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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

OBJECTIVE

To examine usual marine ω-3 fatty acid (mO-3FA) intake in individuals with diabetes; its association with adiposity, lipid, and glucose control; and its changes with behavioral lifestyle intervention for weight loss.

RESEARCH DESIGN AND METHODS

Cross-sectional and 1-year longitudinal analyses were performed on 2,397 Look AHEAD (Action for Health in Diabetes) participants. Look AHEAD is a cardiovascular outcome trial evaluating the effects of intensive lifestyle intervention for weight loss in overweight/obese subjects with type 2 diabetes.

RESULTS

Baseline mO-3FA intake was 162 ± 138 mg/day. It was inversely associated with triglycerides (β = −0.41, P < 0.001) and weakly with HDL (β = 4.14, P = 0.050), after multiple covariate adjustment. One-year mO-3FA and fried/sandwich fish intake decreased with intensive lifestyle intervention (P < 0.001).

CONCLUSIONS

mO-3FA intake in Look AHEAD participants was low but associated favorably with lipids. These results encourage investigation on the potential benefits of increasing mO-3FA intake in lifestyle interventions for weight loss in individuals with diabetes.

OBJECTIVE

Insulin resistance and β-cell function are major predictors of type 2 diabetes, but studies using direct methods of insulin resistance and secretion are few and relatively small. Furthermore, the strength of these associations has not been tested in different ethnic groups and various states of glucose tolerance, family history of diabetes, and obesity.

RESEARCH DESIGN AND METHODS

Predictors of incident diabetes were evaluated in Hispanic, non-Hispanic white, and African American participants in the Insulin Resistance Atherosclerosis Study (aged 40–69 years). In 557 participants with normal glucose tolerance and 269 with impaired glucose tolerance (IGT), insulin sensitivity (insulin sensitivity index [SI]) and first-phase insulin secretion (acute insulin response [AIR]) were directly measured using the frequently sampled intravenous glucose tolerance test.

RESULTS

At the 5-year follow-up examination, 128 (15.5%) individuals had developed diabetes. Both SI (odds ratio × 1 SD 0.50 [95% CI 0.37–0.68]) and AIR (0.51 [0.40–0.65]) were independent predictors of incident diabetes even after adjustment for age, sex, ethnicity, center, IGT, family history of diabetes, and BMI. The strength of the relation of SI and AIR to incident diabetes was not significantly affected by potential interactions of age, sex, ethnicity, glucose tolerance, BMI, or family history of diabetes (P ≥ 0.15).

CONCLUSIONS

Both insulin sensitivity and β-cell function predict conversion to diabetes in different ethnic groups and various states of glucose tolerance, family history of diabetes, and obesity. The prevention of type 2 diabetes should focus on interventions that improve both insulin resistance and insulin secretion.

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 1,730 participants in the San Antonio Heart Study (age range, 25 to 64 years) after 7.4 years of follow-up. Height predicted diabetes in neither men (odds ratio [OR] × 1 standard deviation [SD], 1.14 [0.85 – 1.51]) nor women (OR × 1 SD, 0.88 [0.70 – 1.11]) after adjusting for age and ethnicity. The area under the receiver operating characteristic curve (AUC) 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 = 0.702; in women, 0.783, p = 0.680) or waist-to-height ratio (in men, 0.764, p = 0.161; in women, 0.783, p = 0.619). 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 <0.001; in men, 2.00 (1.11 – 3.58) vs. 2.74 (1.52 – 4.95), p <0.001). 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.

OBJECTIVE

Prehypertension is associated with cardiovascular disease and insulin resistance. However, whether subjects with prehypertension have more diabetes risk is not known. We examine whether prehypertension is a risk factor for developing type 2 diabetes.

RESEARCH DESIGN AND METHODS

Incident diabetes was examined in nondiabetic normotensive participants in the San Antonio Heart Study (n = 2,767; aged 25–65 years; median follow-up 7.8 years).

