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1.  Components of metabolic syndrome and 5-year change in insulin clearance - The Insulin Resistance Atherosclerosis Study (IRAS) 
Diabetes, obesity & metabolism  2013;15(5):10.1111/dom.12049.
Aims
Cross-sectional evidence indicates that abdominal adiposity, hypertension, dyslipidemia and glycemia are associated with reduced metabolic clearance of insulin (MCRI). Little is known about the progression of MCRI and whether components of metabolic syndrome are associated with the change in MCRI. In this study, we examined the association between components of metabolic syndrome and the 5-year change of MCRI.
Methods and Materials
At baseline and 5-year follow-up, we measured fasting plasma triglycerides (TG), high density lipoprotein (HDL)-cholesterol, blood pressure (BP), waist circumference (WC) and fasting blood glucose (FBG) in 784 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. MCRI, insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests.
Results
We observed a 29% decline of MCRI at follow-up. TG, systolic BP and WC at baseline were inversely associated with a decline of MCRI regression models adjusted for age, sex, ethnicity, smoking, alcohol consumption, energy expenditure, family history of diabetes, BMI, SI and AIR (β= −0.057 [95% CI −0.11, −0.0084] for TG, β= −0.0019 [95% CI −0.0035, −0.00023] for systolic BP, β= −0.0084 [95% CI −0.013, −0.0039] for WC; all p<0.05). Higher HDL-cholesterol at baseline was associated with an increase in MCRI (multivariable-adjusted β= 0.0029 [95% CI 0.0010, 0.0048], p=0.002). FBG at baseline was not associated with MCRI at follow-up (multivariable-adjusted β= 0.0014 [95% CI −0.0026, 0.0029]).
Conclusions
MCRI declined progressively over 5 years in a non-diabetic cohort. Components of metabolic syndrome at baseline were associated with a significant change in MCRI.
doi:10.1111/dom.12049
PMCID: PMC3810428  PMID: 23216702
2.  A Metabolically Healthy Obese Phenotype in Hispanic Participants in the IRAS Family Study 
Obesity (Silver Spring, Md.)  2013;21(11):2303-2309.
Objective
Some obese individuals appear to be protected from developing type 2 diabetes mellitus and cardiovascular disease (CVD). This has led to characterizing body size phenotypes based on cardiometabolic risk factors specifically as obese or overweight, and as metabolically healthy (MH) or metabolically abnormal (MA) based upon blood pressure, lipids, glucose homeostasis and inflammatory parameters. The aim of this study was to measure the prevalence of and describe fat distribution across these phenotypes in a minority population.
Design and Methods
Hispanic participants (N=1054) in the IRAS Family Study were categorized into different body size phenotypes. Computed tomography (CT) abdominal scans were evaluated for measures of non-alcoholic fatty liver disease (NAFLD) and abdominal fat distribution. Statistical models adjusting for familial relationships were estimated.
Results
Seventy percent (70%) of the Hispanic cohort was overweight (32%) or obese (38%). Forty-one percent (n=138) of overweight participants and 19% (n=74) of obese participants met criteria for MH. Adjusted analyses showed the MH phenotype was associated with lower visceral adipose tissue (VAT) and higher liver density (indicating lower fat content) in obese participants (p=0.0005 and p=0.0002, respectively), and lower VAT but not liver density in overweight participants (p=0.008 and p=0.162, respectively) compared to their MA counterparts. Odds of NAFLD were reduced in MH obese (OR=0.34, p=0.0007) compared to MA obese. VAT did not differ between MH obese or overweight and normal weight groups.
Conclusions
These findings suggest that lower levels of visceral and liver fat, despite overall increased total body fat, may be a defining feature of MH obesity in Hispanic Americans.
doi:10.1002/oby.20326
PMCID: PMC3661693  PMID: 23418072
3.  Variant in the 3′ Region of the IκBα Gene Associated With Insulin Resistance in Hispanic Americans: The IRAS Family Study 
Obesity (Silver Spring, Md.)  2009;18(3):555-562.
The IKKβ/NF-κB pathway is known to play an important role in inflammatory response and has also recently been implicated in the process of insulin resistance. We hypothesized that one or more variants in the IκBα gene (NFKBIA) or surrounding untranslated regions would be associated with insulin sensitivity (SI) in Hispanic-American families. We tested for association between 25 single-nucleotide polymorphisms (SNPs) in and near NFKBIA and SI in 981 individuals in 90 Hispanic-American families from the Insulin Resistance Atherosclerosis (IRAS) Family Study. SNP rs1951276 in the 3′ flanking region of NFKBIA was associated with SI in the San Antonio (SA) sample after adjusting for age, gender, and admixture (uncorrected P = 1.69 × 10−5; conservative Bonferroni correction P = 3.38 × 10−4). Subjects with at least one A allele for NFKBIA rs1951276 had ~29% lower SI compared to individuals homozygous for the G allele in the SA sample. Although not statistically significant, the effect was in the same direction in the San Luis Valley (SLV) sample alone (P = 0.348) and was significant in the combined SA and SLV samples (P = 5.37 × 10−4; presence of A allele associated with ~20% lower SI). In SA, when adjusted for subcutaneous adipose tissue area (SAT, cm2), the association was modestly attenuated (P = 1.25 × 10−3), but the association remained highly significant after adjustment for visceral adipose tissue area (VAT, cm2; P = 4.41 × 10−6). These results provide corroborating evidence that the NF-κB/IKKβ pathway may mediate obesity-induced insulin resistance in humans.
