in a proportional hazards model, subjects with severe periodontal disease had 3.2 times the risk (95% CI 1.1-9.3) of cardiorenal mortality (IHD and diabetic nephropathy combined) compared with the reference group (no or mild periodontal disease and moderate periodontal disease combined)., Conclusions: Periodontal disease is a strong predictor of mortality from IHD and diabetic nephropathy in Pima Indians with type 2 diabetes. The effect of periodontal disease is in addition to the effects of traditional risk factors for these diseases.

Adiponectin is an abundant adipose tissue-derived protein with important metabolic effects. Plasma adiponectin levels are decreased in obese individuals, and low adiponectin levels predict insulin resistance and type 2 diabetes. Two variants in the adiponectin gene ACDC have been previously associated with plasma adiponectin levels, obesity, insulin resistance, and type 2 diabetes. To determine the role of genetic variation in ACDC in susceptibility to obesity and type 2 diabetes in Pima Indians, we screened the promoter, exons, and exon-intron boundaries of the gene to identify allelic variants. We identified 17 informative polymorphisms that comprised four common (minor allele frequency >15%) linkage disequilibrium clusters consisting of 1-4 variants each. We genotyped one representative polymorphism from each cluster in 1,338 individuals and assessed genotypic association with type 2 diabetes, BMI, serum lipid levels, serum adiponectin levels, and measures of insulin sensitivity and secretion. None of the ACDC variants were associated with type 2 diabetes, BMI, or measures of insulin sensitivity or secretion. One variant, single nucleotide polymorphism (SNP)-12823, was associated with serum adiponectin levels (P = 0.002), but this association explained only 2% of the variance of serum adiponectin levels. Our findings suggest that these common ACDC polymorphisms do not play a major role in susceptibility to obesity or type 2 diabetes in this population.

11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a candidate gene for hypertension, diabetes, and obesity through altered glucocorticoid production. This study explored the association of 11betaHSD1 gene variants with diabetes, hypertension, and obesity in a longitudinal population study of American Indians (N=918; exams=5508). In multivariate mixed models assuming an additive effect of genotype, a 5' upstream variant (rs846910) was associated with blood pressure (diastolic blood pressure beta=1.58 mm Hg per copy of the A allele, P=0.0008; systolic blood pressure beta=2.28 mm Hg per copy of the A allele, P=0.004; mean arterial blood pressure beta=1.83 mm Hg per copy of the A allele, P=0.0006) and hypertension (odds ratio=1.27 per copy of the A allele, P=0.02). However, birth date modified these associations (test for interaction: diastolic blood pressure P=0.16; systolic blood pressure P=0.007; mean arterial blood pressure P=0.01), such that the magnitude and direction of association between genotype and blood pressure changed with time. Finally, in models controlling for potential confounding by population stratification, we observed evidence of within-family effects for blood pressure (diastolic blood pressure beta=1.77 mm Hg per copy of the A allele, P=0.004; systolic blood pressure beta=2.04 mm Hg per copy of the A allele, P=0.07; mean arterial blood pressure beta=1.85 mm Hg per copy of the A allele, P=0.01) and for hypertension (odds ratio=1.26 per copy of the A allele; P=0.08). No association was observed for obesity. Associations with diabetes were similar in magnitude as reported previously but were not statistically significant. These data demonstrate association between genetic variability at 11betaHSD1 with hypertension, but these effects are modified by environmental factors.

This study, examining the longitudinal relation among physical activity, body mass index, and development of type 2 diabetes in a high-risk population, is unique because diabetes was determined by oral glucose tolerance testing rather than by self-report. A physical activity questionnaire assessing past year leisure and occupational activity was administered to 1,728 nondiabetic Pima individuals aged 15-59 years as part of a series of clinic examinations in the Gila River Indian Community from 1987 to 2000. During an average follow-up period of 6 years, 346 subjects developed diabetes. Using time-dependent Cox proportional hazards modeling adjusting for age, the authors found that total activity was related to diabetes incidence in women and men (p < 0.05 in women only). After additional adjustment for body mass index, the relation between activity and diabetes incidence was weakened in both men and women. When the age-adjusted diabetes incidence rates were examined by levels of activity stratified by tertile of body mass index, the diabetes incidence rate remained lower in more active than in less active men and women from all body mass index groups, with the exception of the middle body mass index tertile in men (p < 0.05 in women only). These results suggest that the adoption and maintenance of a physically active lifestyle can play a significant role in preventing type 2 diabetes.

Objective: To determine whether measures of physical activity are related to an insulin sensitivity index ([ISI] 10(4)/fasting insulin x glucose) independent of weight or adiposity in children., Research Design and Methods: We conducted a longitudinal study of 90 Pima Indian children (39 boys and 51 girls) at 5 and 10 years of age measuring adiposity (dual-energy X-ray absorptiometry), physical activity behavior (questionnaire: number of activities per week [ACT], average hours per week [TIME]), and energy expenditure (doubly labeled water: physical activity level [PAL])., Results: In cross-sectional analyses, ACT was correlated with ISI at 5 years of age (r = 0.24, P = 0.02) and at 10 years of age (r = 0.21, P = 0.05), but these relationships were not independent of weight or adiposity. PAL was correlated with ISI at 10 years of age (r = 0.39, P = 0.03) but was not independent of weight or adiposity. Longitudinally, ISI decreased from 5 to 10 years of age, and increases in weight and adiposity were associated with decreases in ISI (r = -0.51 and -0.41, respectively; both P < 0.0001). ACT decreased from 5 to 10 years of age, but children who had smaller decreases in ACT had smaller decreases in ISI, independent of increases in weight or adiposity (partial r = 0.22, P = 0.04 adjusted for either weight or adiposity)., Conclusions: These data suggest that early establishment and maintenance of an active lifestyle can have a beneficial effect on ISI that is partially independent of changes in weight or adiposity. This is particularly relevant considering the current epidemics of both obesity and type 2 diabetes in children.

