Diabetes is more lethal in Mexicans and Mexican-Americans compared to Non-Hispanic whites.

PURPOSE: To examine the mortality risk associated with diabetes in the Mexico City Diabetes Study (MCDS) and the San Antonio Heart Study (SAHS). METHODS: Prospective cohorts conducted 1990-2007 in MCDS and 1979-2000 in SAHS. Mortality risk was examined using Cox proportional hazard models in 1402 non-Hispanic whites (NHW), 1907 U.S.-born Mexican-Americans (MA), 444 Mexican-born MA, and 2281 Mexico City residents (MCR) between the ages of 35-64. RESULTS: Age- and sex-adjusted mortality hazard ratios (HR) comparing U.S.-born MA, Mexican-born MA, and MCR to NHW were 1.09 (95% confidence interval [CI]: 0.86, 1.37), 1.23 (95% CI: 0.86, 1.76), and 0.97 (95% CI: 0.77, 1.23), respectively, in nondiabetic individuals; in contrast, mortality risk varied in diabetic individuals with respective HRs of 1.77 (95% CI: 1.20, 2.61), 1.08 (95% CI: 0.59, 1.97), and 2.27 (95% CI: 1.53, 3.35) (interaction p = .0003). Excluding Mexican-born MA and nondiabetic individuals, controlling for medication use, insulin use, fasting glucose levels, and duration of diabetes explained a significant proportion of the mortality differential (HRs relative to NHW were 1.31 [95% CI: 0.87, 1.98] in U.S.-born MA and 1.38 [95% CI: 0.89, 2.12] in MCR). CONCLUSIONS: This study provides evidence that diabetes is more lethal in U.S.-born MA and MCR than in NHW.

Two-step approach for the prediction of future type 2 diabetes risk.

OBJECTIVE: To develop a model for the prediction of type 2 diabetes mellitus (T2DM) risk on the basis of a multivariate logistic model and 1-h plasma glucose concentration (1-h PG). RESEARCH DESIGN AND METHODS: The model was developed in a cohort of 1,562 nondiabetic subjects from the San Antonio Heart Study (SAHS) and validated in 2,395 nondiabetic subjects in the Botnia Study. A risk score on the basis of anthropometric parameters, plasma glucose and lipid profile, and blood pressure was computed for each subject. Subjects with a risk score above a certain cut point were considered to represent high-risk individuals, and their 1-h PG concentration during the oral glucose tolerance test was used to further refine their future T2DM risk. RESULTS: We used the San Antonio Diabetes Prediction Model (SADPM) to generate the initial risk score. A risk-score value of 0.065 was found to be an optimal cut point for initial screening and selection of high-risk individuals. A 1-h PG concentration >140 mg/dL in high-risk individuals (whose risk score was >0.065) was the optimal cut point for identification of subjects at increased risk. The two cut points had 77.8, 77.4, and 44.8% (for the SAHS) and 75.8, 71.6, and 11.9% (for the Botnia Study) sensitivity, specificity, and positive predictive value, respectively, in the SAHS and Botnia Study. CONCLUSIONS: A two-step model, based on the combination of the SADPM and 1-h PG, is a useful tool for the identification of high-risk Mexican-American and Caucasian individuals.

The Ser(326)Cys polymorphism of 8-oxoguanine glycosylase 1 (OGG1) is associated with type 2 diabetes in Mexican Americans.

OBJECTIVE: Human 8-oxoguanine glycosylase 1 (OGG1) excises oxidatively damaged promutagenic base 8-oxoguanine, a lesion previously observed in a rat model of type 2 diabetes (T2DM). The objective of the present study is to determine whether genetic variation in OGG1 is associated with type 2 diabetes (T2DM) in a Mexican American cohort. METHODS: Ten SNPs including two tagging SNPs (rs1052133, rs2072668) across the OGG1 gene region were selected from the Hapmap database and genotyped in the entire cohort (n = 670; 29% diabetes; 39 families) by TaqMan assay. Association analyses between the SNPs and T2DM were performed using the measured genotype approach as implemented in the program SOLAR. RESULTS: Of the ten SNPs genotyped, only five were polymorphic. The minor allele frequencies of these 5 SNPs ranged from 1-38%. Of the SNPs examined for association, the Ser(326)Cys (rs1052133) exhibited significant association with T2DM (p = 0.016) after accounting for age and sex effects. Another intronic variant (rs2072668), which was in strong linkage disequilibrium (r(2) = 0.96) with Ser(326)Cys also exhibited significant association with T2DM (p = 0.031). CONCLUSIONS: These results suggest for the first time that the variants in OGG1 could influence diabetes risk in these Mexican American families and support a role for alterations of OGG1 in the pathogenesis of T2DM.