doi:10.1038/oby.2009.303
PMCID: PMC3992855  PMID: 19798070
4.  Insulin Clearance and the Incidence of Type 2 Diabetes in Hispanics and African Americans 
Diabetes Care  2013;36(4):901-907.
OBJECTIVE
We aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans.
RESEARCH DESIGN AND METHODS
We investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (SI), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report.
RESULTS
We observed that SI and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30–3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI).
CONCLUSIONS
Our data showed that lower MCRI predicts the incidence of type 2 diabetes.
doi:10.2337/dc12-1316
PMCID: PMC3609510  PMID: 23223351
5.  Impact of Differences in Glucose Tolerance on the Prevalence of a Negative Insulinogenic Index 
Objective
To determine the prevalence of a negative insulinogenic index (change in plasma insulin/change in plasma glucose from 0–30 minutes) from an oral glucose tolerance test according to glucose tolerance category.
Materials and Methods
Data from the San Antonio Heart Study (n=2494), Japanese American Community Diabetes Study (JACDS; n=594) and Genetics of NIDDM Study (n=1519) were examined. Glucose tolerance was defined by ADA criteria.
Results
In the combined cohort, the prevalence of a negative insulinogenic index was significantly higher in diabetes 20/616 (3.2%) compared to normal glucose tolerance 43/2667 (1.6%) (p<0.05). Longitudinally, in the JACDS cohort, the prevalence did not change from baseline (3/594; 0.5%) to 5 (4/505; 0.7%) and 10 years (8/426; 1.9%) (p=0.9) and no subject had a repeat negative insulinogenic index.
Conclusions
A negative insulinogenic index occurs at a low prevalence across glucose tolerance categories although more often in diabetes, but without recurrence over time.
doi:10.1016/j.jdiacomp.2012.09.011
PMCID: PMC3618472  PMID: 23140910
oral glucose tolerance test; glucose; insulin; insulinogenic index; impaired glucose
6.  Relationship of Insulin Sensitivity, Insulin Secretion, and Adiposity With Insulin Clearance in a Multiethnic Population 
Diabetes Care  2012;36(1):101-103.
OBJECTIVE
We aimed to examine insulin clearance, a compensatory mechanism to changes in insulin sensitivity, across sex, race/ethnicity populations, and varying states of glucose tolerance.
RESEARCH DESIGN AND METHODS
We measured insulin sensitivity index (SI), acute insulin response (AIR), and metabolic clearance rate of insulin (MCRI) by the frequently sampled intravenous glucose tolerance test in 1,295 participants in the Insulin Resistance Atherosclerosis Study.
RESULTS
MCRI was positively related to SI and negatively to AIR and adiposity across sex, race/ethnicity populations, and varying states of glucose tolerance, adiposity, and family history of diabetes. Differences in MCRI by race/ethnicity (lower in African Americans and Hispanics compared with non-Hispanic whites) and glucose tolerance were largely explained by differences in adiposity, SI, and AIR.
CONCLUSIONS
Insulin sensitivity, insulin secretion, and adiposity are correlates of insulin clearance and appear to explain differences in insulin clearance by race/ethnicity and glucose tolerance status.
doi:10.2337/dc12-0101
PMCID: PMC3526225  PMID: 22933441
7.  ESTIMATING THE CONTRIBUTIONS OF RARE AND COMMON GENETIC VARIATIONS AND CLINICAL MEASURES TO A MODEL TRAIT: ADIPONECTIN 
Genetic epidemiology  2012;37(1):13-24.
