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Abstract: Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome‐wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; β = 0.81 kg/m2 per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10−11), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10–9); genetic distances at HLA were greater than at random markers (P = 1.6 × 10–46). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10–10). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations. [ABSTRACT FROM AUTHOR]

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]

We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped > 2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P = 5.045 × 10 − 6 ) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P = 0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 ( P = 2.563 × 10 − 7 ). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels ( P = 0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was − 3.8% ( P = 8.526 × 10 − 8 ). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8. [ABSTRACT FROM AUTHOR]

Objective: The global epidemics of type 2 diabetes and obesity have been attributed to the interaction between lifestyle changes and genetic predisposition to these diseases. We compared the prevalences of type 2 diabetes and obesity in Mexican Pima Indians, presumed to have a high genetic predisposition to these diseases, to those in their non-Pima neighbors, both of whom over a 15-year period experienced a transition from a traditional to a more modern lifestyle.Research Design and Methods: Prevalence of diabetes, impaired fasting glucose, impaired glucose tolerance, and obesity in Mexican Pimas (n = 359) and non-Pima Mexicans (n = 251) were determined in 2010 using methods identical to those used in 1995.Results: During this 15-year period, age-adjusted diabetes prevalence was unchanged in Pima men (5.8% in 1995 vs. 6.1% in 2010) yet increased in non-Pima men from 0.0 to 8.6% (P < 0.05). Diabetes prevalence tended to increase in both Pima women (9.4 vs. 13.4%) and non-Pima women (4.8 vs. 9.5%). Age-adjusted prevalence of obesity increased significantly in all groups (6.6 vs. 15.7% in Pima men; 8.5 vs. 20.5% in non-Pima men; 18.9. vs 36.3% in Pima women; 29.5 vs. 42.9% in non-Pima women).Conclusions: Type 2 diabetes prevalence increased between 1995 and 2010 in non-Pima men, and to a lesser degree in women of both groups, but it did not increase in Pima men. Prevalence of obesity increased among Pimas and non-Pimas of both sexes. These changes occurred concomitantly with an environmental transition from a traditional to a more modernized lifestyle. [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]

Objective Few coding variants in genes associated with type 2 diabetes (T2D) have been identified, and the underlying physiologic mechanisms whereby susceptibility genes influence T2D risk are often unknown. The objective of this study was to identify coding variation that increases risk for T2D via an effect on a pre-diabetic trait. Methods Whole exome sequencing was done in 177 Pima Indians. Selected variants ( N = 345) were genotyped in 555 subjects characterized for body fatness, glucose disposal rates during a clamp, acute insulin response to glucose, and 2-h plasma glucose concentrations during an OGTT, and were also genotyped in up to 5,880 subjects with longitudinal measures of BMI. Variants associated with quantitative traits were assessed for association with T2D in 7,667 subjects. Results rs7238987 in CYB5A associated with body fatness ( P = 7.0 × 10−6). This SNP and a novel SNP in RNF10 also associated with maximum recorded BMI ( P = 6.2 × 10−7 and P = 7.2 × 10−4) and maximum childhood BMI z-score ( P = 5.9 × 10−4 and P = 8.5 × 10−7). The BMI increasing alleles increased the risk for T2D ( P = 0.01; OR = 1.13 [1.03-1.24] and 9.5 × 10−3; OR = 1.49 [1.10-2.02]). Conclusions CYB5A, which has a role in stearyl-CoA-desaturase activity, and RNF10, with an unknown role in weight regulating pathways, associated with adiposity and nominally increased the risk for T2D in American Indians. [ABSTRACT FROM AUTHOR]

Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499), an KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7,351 Pima Indians from 4,549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test. Statistically significant (P < 0.05) parent-of-origin effects were seen for association with type 2 diabetes for all variants. The strongest effect was seen at rs2299620 in KCNQ1; the C allele was associated with increased diabetes when maternally derived (odds ratio [OR], 1.92; P = 4.1 10-12), but not when paternally derived (OR, 0.93; P = 0.47; P 9.9 x 10-6 for difference in maternal and paternal effects). A maternally derived C allele also was associated with a 28% decrease in insulin secretion (P = 0.002). This study confirms parent-of-origin effects in the association with type 2 diabetes for variants in KLF14, MOB2, and KCNQ1. In Pima Indians, the effect of maternally derived KCNQ1 variants appears to be mediated through decreased insulin secretion and is particularly strong, accounting for 4% of the variance in liability to diabetes. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) have been used to search for susceptibility genes for type 2 diabetes and obesity in the Pima Indians, a population with a high prevalence of both diseases. In these studies, a variant (rs2025804) in the LEPR gene was nominally associated with BMI in 1,082 subjects (P = 0.03 adjusted for age, sex, birth year, and family membership). Therefore the LEPR and leptin overlapping transcript (LEPROT) genes were selected for further sequencing and genotyping in larger population-based samples for association analyses with obesity-related phenotypes. Selected variants (n = 80) spanning these genes were genotyped in a sample of full-heritage Pima Indians (n = 2,842) and several common variants including rs2025804 were nominally associated with BMI (P = 0.05-0.003 adjusted for age, sex, birth year, and family membership). Four common tag variants associated with BMI in the full-heritage Pima Indian sample were genotyped in a second sample of mixed-heritage Native Americans (n = 2,969) and three of the variants showed nominal replication (P = 0.03-0.006 adjusted as above and additionally for Indian heritage). Combining both samples provided the strongest evidence for association (adjusted P = 0.0003-0.0001). A subset of these individuals (n = 403) had been metabolically characterized for predictors of obesity and the BMI risk alleles for the variants tagged by rs2025804 were also associated with lower 24-h energy expenditure (24hEE) as assessed in a human respiratory chamber (P = 0.0007 adjusted for age, sex, fat mass, fat-free mass, activity, and family membership). We conclude that common noncoding variation in the LEPR gene is associated with higher BMI and lower energy expenditure in Native Americans. [ABSTRACT FROM AUTHOR]

Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5--20 years) and adulthood (ages 20--45 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood. Diabetes 61:250--257, 2012 [ABSTRACT FROM AUTHOR]

Abstract: Variants in the engulfment and cell motility 1 gene, ELMO1, have previously been associated with kidney disease attributed to type 2 diabetes. The Pima Indians of Arizona have high rates of diabetic nephropathy, which is strongly dependent on genetic determinants; thus, we sought to investigate the role of ELMO1 polymorphisms in mediating susceptibility to this disease in this population. Genotype distributions were compared among 141 individuals with nephropathy and 416 individuals without heavy proteinuria in a family study of 257 sibships, and 107 cases with diabetic ESRD and 108 controls with long duration diabetes and no nephropathy. We sequenced 17.4kb of ELMO1 and identified 19 variants. We genotyped 12 markers, excluding those in 100% genotypic concordance with other variants or with a minor allele frequency <0.05, plus 21 additional markers showing association with ESRD in earlier studies. In the family study, the strongest evidence for association was with rs1345365 (odds ratio [OR]=2.42 per copy of A allele [1.35–4.32]; P =0.001) and rs10951509 (OR=2.42 per copy of A allele [1.31–4.48]; P =0.002), both of which are located in intron 13 and are in strong pairwise linkage disequilibrium (r 2 =0.97). These associations were in the opposite direction from those observed in African Americans, which suggests that the relationship between diabetic kidney disease and ELMO1 variation may involve as yet undiscovered functional variants or complex interactions with other biological variables. [ABSTRACT FROM AUTHOR]