Minimal contribution of fasting hyperglycemia to the incidence of type 2 diabetes in subjects with normal 2-h plasma glucose.

OBJECTIVE To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration. RESEARCH DESIGN AND METHODS A total of 3,450 subjects with 2-h plasma glucose concentration <140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7-8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations. RESULTS In subjects with 2-h plasma glucose <140 mg/dl, the incidence of type 2 diabetes increased with increasing fasting plasma glucose (FPG) and 1-h and 2-h plasma glucose concentrations. In a multivariate logistic analysis, after adjustment for all diabetes risk factors, the FPG concentration was a strong predictor of type 2 diabetes in both the SAHS and the Botnia Study (P < 0.0001). However, when the 1-h plasma glucose, but not 2-h plasma glucose, concentration was added to the model, FPG concentration was no longer a significant predictor of type 2 diabetes in both studies (NS). When subjects were matched for the level of 1-h plasma glucose concentration, the incidence of type 2 diabetes markedly increased with the increase in 1-h plasma glucose, but the increase in FPG was not associated with a significant increase in the incidence of type 2 diabetes. CONCLUSIONS An increase in postload glycemia in the normal range is associated with an increase in the incidence of type 2 diabetes. After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes.

Pulse pressure, prehypertension, and mortality: the San Antonio heart study.

BACKGROUND: Prehypertension increases mortality risk. Pulse pressure is also associated with increased mortality. Nevertheless, the impact of pulse pressure on the relationship between prehypertension and mortality is not known in individuals who are free of diabetes and cardiovascular disease. METHODS: Cox regression analysis was used to examine mortality risk among 3,632 (97.0%) participants in the San Antonio Heart Study (age range, 25-64 years; mean follow-up, 15.2 years). Results were adjusted for age, sex, ethnicity, education, body mass index (BMI), smoking, and total cholesterol concentration. The Seventh Report of the Joint Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) categories were used for blood pressure staging: normal, <120/80 mm Hg; prehypertension, 120-139/80-89 mm Hg. RESULTS: Prehypertension prevalence was 31.6% at baseline. There were 218 deaths during the follow-up period. Prehypertension-predicted mortality (all-cause, hazard ratio (HR) 1.49 (1.12-1.99); cardiovascular, HR 1.79 (1.07-3.02)). Relative to normal blood pressure plus pulse pressure in the lower tertile, prehypertension plus pulse pressure in the upper tertile was associated with increased mortality (all-cause, HR 2.14 (1.38-3.32); cardiovascular, HR 2.47 (1.13-5.39)); however, prehypertension plus pulse pressure in the lower tertile was not significantly associated with mortality (all-cause, HR 1.19 (0.52-2.67); cardiovascular, HR 0.43 (0.05-3.40)). CONCLUSIONS: Prehypertension increases mortality risk (all-cause and cardiovascular) in individuals who are free of diabetes and cardiovascular disease. Nevertheless, this relationship is not evident in individuals with narrow pulse pressure. Therefore, pulse pressure may be a relevant measure of blood pressure for the definition of normal blood pressure.

Height, ethnicity, and the incidence of diabetes: the San Antonio Heart Study.

Mexican Americans are more obese and have more diabetes than non-Hispanic whites, but are also shorter. Height is used in some diabetes prediction models. Therefore, we examined the effect of height on the relationship between ethnicity and incident diabetes. Incident diabetes was ascertained in 1730 participants in the San Antonio Heart Study (age range, 25-64 years) after 7.4 years of follow-up. Height predicted diabetes in neither men (odds ratio [OR] x 1 SD, 1.14 [0.85-1.51]) nor women (OR x 1 SD, 0.88 [0.70-1.11]) after adjusting for age and ethnicity. The area under the receiver operating characteristic curve for predicting diabetes of a model that included waist circumference (in men, 0.775; in women, 0.781) was similar to that of models that included waist circumference + height (in men, 0.775, P = .702; in women, 0.783, P = .680) or waist-to-height ratio (in men, 0.764, P = .161; in women, 0.783, P = .619). The OR of incident diabetes according to ethnicity was lower in the model that was adjusted for the waist-to-height ratio than in the model that accounted only for waist circumference (in women, 1.45 [0.86-2.46] vs 1.84 [1.10-3.08], P < .001; in men, 2.00 [1.11-3.58] vs 2.74 [1.52-4.95], P < .001). In conclusion, the addition of height to adjust waist circumference does not increase the ability of waist circumference to predict diabetes, but may be useful in exploring differences in diabetic risk between populations of different race/ethnicity.