Common genetic variation frequently accounts for only a modest amount of inter-individual variation in quantitative traits and complex disease susceptibility. Circulating adiponectin, an adipocytokine implicated in metabolic disease, is a model for assessing the contribution of genetic and clinical factors to quantitative trait variation. The adiponectin locus, ADIPOQ, is the primary source of genetically-mediated variation in plasma adiponectin levels. This study sought to define the genetic architecture of ADIPOQ in the comprehensively phenotyped Hispanic (n=1151) and African American (n=574) participants from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Through resequencing and bioinformatic analysis, rare/low frequency (<5% MAF) and common variants (>5% MAF) in ADIPOQ were identified. Genetic variants and clinical variables were assessed for association with adiponectin levels and contribution to adiponectin variance in the Hispanic and African American cohorts. Clinical traits accounted for the greatest proportion of variance (POV) at 31% (p=1.16×10−47) and 47% (p=5.82×10−20), respectively. Rare/low frequency variants contributed more than common variants to variance in Hispanics: POV=18% (p= 6.40×10−15) and POV=5% (p=0.19), respectively. In African Americans, rare/low frequency and common variants both contributed approximately equally to variance: POV=6% (p=5.44×10−12) and POV=9% (P=1.44×10−10), respectively. Importantly, single low frequency alleles in each ethnic group were as important as, or more important than, common variants in explaining variation in adiponectin. Cumulatively, these clinical and ethnicity-specific genetic contributors explained half or more of the variance in Hispanic and African Americans and provide new insight into the sources of variation for this important adipocytokine.
doi:10.1002/gepi.21685
PMCID: PMC3736586  PMID: 23032297
adiponectin; proportion of variation; rare variants; common variants; clinical traits
8.  ASSOCIATION BETWEEN ADIPOQ SNPS WITH PLASMA ADIPONECTIN AND GLUCOSE HOMEOSTASIS AND ADIPOSITY PHENOTYPES IN THE IRAS FAMILY STUDY 
Molecular genetics and metabolism  2012;107(4):721-728.
Context
Adiponectin is an adipocytokine associated with a variety of metabolic traits. These associations in human studies, in conjunction with functional studies in model systems, have implicated adiponectin in multiple metabolic processes.
Objective
We hypothesize that genetic variants associated with plasma adiponectin would also be associated with glucose homeostasis and adiposity phenotypes.
Design and Setting
The Insulin Resistance Atherosclerosis Family Study was designed to identify the genetic and environmental basis of insulin resistance and adiposity in the Hispanic- (n=1,424) and African-American (n=604) population.
Main Outcome Measures
High quality metabolic phenotypes, e.g. insulin sensitivity (SI), acute insulin response (AIR), disposition index (DI), fasting glucose, body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and waist circumference, were explored.
Results
Based on association analysis of more than 40 genetic polymorphisms in the adiponectin gene (ADIPOQ), we found no consistent association of ADIPOQ variants with plasma adiponectin levels and adiposity phenotypes. However, there were two promoter variants, rs17300539 and rs822387, associated with plasma adiponectin levels (P=0.0079 and 0.021, respectively) in the Hispanic-American cohort that were also associated with SI (P=0.0067 and 0.013, respectively). In contrast, there was only a single promoter SNP, rs17300539, associated with plasma adiponectin levels (P=0.0018) and fasting glucose (P=0.042) in the African-American cohort. Strikingly, high impact coding variants did not show evidence of association.
Conclusions
The lack of consistent patterns of association between variants, adiponectin levels, glucose homeostasis, and adiposity phenotypes suggests a reassessment of the influence of adiponectin in these pathways.
doi:10.1016/j.ymgme.2012.10.003
PMCID: PMC3504195  PMID: 23102667
adiponectin; single nucleotide polymorphisms; glucose homeostasis; adiposity; African Americans; Hispanic Americans
9.  Impaired Glucose Tolerance and Obesity as Effect Modifiers of Ethnic Disparities of the Progression to Diabetes 
Diabetes Care  2012;35(12):2548-2552.
OBJECTIVE
The Diabetes Prevention Program (DPP) reported no racial/ethnic differences in the incidence of diabetes in individuals with impaired glucose tolerance (IGT). Therefore, it has been hypothesized that factors associated with racial/ethnic disparities act prior to the development of IGT. Because impaired fasting glucose (IFG) and obesity were also very prevalent in the DPP, we examined IGT, IFG, and obesity as effect modifiers of ethnic disparities in the San Antonio Heart Study.
RESEARCH DESIGN AND METHODS
Participants were 3,015 Mexican Americans and non-Hispanic whites aged 25–64 years. The median follow-up period was 7.8 years. IGT, IFG, and diabetes were defined by the 2003 American Diabetes Association criteria, and obesity was defined as BMI ≥30 kg/m2.
RESULTS
Mexican Americans had an excess risk of incident IGT (odds ratio 1.48 [95% CI 1.16–1.89]) and incident IFG (1.71 [1.31–2.23]) compared with non-Hispanic whites. Mexican Americans also had a higher incidence of diabetes among individuals who had normal 2-h glucose (2.20 [1.48–3.29]) and IGT (1.72 [1.08–2.74]) at baseline. There was an interaction of obesity on the relationship between ethnicity and progression to IGT or diabetes (P = 0.034), with Mexican Americans having a greater risk among the nonobese (1.73 [1.36–2.21]) and a comparable risk among the obese (1.08 [0.75–1.56]).