RESULTS

Incident diabetes was 12.4% in subjects with prehypertension and 5.6% in subjects with normal blood pressure. The odds of incident diabetes were 2.21 greater for individuals with prehypertension than for those with normal blood pressure (95% CI 1.63–2.98) after adjusting for age, sex, and ethnicity. Prehypertension was not associated with incident diabetes after additional adjustment for BMI, impaired glucose tolerance, insulin resistance and secretion, and family history of diabetes (odds ratio 1.42 [95% CI 0.99–2.02]).

CONCLUSIONS

Subjects with prehypertension are at increased risk of diabetes. Much of this risk is explained by disorders related to the insulin resistance syndrome.

The genome-wide association study by Herbert and colleagues identified the INSIG2 single nucleotide polymorphism (SNP) rs7566605 as contributing to increased BMI in ethnically distinct cohorts. The present study sought to further clarify by testing whether SNPs of INSIG2 influenced quantitative adiposity or glucose homeostasis traits in Hispanics of the Insulin Resistance Atherosclerosis Family Study (IRASFS). Using a tagging SNP approach, rs7566605 and 31 additional SNPs were genotyped in 1425 IRASFS Hispanics. SNPs were tested for association with six adiposity measures: BMI, waist circumference (WAIST), waist to hip ratio (WHR), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and VAT to SAT ratio (VSR). SNPs were also tested for association with fasting glucose (GFAST), fasting insulin (FINS), and three measures obtained from the frequently sampled intravenous glucose tolerance test: insulin sensitivity (SI), acute insulin response (AIR), and disposition index (DI). Most prominent association was observed with direct CT-measured adiposity phenotypes, including VAT, SAT, and VSR (P-values range from 0.007 to 0.044 for rs17586756, rs17047718, rs17047731, rs9308762, rs12623648, and rs11673900). Multiple SNP associations were observed with all glucose homeostasis traits (P-values range from 0.001 to 0.031 for rs17047718, rs17047731, rs2161829, rs10490625, rs889904, and rs12623648). Using BMI as a covariate in evaluation of glucose homeostasis traits slightly reduced their association. However, association with adiposity and glucose homeostasis phenotypes is not significant following multiple comparisons adjustment. Trending association after multiple comparisons adjustment remains suggestive of a role for genetic variation of INSIG2 in obesity, but these results require validation.

OBJECTIVE

The Dietary Approaches to Stop Hypertension (DASH) diet has been widely promoted; however, little is known about its impact on type 2 diabetes.

RESEARCH DESIGN AND METHODS

We evaluated the association of the DASH diet with incidence of type 2 diabetes among 862 participants of the Insulin Resistance Atherosclerosis Study (IRAS) who completed a 1-year food frequency questionnaire at baseline. Type 2 diabetes odds ratios (ORs) were estimated at tertiles of the DASH score.

RESULTS

An inverse association was observed in whites (tertile 2 vs. tertile 1, OR 0.66 [95% CI 0.29–1.48]) that became significant for the most extreme contrast (tertile 3 vs. tertile 1, 0.31 [0.13–0.75]), with adjustment for covariates. No association was observed in blacks or Hispanics (tertile 2 vs. tertile 1, 1.16 [0.61–2.18 ]; tertile 3 vs. tertile 1, 1.34 [0.70–2.58 ]).

CONCLUSIONS

Adherence to the DASH dietary pattern, which is rich in vegetables, fruit, and low-fat dairy products, may have the potential to prevent type 2 diabetes.

OBJECTIVE

This study evaluated the influence of somatostatin receptor type 2 (SSTR2) polymorphisms on measures of glucose homeostasis in the Insulin Resistance Atherosclerosis Family Study (IRASFS). SSTR2 is a G-protein–coupled receptor that, in response to somatostatin, mediates inhibition of insulin, glucagon, and growth hormone release and thus may affect glucose homeostasis.

RESEARCH DESIGN AND METHODS

Ten single nucleotide polymorphisms (SNPs) spanning the gene were chosen using a SNP density selection algorithm and genotyped on 1,425 Hispanic-American individuals from 90 families in the IRASFS. These families comprised two samples (set 1 and set 2), which were analyzed individually and as a combined set. Single SNP tests of association were performed for four glucose homeostasis measures—insulin sensitivity (SI), acute insulin response (AIR), disposition index (DI), and fasting blood glucose (FBG)—using generalized estimating equations.