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 ∼ 10[sup -4] to 10[sup -6]) were with common variants (risk allele frequency 0.610.67). The difference in mean BMI between individuals homozygous for the major allele compared with homozygotes for the minor allele was ∼2.2 kg/m² (P = 2 x 10[sup -5] for rs3213541). These associations replicated in the separate sample of subjects from the same community (P = 5 x 10[sup -3] for rs3213541). The strongest associations (P = 4 x 10[sup -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 58:1682-1689, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--In recent genome-wide association studies, variants in CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, CDKN2B, LOC387761, and FTO were associated with risk for type 2 diabetes in Caucasians. We investigated the association of these single nucleotide polymorphisms (SNPs) and some additional tag SNPs with type 2 diabetes and related quantitative traits in Pima Indians. RESEARCH DESIGN AND METHODS--Forty-seven SNPs were genotyped in 3,501 Pima Indians informative for type 2 diabetes and BMI, among whom 370 had measures of quantitative traits. RESULTS--FTO provided the strongest evidence for replication, where SNPs were associated with type 2 diabetes (odds ratio = 1.20 per copy of the risk allele, P = 0.03) and BMI (P = 0.002). None of the other previously reported SNPs were associated with type 2 diabetes; however, associations were found between CDKAL1 and HHEXvariants and acute insulin response (AIR), where the Caucasian risk alleles for type 2 diabetes were associated with reduced insulin secretion in normoglycemic Pima Indians. Multiallelic analyses of carrying risk alleles for multiple genes showed correlations between number of risk alleles and type 2 diabetes and impaired insulin secretion in normoglycemic subjects (P = 0.006 and 0.0001 for type 2 diabetes and AIR, respectively), supporting the hypothesis that many of these genes influence diabetes risk by affecting insulin secretion. CONCLUSIONS--Variation in FTO impacts BMI, but the implicated common variants in the other genes did not confer a significant risk for type 2 diabetes in Pima Indians. However, confidence intervals for their estimated effects were consistent with the small effects reported in Caucasians, and the multiallelic "genetic risk profile" identified in Caucasians is associated with diminished early insulin secretion in Pinto Indians. Diabetes 58: 478-488, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Humans with functional variants in the melanocortin 4 receptor (MC4R) are obese, hyperphagic, and hyperinsulinemic but have been reported to have no difference in energy expenditure. RESEARCH DESIGN AND METHODS--We investigated the association of two MC4R variants, Arg165Gln (R165Q) and A insertion at nucleotide 100 (NT100), with adiposity in 3,074 full-heritage Pima Indians, a subset of whom had metabolic measures including 24-h energy expenditure (n = 252) and resting metabolic rate (RMR) (n = 364). RESULTS--Among the 3,074 subjects, 43 were heterozygous for R165Q and 14 for NT100 (frequency = 0.007 and 0.002). Mean (± SD) BMI was higher among subjects with R165Q (39.3 ± 8.6 kg/m²) or NT100 (41.2 ± 7.8) than subjects without either variant (37.1 ± 8.4) (P = 0.04 and 0.02, adjusted for age, sex, and birth year and accounting for family membership). The 24-h energy expenditure (four with NT100; three with R165Q) or RMR (six with NT100; two with R165Q) was lower in heterozygous subjects but only met statistical significance when heterozygous subjects were combined and compared with subjects without either variant: least-squares means, 2,163 kcal/24 h (95% CI 2,035-2,291) vs. 2,307 kcal/24 h (2,285-2,328), P = 0.03 for 24-h energy expenditure, and 1,617 kcal/24 h (1,499-1,734) vs. 1,754 kcal/24 h (1,736-1,772), P = 0.02 for RMR; adjusted for age, sex, fat-free mass, and fat mass). For RMR, this difference persisted, even after accounting for family membership. CONCLUSIONS--Pima Indians heterozygous for R165Q or NT100 in MC4R have higher BMIs and lower energy expenditure (by ∼140 kcal/day), indicating that lower energy expenditure was a component of the increased adiposity. Diabetes 57: 3267-3272, 2608 [ABSTRACT FROM AUTHOR]

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[sup 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. Diabetes 57:3156-3160, 2008 [ABSTRACT FROM AUTHOR]

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 ≥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 ≥ 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 ≥ 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 ≥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. [ABSTRACT FROM AUTHOR]

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 Cav2.3 Ca2+, 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. Diabetes 56:3089-3094, 2007 [ABSTRACT FROM AUTHOR]

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. Diabetes 56:3082-3088, 2007 [ABSTRACT FROM AUTHOR]