CONCLUSIONS
Ethnic differences can be detected at both the early and later stages of the diabetes disease process. However, non-Hispanic whites lose much of the ethnic advantage once they have developed obesity.
doi:10.2337/dc11-1902
PMCID: PMC3507579  PMID: 22923668
10.  Lack of Association Between Insulin Sensitivity and Colorectal Adenoma Risk 
Nutrition and cancer  2011;63(1):6-11.
Insulin resistance is thought to mediate the association between obesity and colorectal neoplasia, but no prior studies have assessed stimulated insulin sensitivity as a risk factor for colorectal neoplasia. This prospective study examined the association between insulin sensitivity measured directly using the frequently sampled intravenous glucose tolerance test (FSIGT) and later risk of colorectal adenomas. Among participants with a range of glucose tolerance levels enrolled in the Insulin Resistance Atherosclerosis Study, colonoscopies were conducted on 600 participants ages ≥ 50 yr, regardless of symptoms, about 10 yr after the first FSIGT and 5 yr after the second. Multiple logistic regression analyses were used. Within this cohort, diabetes was not associated with colorectal adenoma risk [~10 yr prior to colonoscopy adjusted odds ratio (ORadj) 1.00; 95% confidence interval (CI), 0.62–1.62 or ~5 yr prior to colonoscopy ORadj 0.96; 95% CI, 0.62–1.50]. Among non-diabetic participants, insulin sensitivity was not associated with colorectal adenoma risk at either prior study visit [lowest vs. highest insulin sensitivity, ~10 yr prior to colonoscopy ORadj 0.93; 95% CI 0.50–1.71 and ~5 yr prior to colonscopy ORadj 0.74; 95% CI, 0.38–1.46]. These results suggest that factors other than insulin sensitivity mediate the relationship between obesity and colorectal neoplasia.
doi:10.1080/01635581.2010.516866
PMCID: PMC3752663  PMID: 21154114
11.  Predictors of cardiovascular events in a contemporary population with impaired glucose tolerance: an observational analysis of the Nateglinide and Valsartan in impaired glucose tolerance outcomes research (NAVIGATOR) trial 
BMJ Open  2012;2(6):e001925.
Objectives
Risk factors for cardiovascular events are well established in general populations and those with diabetes but have been sparsely studied in impaired glucose tolerance (IGT). We sought to identify predictors of (1) a composite cardiovascular outcome (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and (2) cardiovascular death, among patients with IGT.
Design
We studied participants enrolled in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Predictors of cardiovascular events were identified in observational analyses.
Setting
Clinical trial participants in 40 countries.
Participants
9306 participants with biochemically confirmed IGT at high risk of cardiovascular events participated in NAVIGATOR.
Primary and secondary outcome measures
Cox proportional hazard regression models were constructed using variables (demographic data, medical history, clinical features, biochemical results and ECG findings) recorded at baseline to identify variables associated with and predictive of cardiovascular events.
Results
Over 6.4 years, 639 (6.9%) participants experienced a cardiovascular event, and 244 (2.6%) cardiovascular death. While predictors of both outcomes included established risk factors such as existing cardiovascular disease, male gender, older age, current smoking status and higher low-density lipoprotein cholesterol, other variables such as reduced estimated glomerular filtration rate, previous thromboembolic disease, atrial fibrillation, higher urinary albumin/creatinine ratio and chronic obstructive pulmonary disease were also important predictors. Glycaemic measures were not predictive of cardiovascular events. c-Statistics for predicting cardiovascular events and cardiovascular death were 0.74 and 0.82, respectively. This compares with c-statistics for cardiovascular events and cardiovascular death of 0.65 and 0.71, respectively, using the classical Framingham risk factors of age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, treatment for hypertension and smoking status.
Conclusions
The most powerful independent predictors of cardiovascular events in IGT included both established risk factors and other variables excluding measures of glycaemia, allowing effective identification of high-risk individuals.
doi:10.1136/bmjopen-2012-001925
PMCID: PMC3533049  PMID: 23204139
12.  Adiponectin and the Incidence of Type 2 Diabetes in Hispanics and African Americans 
Diabetes Care  2011;34(10):2231-2236.
OBJECTIVE
A recent meta-analysis of 13 prospective studies reported that higher levels of adiponectin were significantly associated with lower risk of type 2 diabetes. Most previous studies, however, were limited in their ability to adjust for appropriate confounding variables. Our objective, therefore, was to study this association after adjustment for directly measured adiposity and insulin sensitivity, expressed as the insulin sensitivity index (SI).
RESEARCH DESIGN AND METHODS
The study included 1,096 Hispanic and African American participants free of diabetes at baseline (2000–2002) who returned for follow-up after 5 years. SI was determined from frequently sampled intravenous glucose tolerance tests with minimal model analysis. Visceral adipose tissue (VAT) area was determined by computed tomography. Diabetes and impaired fasting glucose (IFG) were defined using American Diabetes Association criteria. Multivariate generalized estimating equation logistic regression models were used to account for correlations within families.
