Insulin sensitivity and insulin clearance are heritable and have strong genetic correlation in Mexican Americans.

OBJECTIVE: The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium is described, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI). METHODS: GUARDIAN is comprised of seven cohorts, consisting of 4,336 Mexican-American individuals in 1,346 pedigrees. Insulin sensitivity (SI ), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3,925 individuals) using variance components. RESULTS: Across studies, age, and gender-adjusted heritability of insulin sensitivity (SI , M, M/I) ranged from 0.23 to 0.48 and of MCRI from 0.35 to 0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and -0.57 to -0.59 for AIRg and MCRI (all P < 0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P < 0.0001); and -0.16 to -0.36 for AIRg and MCRI (P < 0.0001-0.06). CONCLUSIONS: These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.

Exploring differences in adiposity in two U.S. Hispanic populations of Mexican origin using social, behavioral, physiologic and genetic markers: the IRAS Family Study.

OBJECTIVE: The census classification of Hispanic origin is used in epidemiological studies to group individuals, even though there is geographical, cultural, and genetic diversity within Hispanic Americans of purportedly similar backgrounds. We observed differences in our measures of adiposity between our two Mexican American populations, and examined whether these differences were attributed to social, behavioral, physiologic or genetic differences between the two populations. RESEARCH DESIGN AND METHODS: In the IRAS Family Study, we examined 478 Hispanics from San Antonio, Texas and 447 Hispanics from the San Luis Valley, Colorado. Associations with body mass index (BMI), visceral adipose tissue area (VAT), and subcutaneous adipose tissue area (SAT) using social, behavioral, physiologic and genetic variables were examined. RESULTS: Hispanics of Mexican origin in our clinic population in San Antonio had significantly higher mean BMI (31.09 vs. 28.35 kg/m2), VAT (126.3 vs. 105.5 cm2), and SAT (391.6 vs. 336.9 cm2), than Hispanics of Mexican origin in the San Luis Valley. The amount of variation in adiposity explained by clinic population was 4.5% for BMI, 2.8% for VAT, and 2.7% for SAT. After adjustment, clinic population was no longer associated with VAT and SAT, but remained associated with BMI, although the amount of variation explained by population was substantially less (1.0% for BMI). CONCLUSION: Adiposity differences within this population of Mexican origin can be largely explained by social, behavioral, physiologic and genetic differences.

Insulin resistance and excess risk of diabetes in Mexican-Americans: the San Antonio Heart Study.

CONTEXT: Mexican-Americans have more diabetes than non-Hispanic whites, but the extent to which insulin resistance and insulin secretion explain the ethnic difference is unknown. OBJECTIVE: We analyzed selected indices of insulin resistance and secretion for both the ethnic difference and predictive discrimination. DESIGN AND SETTING: The San Antonio Heart Study is a longitudinal population-based study with a follow-up period of 7.5 yr. PARTICIPANTS: A total of 1540 nondiabetic individuals aged 25-64 yr were enrolled from January 1984 to December 1988. INTERVENTIONS: Homeostasis model assessment (HOMA) of insulin resistance and secretion were estimated by available formulas (HOMA-IR and HOMA ß-cell) and computer program (HOMA2S and HOMA2B). Matsuda index and insulinogenic index from 0 to 30 and 0 to 120 min (ΔI0-30/ΔG0-30 and ΔI0-120/ΔG0-120) were also calculated. MAIN OUTCOME MEASURE: Incident diabetes was defined by the 2003 American Diabetes Association criteria. RESULTS: Incident diabetes was in excess in Mexican-Americans [odds ratio 2.26 (95% confidence interval, 1.53-3.34)]. Matsuda index explained a larger proportion of the ethnic difference than did HOMA-IR (49.2 vs. 31.0%; P<0.001). The ethnic difference was not explained by measures of insulin secretion. Matsuda index and ΔI0-30/ΔG0-30 had a better predictive discrimination than their HOMA equivalents and ΔI0-120/ΔG0-120. HOMA estimates by the computer program offered no advantage over simple formulas for HOMA. CONCLUSIONS: Insulin resistance accounts for a large and significant proportion of the excess risk of diabetes in Mexican-Americans. Matsuda index is better than HOMA-IR for both explaining the ethnic difference and predicting diabetes.