Evaluation of gremlin 1 (GREM1) as a candidate susceptibility gene for albuminuria-related traits in Mexican Americans with type 2 diabetes mellitus.

Several novel genes that are up-regulated in the kidney in diabetes have been identified including GREM1, which encodes gremlin 1. GREM1 maps to human chromosome 15q12, a region previously found to be linked to albumin to creatinine ratio (ACR) in Mexican Americans. The objective of this study is to investigate whether genetic variants in GREM1, a positional candidate gene, contribute to variation in ACR. By sequencing 32 individuals for both exons and 2-kilobase putative promoter region of GREM1, we identified 19 genetic variants including 5 in the promoter region and 13 in the 3' untranslated region. Of 19 polymorphisms identified, 13 polymorphisms were genotyped in the entire cohort (N = 670, 39 large families) either by restriction fragment length polymorphism or by TaqMan (Applied Biosystems, Foster City, CA) assays. Association analyses between the genotypes and ACR, type 2 diabetes mellitus, and related phenotypes were carried out using a measured genotype approach as implemented in the variance component analytical tools (SOLAR). Of the variants examined for association, none exhibited statistically significant association with ACR after accounting for the effects of covariates such as age, sex, diabetes, duration of diabetes, systolic blood pressure, and antihypertensive medications. However, 2 novel variants at the 3' untranslated region showed significant association with estimated glomerular filtration rate (P = .010 and P = .049) and body mass index (P = .013 and P = .019) after accounting for trait-specific covariate influences. Furthermore, a novel variant located in the promoter exhibited a significant association with systolic (P = .038) and diastolic blood pressure (P = .005) after adjusting for the effects of age, sex, diabetes, and antihypertensive medications. In conclusion, the variants examined at GREM1 are not significant contributors to variation in ACR in Mexican Americans, although they appear to minimally influence risk factors related to ACR.

Endothelial nitric oxide synthase (eNOS) gene polymorphisms and their association with type 2 diabetes-related traits in Mexican Americans.

Genetic variants of the endothelial nitric oxide synthase (eNOS) gene such as T-786C, Glu298Asp and 27bp-VNTR have been examined for their association with type 2 diabetes (T2DM)-related traits in various populations but not in Mexican Americans. However, the results from such studies have been controversial. This study investigated whether these three polymorphisms are associated with T2DM and its related traits in Mexican Americans, a population at high risk for T2DM and its complications. The study participants (n=670; 39 families) were genotyped for the three polymorphisms using polymerase chain reaction followed by restriction fragment length polymorphism assay. Association analyses between these polymorphisms and T2DM and its related phenotypes were carried out using a measured genotype approach as implemented in the computer program SOLAR. Of the variants examined, only the 27bp-VNTR variant exhibited significant association with high-density lipoprotein cholesterol (HDL-C) (p=0.04) and diastolic blood pressure (DBP) levels (p=0.02) after accounting for trait-specific covariates. The carriers of the rare allele (27bp-VNTR-4a) were found to have decreased HDL-C and increased DBP levels. In conclusion, of the genetic polymorphisms examined at the eNOS locus, only 27bp-VNTR appears to be a minor contributor to the variation in T2DM-related traits in Mexican Americans.

Fueling the obesity epidemic? Artificially sweetened beverage use and long-term weight gain.