OBJECTIVE--The transition of an individual from normoglycemia to diabetes has generally been thought to involve either moderate or rapid changes in glucose over time, although few studies have analyzed these changes. We sought to determine whether a general pattern of glucose change exists in most individuals who become diabetic. RESEARCH DESIGN AND METHODS--We examined longitudinal data from Pima Indians who developed diabetes after several biennial examinations to characterize changes in 2-h plasma glucose. A distinct pattern of glucose change was apparent in the time course of most individuals, an initial linear trend followed by a steeper rise in glucose values. A model consisting of additive linear and exponential functions was hypothesized to account for this pattern and was tested for goodness of fit on 55 individuals who became diabetic after at least 10 previous examinations. RESULTS--The combined linear and exponential model provided a significantly better fit than linear or exponential models alone in 40 of the 55 cases (P < 10[sup -38]). Using this model, the timeframe over which glucose values rose suddenly was estimated, having a median time to onset of <4.5 years from the time at which the exponential effect had contributed a modest increase of 10 mg/dl to the initial linear trend. CONCLUSIONS--We conclude that there are two distinct processes affecting glucose levels in most individuals who progress to type 2 diabetes and that the rapid glucose rise identified in these people may be an important period for physiologic and preventive research. Diabetes 56:2054-2061, 2007 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The rising prevalence of obesity and high prevalence of diabetes among Pima Indians suggest that the incidence of diabetes has risen over time. We examined trends in the incidence rate of type 2 diabetes among Pima Indians between 1965 and 2003. RESEARCH DESIGN AND METHODS -- Incidence rates were computed independently in three 13-year time periods in Pima Indians aged ≥5 years. Diabetes was defined by the presence of at least one of two criteria: 1) 2-h plasma glucose concentration ≥200 mg/dl (11.1 mmol/l) or 2) hypoglycemic treatment. RESULTS -- Among 8,236 subjects without diabetes at baseline, 1,005 incident cases occurred during follow-up. Age- and sex-adjusted incidence rates of diabetes were 25.3 cases/ 1,000 patient-years (95% CI 22.5-28.0) in 1965-1977, 22.9 cases/i,000 patient years (20.0-25.8) in 1978-1990, and 23.5 cases/1,000 patient years (20.5-26.5) in 1991-2003 (P = 0.3). The incidence rate in subjects aged 5-14 years was 5.7 (1.9-17.4) times as high in the last as in the first period, but the rate declined in those aged 25-34 years (incidence rate ratio 0.6 [0.4-0.8]). Sex-adjusted prevalence increased significantly over time only in those aged 5-24 years (Ptrend < 0.0001). CONCLUSIONS -- The overall incidence of diabetes among Pima Indians remained stable over the past four decades, with a significant rise occurring only in the youth. [ABSTRACT FROM AUTHOR]

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, hill-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 = < 0.01). These findings suggest that variation within ARHGEF11 nominally increases risk of type 2 diabetes, possibly as a result of increased insulin resistance. Diabetes 56:1454-1459, 2007 [ABSTRACT FROM AUTHOR]

There is evidence that susceptibility to diabetic nephropathy has a significant genetic component. This investigation tested the hypothesis that variations in the structural or regulatory regions of the MEP1B gene are related to susceptibility to diabetic nephropathy in the Pima Indian population. The structure of the human MEP1B gene on chromosome 18 was determined by polymerase chain reaction (PCR) amplification. Samples from 154 diabetic individuals were analyzed for polymorphisms. These individuals belonged to 65 sibships with at least one sibling pair discordant for diabetic nephropathy. Approximately half of the individuals had diabetic nephropathy. Of the 154 samples, there were 91 discordant sibling pairs. Sequencing revealed 19 single nucleotide polymorphisms (SNPs) in the MEP1B gene. SNPs 1–5 were in the 5′ region upstream of the start site for transcription; SNPs 6, 7, 9, 11–15, 17, and 19 were within introns; SNPs 8, 10, 16, and 18 were in exons 4, 9, 12, and 14. SNP 18 was the only one that results in an amino acid change (proline to leucine in the cytoplasmic tail). No overall associations were found for individual SNPs. Within-family association tests found significant results for SNPs 1, 3, 4, 5, 6, 9, 11, 18, and 19 such that the more common allele was more frequently observed in those with nephropathy than in their unaffected siblings. The present study demonstrates significant within-family association for SNPs in MEP1B gene with diabetic nephropathy. These results could be explained by functional effects of one or more of these SNPs or by linkage disequilibrium with a nearby functional locus. [ABSTRACT FROM AUTHOR]

Inhibition of fatty acid synthase (FAS) induces a rapid decline in fat stores in mice, suggesting a role for this enzyme in energy homeostasis. The human FAS gene (FAS) maps to chromosome 17q25, a region previously shown to have suggestive linkage to adiposity in a genome-wide linkage scan for genetic determinants of obesity in Pima Indians. To investigate the potential role of FAS in the pathophysiology of human obesity, the FAS gene was sequenced and 13 single nucleotide polymorphisms (SNPs) were identified. Five representative SNPs were genotyped in 216 full-blooded, nondiabetic Pima Indians for association analyses. A Val1483Ile polymorphism (GTC to ATC; allele frequency of A = 0.10) was associated with percentage of body fat and 24-h substrate oxidation rates measured in a respiratory chamber. Compared with homozygotes for the Val variant, subjects with Ile/x had a lower mean percentage of body fat (30 +/- 1 vs. 33 +/- 1%, P = 0.002; adjusted for age, sex, and family membership) and a lower mean carbohydrate oxidation rate (983 +/- 41 vs. 1,094 +/- 19 kcal/day, P = 0.03), which resulted in a lower mean 24-h respiratory quotient (0.845 +/- 0.01 vs. 0.850 +/- 0.01 kcal/day, P = 0.04; both adjusted for age, sex, family membership, percentage of body fat, and energy balance). Our findings indicate that the Val1483Ile substitution in FAS is protective against obesity in Pima Indians, an effect possibly explained by the role of this gene in the regulation of substrate oxidation. [ABSTRACT FROM AUTHOR]