Association of abdominal adiposity with diabetes and cardiovascular disease in Latin America.

The authors explored whether the waist circumference (WC) cutoffs currently proposed to define abdominal obesity (AO) are associated with diabetes and cardiovascular disease (CVD) in Latin America. Primary care physicians in 12 countries were randomly chosen to measure WC and body mass index and record the presence of diabetes and CVD in all consecutive adult patients, consulting them on 2 prespecified half-days. Overall, 70% of 9719 men, and 76% of 18,526 women had AO. Diabetes was reported in 10% of men and 9% of women and CVD in 9% of men and 7% of women. AO was significantly related with diabetes (age-adjusted odds ratio, 1.63 for men and 2.86 for women) and with CVD (odds ratio, 1.41 for men and 1.62 for women). Obesity was also significantly related with diabetes and CVD. Strikingly, abdominal adiposity was very frequent in women with normal body mass index, suggesting that an evidence-based definition of abdominal adiposity in Latin America is needed.

Evidence of interaction between PPARG2 and HNF4A contributing to variation in insulin sensitivity in Mexican Americans.

OBJECTIVE: We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes-related quantitative traits in Mexican-American families of a proband with previous gestational diabetes. RESEARCH DESIGN AND METHODS: The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests. RESULTS: Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes-related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (S(I)) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher S(I) compared with individuals with at least one G allele. S(I) did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for S(I) was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher S(I) compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401). CONCLUSIONS: Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes.

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.

Geographic variations of the International Diabetes Federation and the National Cholesterol Education Program-Adult Treatment Panel III definitions of the metabolic syndrome in nondiabetic subjects.

OBJECTIVE: We have carried out international comparisons of the metabolic syndrome using the International Diabetes Federation (IDF) and National Cholesterol Education Program-Adult Treatment Panel III (ATP III) definitions. This analysis could help to discern the applicability of these definitions across populations. RESEARCH DESIGN AND METHODS: Nondiabetic subjects aged 35-64 years were eligible for analysis in population-based studies from San Antonio (Mexican Americans and non-Hispanic whites, n = 2,473), Mexico City (n = 1,990), Spain (n = 2,540), and Peru (n = 346). Kappa statistics examined the agreement between metabolic syndrome definitions. RESULTS: Because of the lower cutoff points for elevated waist circumference, the IDF definition of the metabolic syndrome generated greater prevalence estimates than the ATP III definition. Prevalence difference between definitions was more significant in Mexican-origin and Peruvian men than in Europid men from San Antonio and Spain because the IDF definition required ethnic group-specific cutoff points for elevated waist circumference. ATP III and IDF definitions disagreed in the classification of 13-29% of men and 3-7% of women. In men, agreement between these definitions was 0.54 in Peru, 0.43 in Mexico City, 0.62 in San Antonio Mexican Americans, 0.69 in San Antonio non-Hispanic whites, and 0.64 in Spain. In women, agreement between definitions was 0.87, 0.89, 0.86, 0.87, and 0.93, respectively. CONCLUSIONS: The IDF definition of the metabolic syndrome generates greater prevalence estimates than the ATP III definition. Agreement between ATP III and IDF definitions was lower for men than for women in all populations and was relatively poor in men from Mexico City.

The prevalence of the metabolic syndrome did not increase in Mexico City between 1990-1992 and 1997-1999 despite more central obesity.