We have examined the relationship between artificially sweetened beverage (ASB) consumption and long-term weight gain in the San Antonio Heart Study. From 1979 to 1988, height, weight, and ASB consumption were measured among 5,158 adult residents of San Antonio, Texas. Seven to eight years later, 3,682 participants (74% of survivors) were re-examined. Outcome measures were incidence of overweight/obesity (OW/OB(inc)) and obesity (OB(inc)) (BMI > or = 25 and > or = 30 kg/m(2), respectively), and BMI change by follow-up (DeltaBMI, kg/m(2)). A significant positive dose-response relationship emerged between baseline ASB consumption and all outcome measures, adjusted for baseline BMI and demographic/behavioral characteristics. Consuming >21 ASBs/week (vs. none) was associated with almost-doubled risk of OW/OB (odds ratio (OR) = 1.93, P = 0.007) among 1,250 baseline normal-weight (NW) individuals, and doubled risk of obesity (OR = 2.03, P = 0.0005) among 2,571 individuals with baseline BMIs <30 kg/m(2). Compared with nonusers (+1.01 kg/m(2)), DeltaBMIs were significantly higher for ASB quartiles 2-4: +1.46 (P = 0.003), +1.50 (P = 0.002), and +1.78 kg/m(2) (P < 0.0001), respectively. Overall, adjusted DeltaBMIs were 47% greater among artificial sweetener (AS) users than nonusers (+1.48 kg/m(2) vs. +1.01 kg/m(2), respectively, P < 0.0001). In separate analyses--stratified by gender; ethnicity; baseline weight category, dieting, or diabetes status; or exercise-change category--DeltaBMIs were consistently greater among AS users. These differences, though not significant among exercise increasers, or those with baseline diabetes or BMI >30 kg/m(2) (P = 0.069), were significant in all 13 remaining strata. These findings raise the question whether AS use might be fueling--rather than fighting--our escalating obesity epidemic.

Association of genetic variation in ENPP1 with obesity-related phenotypes.

Ectonucleotide pyrophosphatase phosphodiesterase (ENPP1) is a positional candidate gene at chromosome 6q23 where we previously detected strong linkage with fasting-specific plasma insulin and obesity in Mexican Americans from the San Antonio Family Diabetes Study (SAFDS). We genotyped 106 single-nucleotide polymorphisms (SNPs) within ENPP1 in all 439 subjects from the linkage study, and measured association with obesity and metabolic syndrome (MS)-related traits. Of 72 polymorphic SNPs, 24 were associated, using an additive model, with at least one of eight key metabolic traits. Three traits were associated with at least four SNPs. They were high-density lipoprotein cholesterol (HDL-C), leptin, and fasting plasma glucose (FPG). HDL-C was associated with seven SNPs, of which the two most significant P values were 0.0068 and 0.0096. All SNPs and SNP combinations were analyzed for functional contribution to the traits using the Bayesian quantitative-trait nucleotide (BQTN) approach. With this SNP-prioritization analysis, HDL-C was the most strongly associated trait in a four-SNP model (P=0.00008). After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to our previous linkage peak with MS-related traits in Mexican Americans. However, these results indicate that ENPP1 is a genetic determinant of these traits in this population, and are consistent with multiple positive association findings in independent studies in diverse human populations.

Meta-analysis of genome-wide linkage studies in BMI and obesity.

OBJECTIVE: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. RESEARCH METHODS AND PROCEDURES: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. RESULTS: Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). CONCLUSION: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.

Risk of progression to hypertension in a low-income Mexican population with prehypertension and normal blood pressure.

BACKGROUND: Blood pressure (BP) levels below the prehypertensive category may be associated with the risk of developing hypertension. We estimated the incidence rates of hypertension in a low-income Mexican population according to several subcategories of baseline BP within normal and prehypertensive categories. METHODS: In total, 1572 nonhypertensive men (n = 632) and nonpregnant women (n = 940), aged 35 to 64 years at baseline, were followed for a median of 5.8 years. Hypertension was defined as systolic blood pressure (SBP) >or=140 mm Hg, diastolic blood pressure (DBP) >or=90 mm Hg, or a self-reported physician's diagnosis with antihypertensive medications. RESULTS: During follow-up, 267 subjects developed hypertension, of whom 83 were men and 184 were women. The age-adjusted incidence rate was higher in women (37.1 per 1000 person-years) than in men (23.7 per 1000 person-years). There was a significant association between BP levels at baseline and incidence of hypertension, even within the normal category. For the upper levels of normal SBP (110 to 119 mm Hg), the hazards ratio (HR) was 2.43 (95% confidence interval [CI], 1.50 to 3.93) in women and 2.44 (95% CI, 1.05 to 5.69) in men, compared with SBP <110 mm Hg. For the upper levels of normal DBP (70 to 79 mm Hg), the HR was 2.33 (95% CI, 1.65 to 3.31) in women and 1.80 (95% CI, 0.92 to 3.52) in men, compared with DBP <70 mm Hg, after adjustment for recognized predictors. CONCLUSIONS: A high risk for the incidence of hypertension was associated with levels of BP, even within the normal category. This information could help define a population at high risk of progression to hypertension, to establish preventive measures.

Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans.

OBJECTIVE: Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed linkage analysis to localize genes that influence GFR using estimated GFR data from the San Antonio Family Diabetes/Gallbladder Study. We also examined the effect of genotype by diabetes interaction (G x DM) on the detection of linkage to address whether genetic effects on GFR differ in diabetic and nondiabetic subjects. RESEARCH DESIGN AND METHODS: GFR (N = 453) was estimated using the recently recalculated Cockcroft-Gault (GFR-CGc) and the simplified Modification of Diet in Renal Disease (GFR-4VMDRD) formulae. Both estimates of GFR exhibited significant heritabilities, but only GFR-CGc showed significant G x DM interaction. We therefore performed multipoint linkage analyses on both GFR measures using models that did not include G x DM interaction effects (Model 1) and that included G x DM interaction effects (Model 2, in the case of GFR-CGc). RESULTS: The strongest evidence for linkage (Model 1) of both GFR-CGc (logarithm of odds [LOD] 2.9) and GFR-4VMDRD (LOD 2.6) occurred between markers D9S922 and D9S1120 on chromosome 9q. However, using Model 2, the strongest evidence for linkage of GFR-CGc on chromosome 2q was found near marker D2S427 (corrected LOD score [LOD(C)] 3.3) compared with the LOD score of 2.7 based on Model 1. Potential linkages (LOD or LOD(C) >or=1.2) were found only for GFR-CGc on chromosomes 3p, 3q, 4p, 8q, 11q, and 14q. CONCLUSIONS: We found a major locus on chromosome 2q that differentially influences GFR in diabetic and nondiabetic environments in the Mexican-American population.

Carotid intima-media thickness in confirmed prehypertensive subjects: predictors and progression.

OBJECTIVE: The purpose of this study was to test whether carotid intima-media thickness (IMT) is already increased in normotensive subjects who progress to hypertension (confirmed prehypertensives) independently of known determinants of vessel wall thickness. METHODS AND RESULTS: Common carotid artery (CCA) far-wall IMT was measured (B-mode ultrasound) in 1536 subjects from the population-based Mexico City Diabetes Study at baseline and 3.5 years later. In the 136 confirmed prehypertensives, CCA-IMT (720 [253] microm, median[interquartile range]) was intermediate between normotensives (615 [140] microm) and hypertensives (725 [215] microm). After multiadjusting for gender, age, BMI, blood pressure, total cholesterol, antihypertensive therapy, and diabetes, converter status was independently associated with a higher CCA-IMT (+93+/-14 microm). At follow-up, CCA-IMT increased by 35 [180] microm. Gender, age, blood pressure, and presence of diabetes, but not the converter status, were significant independent predictors of CCA-IMT progression. In a model adjusting for gender, age, blood pressure (level, status and treatment), diabetes status, total and HDL-cholesterol, the G variant of the 45T/G polymorphism of the adiponectin gene was associated with a hazard ratio of 1.45 (95% CI: 1.04 to 2.01) of a baseline CCA-IMT in the top quintile. CONCLUSIONS: In confirmed prehypertensives, CCA-IMT is increased independently of blood pressure and known determinants of wall thickness, but short-term CCA-IMT progression is not accelerated.

The metabolic syndrome and the impact of diabetes on coronary heart disease mortality in women and men: the San Antonio Heart Study.