Objective: To investigate which anthropometric measurements of obesity best predict type 2 diabetes in a population of Pima Indians and whether additional information on diabetes risk could be obtained by combining measures of general obesity with measures of body fat distribution., Research Design and Methods: We conducted a prospective study of 624 men and 990 nonpregnant women >18 years of age without diabetes. Subjects were followed a mean of 5.25 years for the development of type 2 diabetes (using 1997 American Diabetes Association criteria)., Results: A total of 322 new cases of type 2 diabetes (107 men and 215 women) were diagnosed during follow-up. Baseline obesity measurements were highly correlated and predicted diabetes in proportional hazards models adjusted for age. BMI had the highest hazard ratio in men and women, with age-adjusted hazard ratios per SD of 1.73 (95% CI 1.44-2.07) and 1.67 (1.45-1.91), respectively. According to receiver-operating characteristic analysis, BMI and waist-to-height ratio were the best predictors of diabetes in men, while in women BMI, waist-to-height ratio, waist circumference, and waist-to-thigh ratio were the best predictors. The predictive abilities of models containing BMI were not significantly improved by including other measures of general obesity or measures of the body fat distribution., Conclusions: Throughout its range, BMI was an excellent predictor of type 2 diabetes risk in Pima Indians and was not significantly improved by combining it with other measures of general adiposity or body fat distribution.

Objective: To examine incidence and progression of retinopathy using retinal photographs in Pima Indians and to compare the results with those obtained when retinopathy is assessed by direct ophthalmoscopy., Research Design and Methods: We undertook an analysis of examinations conducted between 1 April 1982 and 31 December 1990 in residents of the Gila River Community in central Arizona. Data were taken from 411 people with diabetes who had at least two examinations during this period. Incidence and progression of retinopathy were evaluated by retinal photography and fundoscopy, and hazard rate ratios were calculated for various potential risk factors measured at baseline., Results: Previously diagnosed retinopathy tended to progress, except in individuals with minimal nonproliferative retinopathy, among whom follow-up examinations were more likely to show no retinopathy. Diabetes duration (hazard rate ratio [HRR], 1.06 per year difference [P = 0.007]), hyperglycemia (HbA(1) HRR, 1.27 per 1% difference [P < 0.0001]), the type of treatment for diabetes (insulin use HRR, 3.06 [P = 0.0007], and oral hypoglycemic use HRR, 2.40 [P = 0.0034], compared with individuals on no pharmacotherapy), and macroalbuminuria (HRR, 2.86, compared with individuals without macroalbuminuria [P = 0.0486]) were associated with the development of retinopathy. Although fundoscopy detected fewer cases of retinopathy, HRRs for most risk factors were similar when retinopathy was assessed by fundoscopy rather than retinal photography., Conclusions: Although retinopathy tends to worsen over time, some eyes show improvement, especially in patients with minimal nonproliferative retinopathy. As in other populations, glycemic control is the major modifiable risk factor for the development and progression of retinopathy.

Adiponectin is a collagen-like circulating protein secreted by adipocytes that is proposed to mediate obesity-related resistance to insulin. In a case-control series, we assessed the role of adiponectin in later development of type 2 diabetes in 70 patients who later developed type 2 diabetes and 70 controls, matched for body-mass index, age, and sex. Cases and controls were taken from the longitudinal study of health in the Pima Indian population. At baseline, the concentration of adiponectin was lower in cases than in controls (p=0.01) and individuals with high concentrations of this protein were less likely to develop type 2 diabetes than those with low concentrations (incidence rate ratio 0.63 [95% CI 0.43-0.92]; p=0.02).

Objective: To determine the period of childhood in which weight relative to height increases in Pima Indian children and young adults in comparison with the general US population., Methods: Heights and weights of children in the Pima Indian population were derived from either clinical examinations conducted by the Department of Public Health Nursing (from 1-48 months of age), or from examinations in the National Institutes of Health longitudinal survey of health in the Pima population (for birth and ages 5-20 years), and compared with standards for the US population recently published by the National Center for Health Statistics., Results: Weight relative to height (weight-for-length in children aged <24 months, body mass index at ages > or =2 years) was significantly higher in Pima children at all ages examined after the first month of life. Compared with reference values, the most dramatic increases in weight relative to height occurred in 2 stages of childhood: mean z scores of weight-for-length increased between 1 month (mean +/- SEM: males: -0.2 +/- 0.19; females: -0.02 +/- 0.14) and 6 months (males: 0.8 +/- 0.04; females: 0.7 +/- 0.04) of age; mean z scores for body mass index increased gradually between 2 years (males: 0.4 +/- 0.06; females: 0.4 +/- 0.08) and 11 years (males: 1.4 +/- 0.08; females: 1.4 +/- 0.08) and remained stable thereafter., Conclusion: Excessive weight gain occurs early in the Pima population with changes relative to reference values most marked in the first 6 months of life and between 2 and 11 years. Interventions toward primary prevention of obesity may need to be targeted at children rather than adults in this population.