Studies the genetics of type 2 diabetes in the Pima Indians. Analysis of candidate genes as well as employment of genomic wide linkage scans as approaches in identifying susceptibility genes in the Indian population; Detection of functional variants in biological candidate genes; Significance of the identification of these genes for the development of therapeutic and preventative interventions for populations worldwide.

The insulin receptor substrate-1 (IRS1) is a critical element in insulin-signaling pathways, and mutations in the IRS1 gene have been reported to have a role in determining susceptibility to traits related to type 2 diabetes. In gene expression studies of tissue biopsies from nondiabetic Pima Indians, IRS1 mRNA levels were reduced in adipocytes from obese subjects compared with lean subjects, and IRS1 mRNA levels were also reduced in skeletal muscle from insulin-resistant subjects compared with insulin-sensitive subjects (all P < 0.05). Based on these expression differences and the known physiologic role of IRS1, this gene was investigated as a candidate gene for susceptibility to type 2 diabetes in Pima Indians, a population with an extremely high incidence and prevalence of type 2 diabetes. Thirteen variants were identified, and among these variants, several were in complete linkage disequilibrium. Four genotypically unique variants were further genotyped in 937 DNA samples from full-heritage Pima Indians. Three of the variants were modestly associated with type 2 diabetes (P < 0.05), one of which was additionally associated with 2-h plasma insulin and glucose as well as insulin action at physiologic and maximally stimulating insulin concentrations (all P < 0.05). The association of variants in IRS1 with type 2 diabetes and type 2 diabetes-related phenotypes and the differential expression of IRS1 in adipocytes and skeletal muscle suggest a role of this gene in the pathogenesis of type 2 diabetes in Pima Indians. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Adiponectin is a circulating protein secreted by adipocytes and is thought to have insulin-sensitizing effects. We present genetic analysis of adiponectin levels in 517 Pima Indians without diabetes (from 162 families, 750 sib-pairs). Adiponectin concentrations were heritable, with 39% of the variance of age- and sex-adjusted adiponectin potentially accounted for by additive genetic influences in this population. In genome-wide linkage analyses, suggestive linkage (logarithm of odds [LOD] = 3.0) of adiponectin adjusted for age and sex was found on chromosome 9p at 18 cM. Linkage was also present after inclusion of adiponectin concentrations of siblings with type 2 diabetes not treated pharmacologically (total siblings 582, 182 families, 860 sib-pairs: LOD = 3.5). Tentative evidence of linkage was also found on chromosomes 2 (LOD = 1.7 at 89 cM), 3 (LOD = 1.9 at 124 cM), and 10 (LOD = 1.7 at 70 cM), offering some support to findings of a previous genome-wide scan of adiponectin. Our data suggest that quantitative trait loci on chromosomes 2, 3, 9, and 10 may influence circulating adiponectin concentrations in the Pima population. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between adiponectin, a known predictor of diabetes in Pima Indians, and markers of inflammation and endothelial function in nondiabetic subjects and to assess whether these markers predict later diabetes in a case-control study within a longitudinal health study in Pima Indians.Research Design and Methods: Participants with normal glucose tolerance at baseline were selected. Case subjects (who later developed type 2 diabetes), and control subjects (n = 71 pairs) were matched for BMI, age, and sex. Adiponectin, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha, phospholipase A2 (sPLA2), soluble E-selectin (SE-selectin), soluble intracellular adhesion molecule-1, soluble vascular adhesion molecule-1, and von Willebrand factor (vWF) were measured in baseline samples.Results: Adiponectin was negatively correlated with CRP (r = -0.25, P < 0.05), IL-6 (r = -0.20, P < 0.05), sPLA2 (r = -0.22, P < 0.05), and SE-selectin (r = -0.20, P < 0.05). CRP and IL-6 did not predict diabetes. Only vWF predicted the development of diabetes (incidence rate ratio 0.67 for a 1-SD difference, 95% CI 0.41-1.00, P = 0.05), but this was not significant after adjustment for age, glucose, HbA(1c), waist circumference, and fasting insulin (hazard rate ratio 0.73, 95% CI 0.46-1.16, P = 0.18).Conclusions: Adiponectin is negatively correlated with markers of inflammation in vivo. In case and control subjects matched for BMI, with the exception of vWF, none of the inflammatory markers predicted diabetes. Adiponectin may be the link between adiposity, inflammation, and type 2 diabetes. [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]