RESULTS
A total of 82 subjects met criteria for incident diabetes. After adjustment for age, sex, ethnicity, and smoking, adiponectin was significantly inversely associated with diabetes (odds ratio [OR] 0.54 per 1 SD difference [95% CI 0.38–0.76]). The association remained significant after additional adjustment in individual models for BMI, homeostasis model assessment of insulin resistance, or VAT (all P < 0.05). However, adiponectin was no longer associated in separate models adjusted for SI or IFG (OR 0.81 [0.56–1.16] and 0.75 [0.53–1.06], respectively).
CONCLUSIONS
Adiponectin was inversely associated with incident diabetes after adjustment for conventional anthropometric and metabolic variables or VAT. Adjustment for detailed measures of SI attenuated this relationship, however, suggesting that the link between adiponectin and diabetes may operate at least in part through insulin resistance.
doi:10.2337/dc11-0531
PMCID: PMC3177725  PMID: 21816973
13.  Cross-Sectional and Longitudinal Changes of Glucose Effectiveness in Relation to Glucose Tolerance 
Diabetes Care  2011;34(9):1959-1964.
OBJECTIVE
Glucose effectiveness (SG), the capacity of glucose to enhance its own disposition, is an independent predictor of future diabetes. However, there are data on cross-sectional and longitudinal changes of SG and its components, basal insulin effect on SG (BIE) and SG at zero insulin (GEZI), but the natural course of SG has not been described in a large population.
RESEARCH DESIGN AND METHODS
SG was measured at baseline in 1,265 participants (aged 40–69 years) and at the 5-year examination in 827 participants in the Insulin Resistance Atherosclerosis Study (IRAS) using the frequently sampled intravenous glucose tolerance test. None of these participants were treated with glucose-lowering agents.
RESULTS
In cross-sectional analyses, SG, BIE, and GEZI deteriorated with worsening of glucose tolerance (P < 0.001 for all three associations). In longitudinal analyses among subjects with normal glucose tolerance (NGT) at baseline, SG, BIE, and GEZI declined in those who progressed to impaired glucose tolerance (IGT) or diabetes (P < 0.001 for all three measures). More modest longitudinal changes were demonstrated in individuals with IGT. The transition back to NGT (as opposed to no change) compared with the transition to diabetes was statistically significant for SG (P = 0.049) and BIE (P = 0.042) and was not a statistically significant trend for GEZI (P = 0.332). In individuals with diabetes, only BIE had a significant decline (P = 0.003).
CONCLUSIONS
SG, BIE, and GEZI decline in subjects whose glycemic status worsens. SG and GEZI deteriorate more in the initial stages of the disease process.
doi:10.2337/dc10-2120
PMCID: PMC3161274  PMID: 21788626
14.  Metabolic factors, adipose tissue and plasminogen activator inhibitor-1 levels in type 2 diabetes: Findings from the Look AHEAD Study 
Objective
Plasminogen activator inhibitor-1 (PAI-1) production by adipose tissue is increased in obesity and its circulating levels are high in type 2 diabetes. PAI-1 increases cardiovascular risk by favoring clot stability and/or interfering with vascular remodeling. We investigated in obese diabetic persons whether an intensive lifestyle intervention for weight loss (ILI) would decrease PAI-1 levels independently of weight loss and whether PAI-1 reduction would be associated with changes in fibrinogen, an acute phase reactant, and/or fibrin fragment D-dimer (D-dimer), a marker of ambient coagulation balance.
Methods and Results
We examined 1-year changes in PAI-1, D-dimer and fibrinogen levels, adiposity, fitness, glucose and lipid control with ILI in 1,817 participants from Look AHEAD, a randomized trial investigating the effects of ILI, compared to usual care, on cardiovascular events in overweight/obese diabetic persons. Median PAI-1 levels decreased 29% with ILI, 2.5% with usual care (p<0.0001). Improvements in fitness, glucose control and HDL-cholesterol were associated with decreased PAI-1, independently of weight loss (p=0.03 for fitness, p<0.0001 for others). Fibrinogen and D-dimer remained unchanged.
Conclusions
Reductions in PAI-1 levels with ILI in obese diabetic individuals may reflect an improvement in adipose tissue health that could impact cardiovascular risk without changing fibrinogen or D-dimer levels.
doi:10.1161/ATVBAHA.111.224386
PMCID: PMC3130500  PMID: 21512162
15.  Effects of Rosiglitazone, Glyburide, and Metformin on β-Cell Function and Insulin Sensitivity in ADOPT 
Diabetes  2011;60(5):1552-1560.
OBJECTIVE
ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial monotherapy with rosiglitazone provided superior durability of glycemic control compared with metformin and glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine measures of β-cell function and insulin sensitivity from an oral glucose tolerance test (OGTT) over a 4-year period among the three treatments.