PURPOSE: An explanation for the differential impact of diabetes on coronary heart disease (CHD) mortality in men and women is that diabetes and cardiovascular disease (CVD) share a common antecedent that differentially affects men and women. In the San Antonio Heart Study we examined the relationship between gender, the metabolic syndrome defined by the National Cholesterol Education Program (NCEP-MetS) and diabetes and their ability to predict CHD mortality. METHODS: Over 15.5 years, 4996 men and women 25 to 64 years of age experienced 254 cardiovascular deaths, including 121 from CHD (International Classification of Diseases, Ninth Revision codes 410-414). RESULTS: At baseline, NCEP-MetS occurred more often in men than in women among those with normal glucose levels (12.3% vs. 9.7%, p < 0.05), but less often in men than in women among those with diabetes (65.7% vs. 74.4%, p < 0.05). Adjusted for age, ethnic group, and a history of CVD, relative to women with neither diabetes nor NCEP-MetS, women with both had a 14-fold (hazard ratio [HR] = 14.3 [95% confidence interval: 6.62, 30.7]) increased risk of CHD mortality, whereas men had only a 4-fold (HR = 4.21 (95% confidence interval: 2.32, 7.65]) increased risk, respectively. CONCLUSION: When diabetes occurred with NCEP-MetS, gender was a strong modifier of the joint effect of diabetes and NCEP-MetS on CHD mortality.

Which obesity index best explains prevalence differences in type 2 diabetes mellitus?

OBJECTIVE: Obesity drives the diabetes epidemic. However, it is not known which obesity index best explains variations in type 2 diabetes mellitus prevalence across populations. RESEARCH METHODS AND PROCEDURES: We analyzed three cross-sectional studies from San Antonio, TX, (Mexican-Americans and non-Hispanic whites, n = 2839), Mexico City (n = 2233), and Spain (n = 2161) (age range, 35 to 64 years). We used the area under the receiver operating characteristic curve (AUC) to assess performance for identifying diabetic subjects and logistic regression analysis to examine differences in diabetes prevalence. RESULTS: AUCs for waist circumference and BMI were similar in white subjects, but the AUC for waist circumference was greater in Mexican-origin subjects (Mexican men, 0.594 vs. 0.549, p = 0.008; and women, 0.605 vs. 0.557, p = 0.002; Mexican-American men, 0.648 vs. 0.600, p < 0.001; and women, 0.744 vs. 0.693, p < 0.001). The AUC for waist-to-height ratio tended to be greater than that for waist circumference, but statistical significance was demonstrated only in Mexican women (0.628 vs. 0.613, p = 0.044), Mexican-American women (0.774 vs. 0.758, p < 0.001), and Spanish women (0.734 vs. 0.715, p = 0.039). No obesity index was consistently superior to the others for explaining differences in diabetes prevalence among populations. CONCLUSIONS: In white and Mexican-origin men, waist circumference may be the preferred marker for identifying diabetic subjects on account of its simplicity; in women, waist-to-height ratio may be better. Differences in diabetes prevalence among these populations cannot be attributed to a single measure of obesity.

SORCS1: a novel human type 2 diabetes susceptibility gene suggested by the mouse.

OBJECTIVE: A small number of susceptibility genes for human type 2 diabetes have been identified by candidate gene analysis or positional cloning. Genes found to influence diabetes or related traits in mice are likely to be susceptibility genes in humans. SorCS1 is the gene identified as responsible for the mouse chromosome 19 T2dm2 quantitative trait locus for fasting insulin levels, acting via impaired insulin secretion and increased islet disruption in obese females. Genes that impair compensatory insulin secretion in response to obesity-induced insulin resistance may be particularly relevant to human diabetes. Thus, we sought to determine whether variation in the human SORCS1 gene was associated with diabetes-related traits. RESEARCH DESIGN AND METHODS: We assessed the contribution of variation in SORCS1 to human insulin-related traits in two distinct Mexican-American cohorts. One cohort (the Mexican-American Coronary Artery Disease [MACAD] cohort) consisted of nondiabetic individuals, allowing assessment of genetic association with subclinical intermediate insulin-related traits; the second cohort (the San Antonio Family Diabetes Study [SAFADS]) contained individuals with diabetes, allowing association analyses with overt disease. RESULTS: We first found association of SORCS1 single nucleotide polymorphisms and haplotypes with fasting insulin levels and insulin secretion in the MACAD cohort. Similar to our results in the mice, the genetic association was strongest in overweight women. We then observed association with diabetes risk and age at diagnosis in women of the SAFADS cohort. CONCLUSIONS: Identification of SORCS1 as a novel gene affecting insulin secretion and diabetes risk is likely to provide important insight into the biology of obesity-induced type 2 diabetes.