OBJECTIVE: Trends in the metabolic syndrome might follow trends in obesity. We examined this hypothesis in the Mexico City Diabetes Study (MCDS), a study that showed rising trends in obesity, and the effect of the metabolic syndrome on the risk of coronary heart disease (CHD). RESEARCH DESIGN AND METHODS: Designed as a population-based study, the MCDS enrolled subjects in 1990-1992 (n = 2,282). Follow-up visits were held in 1993-1995 (n = 1,764) and 1997-1999 (n = 1,754). We used the revised metabolic syndrome definition of the National Cholesterol Education Program and the Framingham equations to estimate the 10-year CHD risk. RESULTS: In men, the age-adjusted prevalence of the metabolic syndrome was 38.9% in 1990-1992, 43.4% in 1993-1995, and 39.9% in 1997-1999; in women, the prevalences were 65.4, 65.7, and 59.9%, respectively. The prevalence did not change in men (P = 0.349) between 1990-1992 and 1997-1999, but decreased in women (P < 0.001). A prevalence increase was demonstrated for elevated waist circumference (men, P < 0.001; women, P < 0.050), elevated fasting glucose value (men and women, P < 0.001), and low HDL cholesterol level (men, P < 0.050; women, P < 0.010); a prevalence decrease was seen for high blood pressure (men and women, P < 0.001) and hypertriglyceridemia (men, P < 0.001; women, P < 0.010). CHD risk decreased marginally in men (P < 0.050) but did not change in women (P = 0.943). CONCLUSIONS: Neither the prevalence of the metabolic syndrome nor CHD risk has increased in Mexico City. Lower blood pressure and triglyceride values appear to have counteracted increases in central obesity and fasting glucose.

Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City diabetes study.

OBJECTIVE: To test the hypothesis that enzymes conventionally associated with liver dysfunction (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase [GGT], and alkaline phosphatase) may predict diabetes. RESEARCH DESIGN AND METHODS: From a population-based diabetes survey, we selected 1,441 men and women in whom serum enzyme levels were < or =3 SDs of the mean population value, alcohol intake was <250 g/week, and hepatitis B and C virus testing was negative. At follow-up (7 years), 94 subjects developed diabetes and 93 impaired glucose tolerance (IGT). RESULTS: At baseline, all four enzymes were related to most of the features of the metabolic syndrome. After controlling for sex, age, adiposity/fat distribution, alcohol intake, serum lipids, and blood pressure, higher alanine aminotransferase and GGT values were significantly (P < 0.01) associated with both IGT and diabetes, whereas alkaline phosphatase was associated with diabetes only (P = 0.0004) and aspartate aminotransferase with IGT only (P = 0.0001). Raised GGT alone was associated with all the features of the metabolic syndrome. Raised GGT was a significant predictor of either IGT or diabetes (odds ratio 1.62 [95% CI 1.08-2.42] top quartile vs. lower quartiles, P < 0.02) after controlling for sex, age, adiposity/fat distribution, alcohol consumption, fasting plasma insulin and proinsulin levels, and 2-h postglucose plasma glucose concentrations. CONCLUSIONS: Although mild elevations in liver enzymes are associated with features of the metabolic syndrome, only raised GGT is an independent predictor of deterioration of glucose tolerance to IGT or diabetes. As GGT signals oxidative stress, the association with diabetes may reflect both hepatic steatosis and enhanced oxidative stress.

Lower hypertension risk in Mexico City than in San Antonio.

BACKGROUND: We examined the effects of blood pressure (BP), weight, and weight gain on hypertension risk in two similar ethnic origin populations, subjects in Mexico City and Mexican Americans in San Antonio. METHODS: The Mexico City Diabetes Study and San Antonio Heart Study are population-based, epidemiologic studies with identical survey protocols. Incident hypertension (BP > or = 140/90 mm Hg or current antihypertensive treatment) was analyzed in subjects aged 35 to 64 years of Mexican ethnicity living in low-income neighborhoods (n = 1467 in Mexico City, n = 628 in San Antonio). RESULTS: In Mexico City, 10.6% of men and 13.1% of women developed hypertension in a 6.5-year period; in San Antonio, 28.6% and 28.7% in a 7.5-year period, respectively. Poisson regression analysis demonstrated a greater hypertension risk in San Antonio for both men (risk ratio [RR] = 1.75, 95% confidence interval [CI]: 1.19-2.56) and women (RR = 1.40, 95% CI: 1.05-1.86). In a multiple linear regression analysis, systolic BP change was associated with weight gain in Mexico City (P < .001 in men and women) and San Antonio (P = .045 in men, and P = .027 in women) independently of age, BP, obesity, alcohol consumption, cigarette smoking, diabetes, and antihypertensive treatment. These covariates did not fully explain greater increments of systolic BP in San Antonio than in Mexico City (P < .001 in men and women). CONCLUSIONS: Hypertension risk is lower in Mexico City than in San Antonio. Systolic BP increases with weight gain, independently of other determinants of hypertension.