RESEARCH DESIGN AND METHODS
Recently diagnosed, drug-naïve patients with type 2 diabetes (4,360 total) were treated for a median of 4.0 years with rosiglitazone, metformin, or glyburide and were examined with periodic metabolic testing using an OGTT.
RESULTS
Measures of β-cell function and insulin sensitivity from an OGTT showed more favorable changes over time with rosiglitazone versus metformin or glyburide. Persistent improvements were seen in those who completed 4 years of monotherapy and marked deterioration of β-cell function in those who failed to maintain adequate glucose control with initial monotherapy.
CONCLUSIONS
The favorable combined changes in β-cell function and insulin sensitivity over time with rosiglitazone appear to be responsible for its superior glycemic durability over metformin and glyburide as initial monotherapy in type 2 diabetes.
doi:10.2337/db10-1392
PMCID: PMC3292330  PMID: 21415383
16.  VISCERAL FAT AND PREVALENCE OF HYPERTENSION AMONG AFRICAN-AMERICANS AND HISPANIC-AMERICANS: FINDINGS FROM THE IRAS FAMILY STUDY 
American journal of hypertension  2008;21(8):910-916.
BACKGROUND
We examined the relationship between visceral adipose tissue (VAT), independent of overall adiposity, and prevalent hypertension among adults enrolled in the Insulin Resistance Atherosclerosis (IRAS) Family Study. We also examined the role of insulin sensitivity (SI) upon hypertension. This was a cross-sectional epidemiological study in which African-American and Hispanic-American families were recruited from three clinical sites. The main outcome measure was prevalent hypertension, as defined by standardized protocol.
METHODS
The relationship between VAT and prevalent hypertension was examined in adjusted marginal models among 1,582 participants. All continuous variables were standardized.
RESULTS
A significant VAT by gender interaction prompted separate analyses for VAT according to gender. Further adjustment for SI was performed to determine its potential role in the VAT-hypertension relationship. The mean age (SD) of the sample was 41.3 (13.8) years, with a mean BMI (SD) of 28.7 (6.0) kg/m2. Women comprised 58.5% of the sample (N = 925), and Hispanic-Americans comprised 69.2% of the sample (N=1095). One in five participants (21.2%) had prevalent hypertension. In women, VAT was significantly associated with hypertension, independent of BMI (OR = 1. 49 p= 0.006). African-American women demonstrated increased odds of prevalent hypertension compared to Hispanic-American women (OR = 3.08, p <0.001). Among men, VAT was not associated with hypertension independent of BMI, and BMI explained a significant amount of the variation in hypertension.
Conclusions
A significant relationship may exist between VAT and hypertension among women, but not men. The relationship between VAT and hypertension in women was not associated with insulin resistance.
doi:10.1038/ajh.2008.213
PMCID: PMC2551313  PMID: 18566594
visceral adipose tissue; body mass index; hypertension; insulin sensitivity; gender; African-Americans; Hispanic-Americans
17.  A 1-Year Lifestyle Intervention for Weight Loss in Individuals With Type 2 Diabetes Reduces High C-Reactive Protein Levels and Identifies Metabolic Predictors of Change 
Diabetes Care  2010;33(11):2297-2303.
OBJECTIVE
We examined whether a 1-year intensive lifestyle intervention (ILI) for weight loss reduced elevated high-sensitivity C-reactive protein (hs-CRP) levels in obese individuals with diabetes and identified metabolic and fitness predictors of hs-CRP change.
RESEARCH DESIGN AND METHODS
Look AHEAD (Action for Health in Diabetes) is an ongoing multicenter clinical trial examining the effects of weight loss achieved through ILI on cardiovascular events and overall mortality in obese/overweight adults with type 2 diabetes. We report on 1,759 Look AHEAD participants who had hs-CRP and fitness data at baseline and 1 year. Subjects were randomly assigned to ILI or to usual care (diabetes support and education [DSE]). ILI involved frequent counseling to increase moderate-intensity exercise to 175 min/week, reduce caloric and saturated fat intake, and change macronutrient composition to improve glycemic control.
RESULTS
ILI reduced median hs-CRP by 43.6% from baseline to 1 year, compared with a 16.7% reduction with DSE (P < 0.001). ILI decreased weight (8.8%), A1C (0.7%), and triglycerides (17%) and increased fitness (19%) and HDL cholesterol (7.5%) (P < 0.0001 vs. changes with DSE). Changes in adiposity and glucose control with ILI remained independent predictors of hs-CRP change at 1 year (P < 0.0001 for each) after adjustment for demographics, smoking, cardiovascular history, statin and thiazolidinedione use, and changes in fitness and lipid control. Neither statin nor insulin therapy modified the association between ILI and hs-CRP.