We examined the hypothesis that imprinted genes may affect the propensity to type 2 diabetes and obesity in Pima Indians. Multipoint variance component methods were used to assess linkage of BMI (kg/m(2)) and age-adjusted diabetes to loci derived from either father (LOD(FA)) or mother (LOD(MO)) in a genome-wide scan. Tentative evidence of loci where imprinted genes might be acting was found for diabetes with maternally derived alleles on chromosomes 5 (LOD(MO) = 1.5) and 14 (LOD(MO) = 1.6). Evidence of linkage of BMI to maternally derived alleles was found on chromosome 5 (LOD(MO) = 1.7) and to paternally derived alleles on chromosome 10p (LOD(FA) = 1.7). Additional analyses of sibling pairs who were affected by diabetes and younger than 25 years of age showed an increase of sharing of maternally derived alleles on chromosome 6 (LOD(MO) = 3.0). We also examined sites of a priori interest where action of imprinted genes has been proposed in diabetes or obesity. We found no evidence of parent-specific linkage (of either diabetes or BMI) on chromosome 11p, a region that contains several imprinted genes, but observed weak evidence of linkage of diabetes to paternally derived alleles (LOD(FA) = 0.9) in the region of chromosome 6q, believed to contain an exclusively paternally expressed gene or genes that cause transient neonatal diabetes mellitus. In conclusion, we determined regions of interest on chromosomes 5, 6, and 10 where imprinted genes might be affecting the risk of type 2 diabetes or obesity in Pima Indians. [ABSTRACT FROM AUTHOR]

Objective: To examine whether the current adult guidelines for diagnosis of diabetes are applicable to youth (age <20 years).Research Design and Methods: We analyzed fasting plasma glucose (FPG) and 2-h plasma glucose (PG) in two groups of Pima Indians, youths aged 5-19 years and adults aged 20-34 years, in relation to the incidence of microvascular disease when subjects were reexamined at ages 25-39 (youths) and 40-54 (adults). Microvascular disease was defined as retinopathy or a urine protein-to-creatinine ratio > or =0.5 g.Results: An increase in the incidence of microvascular disease occurred at nearly the same level of glycemia in both groups. For youths, this increase occurred at FPG approximately 7.3 mmol/l and 2-h PG approximately 10.0 mmol/l; for adults, this increase occurred at FPG approximately 7.5 mmol/l and 2-h PG approximately 10.3 mmol/l. Sensitivity of the adult diagnostic guidelines of FPG > or =7.0 mmol/l and 2-h PG > or =11.1 mmol/l for the detection of microvascular disease was much lower (with higher specificity) in youths than in adults. Receiver operating characteristics (ROC) curve areas were lower for FPG and 2-h PG for youths, suggesting that microvascular disease was less strongly predicted by baseline glucose.Conclusion: The current adult guidelines for diagnosis of diabetes are applicable to youth, as they identify a population at high risk of microvascular complications. [ABSTRACT FROM AUTHOR]

Focuses on a study which examined the long-term effects of a self-assessed traditional or nontraditional dietary pattern on the development of type 2 diabetes in Pima Indians. Research design and methods; Results; Conclusion.

Familial aggregation of diabetic nephropathy suggests the existence of genes determining susceptibility to nephropathy in addition to those leading to diabetes. In the present study, complex segregation analysis was performed in diabetic members of Pima Indian families to determine whether familial aggregation of nephropathy in this population could reflect the action of a single major gene. Nephropathy, defined by a urinary protein-to-creatinine ratio (PCR) > or = 500 mg/g, was analyzed as a discrete trait in a class C regressive logistic model. Individuals with PCR <500 mg/g were considered unaffected. Segregation analysis was performed both for nephropathy at the last examination (prevalent cases) and for duration of diabetes at the onset of nephropathy (incident cases). The REGD program was used for the analysis of the prevalent cases and the REGTL program for the incident cases, both from the Statistical Analysis for Genetic Epidemiology package (Case Western University, Cleveland, OH). The analysis of prevalent cases included 2,107 Pima Indians from 715 nuclear families. A subset of 504 of these families containing 1,403 individuals was used in the analysis of incident cases. Analysis of prevalent cases supported the existence of a gene with a major role, in that hypotheses of no major effect and of no transmission of a major effect were rejected (P = 0.00001; P = 0.003), whereas Mendelian transmission was not rejected (P = 0.85). A dominant model provided the best fit, but a recessive model could not be rejected. The analysis of incident cases, however, did not support a major gene effect on duration of diabetes at the onset of nephropathy, and analyses of lifetime occurrence of nephropathy were inconclusive. The analysis of prevalent cases supports the hypothesis of a major genetic effect on susceptibility to diabetic nephropathy in Pima Indians, but the analysis of incident cases does not support a genetic effect on duration of diabetes at the onset of nephropathy. The discrepancy may reflect the difficulty in precisely dating onset of nephropathy. The parameters of the model derived from segregation analysis of prevalent cases may be useful in linkage studies to detect nephropathy susceptibility loci. [ABSTRACT FROM AUTHOR]