Prediction of type 2 diabetes using simple measures of insulin resistance: combined results from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study.

To determine and formally compare the ability of simple indexes of insulin resistance (IR) to predict type 2 diabetes, we used combined prospective data from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study, which include well-characterized cohorts of non-Hispanic white, African-American, Hispanic American, and Mexican subjects with 5-8 years of follow-up. Poisson regression was used to assess the ability of each candidate index to predict incident diabetes at the follow-up examination (343 of 3,574 subjects developed diabetes). The areas under the receiver operator characteristic (AROC) curves for each index were calculated and statistically compared. In pooled analysis, Gutt et al.'s insulin sensitivity index at 0 and 120 min (ISI(0,120)) displayed the largest AROC (78.5%). This index was significantly more predictive (P < 0.0001) than a large group of indexes (including those by Belfiore, Avignon, Katz, and Stumvoll) that had AROC curves between 66 and 74%. These findings were essentially similar both after adjustment for covariates and when analyses were conducted separately by glucose tolerance status and ethnicity/study subgroups. In conclusion, we found substantial differences between published IR indexes in the prediction of diabetes, with ISI(0,120) consistently showing the strongest prediction. This index may reflect other aspects of diabetes pathogenesis in addition to IR, which might explain its strong predictive abilities despite its moderate correlation with direct measures of IR.

Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study.

OBJECTIVE: Recent evidence suggests that C-reactive protein (CRP) may predict development of diabetes in Caucasian populations. We evaluated CRP as a possible risk factor of the development of diabetes and metabolic syndrome in a 6-year study of 515 men and 729 women from the Mexico City Diabetes Study. RESEARCH DESIGN AND METHODS: Baseline CRP, indexes of adiposity, and insulin resistance (homeostasis model assessment [HOMA-IR]) were used to predict development of the metabolic syndrome, defined as including two or more of the following: 1) dyslipidemia (triglyceride >/=2.26 mmol/l or HDL cholesterol 140/90 mmHg or on hypertensive medication); or 3) diabetes (1999 World Health Organization criteria). RESULTS: At baseline, CRP correlated significantly (P < 0.001) with all metabolic indexes in women, but less so in men. After 6 years, 14.2% of men and 16.0% of women developed the metabolic syndrome. Compared with tertile 1, women with CRP in the highest tertile had an increased relative risk of developing the metabolic syndrome by 4.0 (95% CI 2.0-7.9) and diabetes by 5.5 (2.2-13.5); these risks changed minimally after adjusting for BMI or HOMA-IR. The area under receiver-operating characteristic (ROC) curve for the prediction of the development of the syndrome was 0.684 for CRP, increasing to 0.706 when combined with BMI and to 0.710 for a complex model of CRP, BMI, and HOMA-IR. CONCLUSIONS: CRP was not a significant predictor of the development of the metabolic syndrome in men. Our data strongly support the notion that inflammation is important in the pathogenesis of diabetes and metabolic disorders in women.

Predicting future cardiovascular disease: do we need the oral glucose tolerance test?