CONCLUSIONS
A 1-year lifestyle intervention for weight loss in obese individuals with diabetes was associated with substantial reductions in hs-CRP. Improved glycemic control and reduced adiposity had comparable effects on hs-CRP change.
doi:10.2337/dc10-0728
PMCID: PMC2963483  PMID: 20682679
18.  Genome-wide association study of vitamin D concentrations in Hispanic Americans: The IRAS Family Study 
Vitamin D deficiency is associated with many adverse health outcomes. There are several well established environmental predictors of vitamin D concentrations, yet studies of the genetic determinants of vitamin D concentrations are in their infancy. Our objective was to conduct a pilot genome-wide association (GWA) study of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations in a subset of 229 Hispanic subjects, followed by replication genotyping of 50 single nucleotide polymorphisms (SNPs) in the entire sample of 1,190 Hispanics from San Antonio, Texas and San Luis Valley, Colorado. Of the 309,200 SNPs that met all quality control criteria, three SNPs in high linkage disequilibrium (LD) with each other were significantly associated with 1,25[OH]2D (rs6680429, rs9970802, and rs10889028) at a Bonferroni corrected P-value threshold of 1.62 × 10−7, however none met the threshold for 25[OH]D. Of the 50 SNPs selected for replication genotyping, five for 25[OH]D (rs2806508, rs10141935, rs4778359, rs1507023, and rs9937918) and eight for 1,25[OH]2D (rs6680429, rs1348864, rs4559029, rs12667374, rs7781309, rs10505337, rs2486443, and rs2154175) were replicated in the entire sample of Hispanics (P < 0.01). In conclusion, we identified several SNPs that were associated with vitamin D metabolite concentrations in Hispanics. These candidate polymorphisms merit further investigation in independent populations and other ethnicities.
doi:10.1016/j.jsbmb.2010.06.013
PMCID: PMC2949505  PMID: 20600896
Vitamin D; 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; genome-wide association study; Hispanic
19.  Contribution of Metabolic and Anthropometric Abnormalities to Cardiovascular Disease Risk Factors 
Circulation  2008;118(2):e20-e28.
doi:10.1161/CIRCULATIONAHA.107.189623
PMCID: PMC3170411  PMID: 18566314
AHA Conference Proceedings; cardiovascular diseases; morbidity; mortality; risk factors
20.  Association of Upper Trunk and Visceral Adipose Tissue Volume With Insulin Resistance in Control and HIV-Infected Subjects in the FRAM Study 
Summary
Visceral obesity is associated with insulin resistance, but the association of other regional adipose depots with insulin resistance is not understood. In HIV infection, buffalo hump (upper trunk fat) is associated, but the association of upper trunk fat with insulin resistance has not been examined in controls. To determine the independent association of adipose depots other than visceral with insulin resistance, we performed a cross-sectional analysis of controls and HIV-infected subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, who had measurements of glucose, insulin, and adipose tissue volumes by whole-body magnetic resonance imaging. We studied 926 HIV-positive persons from 16 academic medical center clinics and trials units with demographic characteristics representative of US patients with HIV infection and 258 FRAM controls from the population-based Coronary Artery Risk Development in Young Adults study. We measured visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume in the legs, arms, lower trunk (back and abdomen), and upper trunk (back and chest) and assessed their association with the homeostasis model of assessment (HOMA) and HOMA >4 by stepwise multivariable analysis. The prevalence of HOMA >4 as a marker of insulin resistance was 28% among controls compared with 37% among HIV-infected subjects (P = 0.005). Among controls, those in the highest tertile of upper trunk SAT volume had an odds ratio (OR) of 9.0 (95% confidence interval [CI]: 2.4 to 34; P = 0.001) for having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was lower (OR = 2.09, 95% CI: 1.36 to 3.19; P = 0.001). Among controls, the highest tertile of VAT volume had an OR of 12.1 (95% CI: 3.2 to 46; P = 0.0002) of having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was 3.12 (95% CI: 2.0 to 4.8; P < 0.0001). After adjusting for VAT and upper trunk SAT, the association of other SAT depots with HOMA >4 did not reach statistical significance. Thus, VAT and upper trunk SAT are independently associated with insulin resistance in controls and in HIV-infected persons.
PMCID: PMC3164883  PMID: 18167644
buffalo hump; fat distribution; insulin resistance; lipodystrophy; visceral obesity
21.  Disposition Index, Glucose Effectiveness, and Conversion to Type 2 Diabetes 
Diabetes Care  2010;33(9):2098-2103.
OBJECTIVE
Disposition index (DI) and glucose effectiveness (SG) are risk factors for diabetes. However, the effect of DI and SG on future diabetes has not been examined in large epidemiological studies using direct measures.
RESEARCH DESIGN AND METHODS
Insulin sensitivity index (SI), acute insulin response (AIR), and SG were measured in 826 participants (aged 40–69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as SI × AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes.