Focuses on a study which sought to investigate the mechanisms underlying the association between birth weight and type 2 diabetes in a population of Pima Indian children and adults. Research design and methods; Results; Conclusions.

Presents a study which determined whether alterations in known genes of maturity-onset diabetes of the young contribute to the development of early-onset type 2 diabetes in Pima Indians. Methodology; Results and discussion; Conclusions.

Impaired glucose regulation (impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG)) predicts all-cause and cardiovascular disease (CVD) mortality in some, but not all populations. We computed incidence rates of major ischemic ECG changes, based on Minnesota codes, in 1,878 Pima Indians and death rates from natural causes and from CVD in 2,994 Pima Indians according to five glucose regulation categories defined by current ADA criteria (normal glucose regulation (NGR), IGT alone, IFG alone, combined IGT and IFG (Combined), and diabetes (DM)). During a median follow-up of 7.67 years (range 1.03-27.6 years), 303 subjects developed major ischemic ECG changes; similarly 780 individuals died (229 from CVD) during a median follow up of 10.4 years (range 0.04-29.0 years). The age- sex-adjusted incidence of major ischemic ECG changes was higher, relative to NGR, in those with diabetes duration of ≥ 10 years. Likewise, death rates from natural causes or from CVD were similar within the nondiabetic groups, increasing only after the onset of diabetes and in association with diabetes duration (Table). After additional adjustment for body mass index, serum cholesterol, blood pressure, and smoking in a Cox proportional-hazards model, only subjects with ≥ 15 years of diabetes had higher rates of major ischemic ECG changes (hazard rate ratio (HRR)=2.05; 95% CI=1.25-3.35, relative to NGR) and subjects with diabetes duration of ≥ 5 years had increased CVD mortality (HRR=3.14, 95% CI=1.85-5.34; HRR=3.92, 95% CI=2.36-6.53 and HRR=5.75, 95% CI=3.23-10.07 for DM 5-10 years, DM 10-15 years and DM ≥ 15 years respectively, relative to NGR). The rates of major ischemic ECG changes or natural cause or CVD deaths were not elevated in Pima Indians with IGT and/or IFG. Higher rates were only seen in subjects with diabetes, particularly in those with diabetes of long duration, suggesting that increased CVD risk in this population occurs only with hyperglycemia more severe than that seen in impaired glucose regulation. [ABSTRACT FROM AUTHOR]

Presents the study "Hematocrit and the Incidence of Type 2 Diabetes in the Pima Indians." Conditions associated with insulin resistance; Aim of the study; Results of the study.

We previously completed a genome-wide association (GWA) study using the Affymetrix mapping 100k SNP chip technology to identify potential susceptibility genes for type 2 diabetes (T2D) in Pima Indians. We have recently completed a second GWA using the same 100k chips to identify genes for T2D-related quantitative traits. For the quantitative trait GWA, 615 non-diabetic (pre-diabetic) subjects were genotyped, of which 441 were full-heritage Pima Indian. These subjects had been metabolically phenotyped for measures of body composition, response to a 75 g. oral glucose tolerance test, measures of insulin-stimulated glucose disappearance rates using a hyperinsulinemic, euglycemic clamp, and acute insulin response to a 25 g. bolus of intravenous glucose as a measure of insulin secretory function. SNPs were analyzed for associations with a particular pre-diabetic Wait using both a general analysis and a within family analysis. As a means of prioritizing signals for detailed follow-up studies, we are currently focusing on SNPs that were initially found to be associated with T2D in the initial GWA and have subsequently been found to be associated with a trait that predicts T2D in the second GWA. To date, we have pursued follow-up studies on 56 SNPs that are associated with T2D at a p<0.002 and are also associated with percentage of body fat, insulin action, or acute insulin secretion at a p<0.01. A few of these SNPs map within physiologically-plausible candidate genes, such as FOXO1A, EGFR, PLCE1, ISL1, and NPYSR while the majority of the SNPs map to intergenic regions. Sequencing of positional candidate genes as well as genotyping additional SNPs for fine-mapping is ongoing. ADA-Funded Research [ABSTRACT FROM AUTHOR]