OBJECTIVE: Our objective was to compare the performance of oral glucose tolerance tests (OGTTs) and multivariate models incorporating commonly available clinical variables in their ability to predict future cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: We randomly selected 2,662 Mexican-Americans and 1,595 non-Hispanic whites, 25-64 years of age, who were free of both CVD and known diabetes at baseline from several San Antonio census tracts. Medical history, cigarette smoking history, BMI, blood pressure, fasting and 2-h plasma glucose and serum insulin levels, triglyceride level, and fasting serum total, LDL, and HDL cholesterol levels were obtained at baseline. CVD developed in 88 Mexican-Americans and 71 non-Hispanic whites after 7-8 years of follow-up. Stepwise multiple logistic regression models were developed to predict incident CVD. The areas under receiver operator characteristic (ROC) curves were used to assess the predictive power of these models. RESULTS: The area under the 2-h glucose ROC curve was modestly but not significantly greater than under the fasting glucose curve, but both were relatively weak predictors of CVD. The areas under the ROC curves for the multivariate models incorporating readily available clinical variables other than 2-h glucose were substantially and significantly greater than under the glucose ROC curves. Addition of 2-h glucose to these models did not improve their predicting power. CONCLUSIONS: Better identification of individuals at high risk for CVD can be achieved with simple predicting models than with OGTTs, and the addition of the latter adds little if anything to the predictive power of the model.

High prevalence of cholelithiasis in a low income mexican population: An ultrasonographic syrvey

The authors present the result of a population based survey of cholelititasis carried out in a low income area of Mexico city using high resolution gallbladder ultrasound. The purpose of the study was to estimate the prevalence and selected associated risk factors of cholelithiasis (CL). The population of the studied area was 15,532 subjects, of whom 3,505 (22.6 percent) were eligible for the baseline survey (men and non-pregnant women between 35-64 years of age). Of this group, 1,735 (76.03 percent, 702 men and 1,033 women) were located for a follow-up study. Ultrasonography was performed on all except for 100 subjects who had undergone previous cholecystectomy. Crude prevalence of CL was 14.1 percent (95 percent CI 12.5-15.5). The prevalence was 5.8 percent (95 percent CI 4.1-7.5) in men and 19.7 percent (95 percent CI 17-3-22.1) in women. Presence of gallstones was associated with age, sex (men p<0.006, women p<0.001), and multiparity (p<0.002). Centrality index in men and body mass index in women were positive and significantly associated with CL when compared with subjects without CL. High levels of fasting and post glucose load insulin in women and men respectively were associated with CL. The authors conclude that the population of this study has a high prevalence of CL and confirm some know risk factors such as age, sex, BMI and multiparity. Proper assessment of the magnitude problem and characterization of potentially modifiable risk factors will play a major role in preventing this pathology

Prevalencia de diabetes e intolerancia a la glucosa en una población urbana de nivel económico bajo / Prevalence of type II diabetes and impaired glucose tolerance in a low income urban population

Se presentan los resultados de un estudio epidemiológico en población abierta, en medio urbano, de nivel económico bajo, con el propósito de establecer la prevalencia de diabetes mellitus tipo II (DM) e intolerancia a la glucosa (IG) en este sector de la población. Se seleccionó una zona equivalente a un área geoestadística básica, de acuerdo al Instituto Naccional de Estadística, Geografía e Informática. Se obtuvo un plano de la colonia con sus 39 manzanas. Se seleccionaron aleatoriamente empleando el paquete estadístico Systat. Se enumeraron todos los hogares de cada manzana, listando a todos sus habitantes y definiendo como elegibles a los que tuvieran 35 a 64 años de edad que no estuvieran embarazadas. Se entrevistó en el domicilio a todos los elegibles. Se investigó si padecían o no DM. Después se les invitó a realizarse un exàmen físico con curva de tolerancia a la glucosa. El total de habitantes en la zona fue de 4411. De estos 931 resultaron elegibles: 452 hombres (48.5 porciento) y 479 mujeres (51.5 porciento). La taza de respuesta de la encuesta domiciliaria fue 91.7 porciento y la del exámen físico 69.8 porciento utilizando los criterios de diagnóstico recomendados por la Organización Mundial de la Salud, la taza cruda de prevalencia de DM fue: en hombres 10.6 porciento y en mujeres 14.8 porciento. La taza cruda de prevalencia de IG en hombres resultó 12.8 porciento y en mujeres 12.3 porciento. Estos datos manifiestan que nuestra población tiene un alto grado de susceptibilidad a la DM e IG: ubican en nuestro país entre las poblaciones con mayor prevalencia de DM.