RESULTS
The area under the receiver operating characteristic curve of a model with SI and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and SG, conversion to diabetes was predicted by both SG (odds ratio × 1 SD, 0.61 [0.47–0.80]) and DI (0.68 [0.54–0.85]) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of SG and DI to incident diabetes.
CONCLUSIONS
The predictive power of DI is comparable to that of its components, SI and AIR. SG and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity.
doi:10.2337/dc10-0165
PMCID: PMC2928371  PMID: 20805282
22.  A1C Between 5.7 and 6.4% as a Marker for Identifying Pre-Diabetes, Insulin Sensitivity and Secretion, and Cardiovascular Risk Factors 
Diabetes Care  2010;33(9):2104-2109.
OBJECTIVE
A1C is an optional method for diagnosing diabetes and also for detecting individuals at increased risk of the disease. However, how A1C compares with fasting (FPG) and 2-h plasma glucose for detecting at-risk individuals is not well known.
RESEARCH DESIGN AND METHODS
A 2-h glucose tolerance test, frequently sampled intravenous glucose tolerance test, and A1C were obtained at the follow-up examination in 855 participants in the Insulin Resistance Atherosclerosis Study (IRAS). For this report, 385 individuals were at increased risk of diabetes as defined by A1C between 5.7 and 6.4%, impaired glucose tolerance (IGT), and/or impaired fasting glucose (IFG).
RESULTS
IFG and IGT identified 69.1 and 59.5% of all individuals at increased risk of diabetes, respectively. A1C 5.7–6.4% detected 23.6% of all at-risk individuals, although more African Americans (31.4%) and Hispanics (35.2%) than non-Hispanic whites (9.9%). Relative to A1C, FPG was more strongly related to fasting insulin (r = 0.38 vs. 0.26; P < 0.01), acute insulin response (r = – 0.20 vs. – 0.09; P < 0.01), and waist circumference (r = 0.43 vs. 0.25; P < 0.001) by the Spearman correlation test. Similarly, 2-h plasma glucose was more strongly related to Si (r = – 0.40 vs. – 0.27; P < 0.01) and triglycerides (r = 0.30 vs. 0.08; P < 0.001).
CONCLUSIONS
A1C 5.7–6.4% is less sensitive for detecting at-risk individuals than IFG and IGT, particularly among non-Hispanic whites. Single determinations of FPG and 2-h plasma glucose seem to be more precise correlates of insulin resistance and secretion than A1C and, in general, better for other metabolic disorders.
doi:10.2337/dc10-0679
PMCID: PMC2928372  PMID: 20573754
23.  Exploring Differences in Adiposity in Two US Hispanic Populations of Mexican Origin Using Social, Behavioral, Physiologic and Genetic Markers: The IRAS Family Study 
Ethnicity & disease  2012;22(1):65-71.
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. (Ethn Dis. 2012;22(1):65–71)
PMCID: PMC4020784  PMID: 22774311
Hispanics; Adiposity; Admixture; Environmental Differences; Social Factors; Behavior; Genetics
24.  Performance Characteristics of the New Definition of Diabetes 
Diabetes Care  2009;33(2):335-337.
OBJECTIVE
A1C ≥6.5% has been recently proposed as the defining criterion for diabetes. However, performance characteristics of this definition have not been described.
RESEARCH DESIGN AND METHODS
In the Insulin Resistance Atherosclerosis Study, we compared new to previous definitions of diabetes: 1999 World Health Organization (DM1999WHO) and 2003 American Diabetes Association based on fasting glucose alone (DMFPG126).
RESULTS
Participants with A1C ≥6.5%, DM1999WHO, and DMFPG126 were 44 (5.2%), 132 (15.4%), and 61 (7.1%), respectively. In individuals with DM1999WHO, mean, median, and interquartile range of A1C were 6.3, 5.9, and 5.5–6.6%, respectively; in individuals with DMFPG126, mean, median, and interquartile range of A1C were 7.0, 6.6, and 6.0–7.1%.
CONCLUSIONS
A1C ≥6.5% identifies fewer individuals than DM1999WHO or DMFPG126. Studies are needed to determine that A1C ≥6.5% compromises neither blood pressure and lipid management in early diabetes nor the implementation of lifestyle interventions for diabetes prevention.
doi:10.2337/dc09-1357
PMCID: PMC2809276  PMID: 19880585
25.  Rosiglitazone Decreases C-Reactive Protein to a Greater Extent Relative to Glyburide and Metformin Over 4 Years Despite Greater Weight Gain 
Diabetes Care  2009;33(1):177-183.
OBJECTIVE
C-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown.
RESEARCH DESIGN AND METHODS
In A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years.
RESULTS
Baseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by −47.6% relative to glyburide and by −30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and −2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = −0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups.
CONCLUSIONS
Rosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone.
doi:10.2337/dc09-1661
PMCID: PMC2797969  PMID: 19808911

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