The transition of an individual from normoglycemia to diabetes has generally been thought to involve either moderate or rapid changes in glucose over time, though few studies have analyzed these changes. To address this issue, we explored the glucose trends leading to diabetes in individual Pima Indian participants in a longitudinal epidemiologic study. We identified an initial linear phase of glucose change with a subsequent additive exponential rise. The initial phase comprised individuals whose glucose levels had a distinctly positive linear trend (∼55%), those with a linear decline in glucose (∼25%), and those with erratic glucose changes (∼20%). To pursue the explorative finding, we analyzed 55 individuals with at least 10 nondiabetic biennial measurements preceding diagnosis occurring over an average length of 30 years. A composite linear and exponential model was compared by the F-ratio test for goodness-of-fit against linear and exponential models alone on each individual. The composite model had a significantly better fit than these alternative models in 40 of the 55 cases (P < 10-38). Similar findings were seen in a separate analysis of 219 individuals having 6 to 9 nondiabetic measurements prior to onset of diabetes. The timeframe over which glucose values rose suddenly was calculated from the model. From the time at which the exponential effect had contributed a modest increase of 10 mg/dl to the initial linear trend, the median time to diabetes onset was < 4.5 years. We conclude the existence of two distinct effects in glucose change leading to diabetes onset, and that an exponential rise in glucose values occurs in most of these individuals. This period of rapid glucose rise may be important for physiologic and preventive research. ADA-Funded Research [ABSTRACT FROM AUTHOR]

PIK3C3 has an important role in amino acid mediation of the mTOR signaling pathway, which is involved in several pathogenic responses including insulin resistance. Through a genome-wide association (GWA) approach using the Affymetrix Mapping 100k SNP chip technology to identify susceptibility genes for type 2 diabetes (T2DM) in Pima Indians, 3 single nucleotide polymorphisms (SNPs) (rs52911, rs10502776 and rs593248) within the PIK3C3 gene were associated with T2DM in a case-control study (300 diabetic cases and 334 non-diabetic controls). Moreover, rs10502776 was confirmed to be associated with T2DM in a large, population-based sample (N=3500) of Pima Indians (p=0.003 adjusted for age, sex, birth year and family membership). To further evaluate the potential role of PIK3C3 in T2DM, all 25 exons and 2kb of the promoter region of PIK3C3 was sequenced in 24 Pima Indian subjects. Fourteen SNPs (SNPs from sequencing as well as database SNPs positioning within intronic regions that were not sequenced) were genotyped in the same T2DM case/control subjects analyzed in the GWA as well as 394 additional non-diabetic full-heritage Pima Indians who had undergone detailed metabolic phenotyping for pre-diabetic quantitative traits. Three SNPs (2 novel intronic SNPs and rs1787173) were associated with T2DM (adjusted P=0.01-0.02). The risk alleles for the 2 novel intronic SNPs were also associated with a lower mean acute insulin response during an intravenous glucose tolerance test among 280 normal glucose tolerant full-heritage Pima Indians (adjusted p=0.02 and 0.03), suggesting that impaired insulin secretion underlie the increase in susceptibility to T2DM. The risk allele for rs1787173 was associated with a lower mean glucose uptake during a hyperinsulinemic-euglycemic clamp among 394 non-diabetic Pima Indians (adjusted p= 0.02) suggesting that impaired insulin action also contributed to the increase in T2DM. These results provide the first evidence for a role of PIK3C3 in the development of T2DM. ADA-Funded Research [ABSTRACT FROM AUTHOR]

Presents the results of a study of adiponectin and development of type 2 diabetes in the Pima Indian population. Expression of adipose tissue; Prevalence of type 2 diabetes and obesity among Pima Indians in Arizona; Results of a population assessment; Conclusion that the concentration of adiponectin was lower in cases than in controls and individuals with high concentrations of this protein were less likely to develop type 2 diabetes than those with low concentrations.

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: 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. [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]