RESULTS

The SSTR2 locus was encompassed by a single linkage disequilibrium (LD) block (D′ = 0.91–1.00; r2 = 0.09–0.97) that contained four of the ten SNPs evaluated. Within the SSTR2-containing LD block, evidence of association was observed in each of the two sets and in a combined analysis with decreased SI(βhomozygous = −0.16; Pmeta-analysis = 0.0024–0.0030), decreased DI (βhomozygous = −0.35 to −5.16; Pmeta-analysis = 0.0075–0.027), and increased FBG (βhomozygous = 2.30; Pmeta-analysis = 0.045). SNPs outside the SSTR2-containing LD block were not associated with measures of glucose homeostasis.

CONCLUSIONS

We observed evidence for association of SSTR2 polymorphisms with measures of glucose homeostasis. Thus, variants in SSTR2 may influence pathways of SIto modulate glucose homeostasis.

Multiple studies have identified FTO gene variants associated with measures of adiposity in European-derived populations. The study objective was to determine whether FTO variants were associated with adiposity, including visceral and subcutaneous adipose tissue (VAT; SAT), and glucose homeostasis measures in the Insulin Resistance Atherosclerosis Family Study (IRASFS). A total of 27 SNPs in FTO intron 1, including SNPs prominent in the literature (rs9939609, rs8050136, rs1121980, rs17817449, rs1421085, and rs3751812), were genotyped in 1,424 Hispanic Americans and 604 African Americans. Multiple SNPs were associated with BMI and SAT (p-values ranging from 0.001 to 0.033), and trending or associated with waist circumference (p-values ranging from 0.008 to 0.099) in the Hispanic Americans. No association was observed with VAT, illustrating that FTO variants are associated with overall fat mass instead of specific fat depots. For the glucose homeostasis measures, variants were associated with fasting insulin but, consistent with other studies, after BMI adjustment, no evidence of association remained. The lack of association of FTO SNPs with insulin sensitivity is consistent with the lack of association with VAT, since these traits are strongly correlated. In the African Americans, only rs8050136 and rs9939609 were associated with BMI and WAIST (p-values of 0.011 and 0.034), and associated or trending towards association with SAT (p-values of 0.038 and 0.058). These results confirm that FTO variants are associated with adiposity measures, predisposing individuals to obesity by increasing overall fat mass in Hispanic Americans and to a lesser degree in African Americans.

Background

Several observational studies have recently suggested an inverse association of circulating levels of vitamin D with blood pressure. These findings have been based mainly on Caucasian populations; whether this association also exists among Hispanic and African Americans has yet to be definitively determined. This study investigates the association of 25-hydroxyvitamin D (25[OH]D) with blood pressure in Hispanic and African Americans.

Methods

The data source for this study is the Insulin Resistance Atherosclerosis Family Study (IRASFS), which consists of Hispanic- and African-American families from three U.S. recruitment centers (n=1334). A variance components model was used to analyze the association of plasma 25[OH]D levels with blood pressure.

Results

An inverse association was found between 25[OH]D and both systolic (β for 10 ng/mL difference= −2.05; p<0.01) and diastolic (β for 10 ng/mL difference= −1.35; p<0.001) blood pressure in all populations combined, after adjusting for age, sex, ethnicity and season of blood draw. Further adjustment for body mass index (BMI) weakened this association (β for 10 ng/mL difference= −0.94; p=0.14 and β for 10 ng/mL difference = −0.64; p=0.09, respectively).

Conclusions

25[OH]D levels are significantly inversely associated with blood pressure in Hispanic and African Americans from the IRASFS. However, this association was not significant after adjustment for BMI. Further research is needed to determine the role of BMI in this association. Large, well-designed prospective studies of the effect of vitamin D supplementation on blood pressure may be warranted.

OBJECTIVE

We evaluated insulin sensitivity and insulin secretion across the entire range of fasting (FPG) and 2-h plasma glucose (PG), and we investigated the differences in insulin sensitivity and insulin release in different glucose tolerance categories.

RESEARCH DESIGN AND METHODS

A total of 6,414 Finnish men (aged 57 ± 7 years, BMI 27.0 ± 3.9 kg/m2) from our ongoing population-based METSIM (Metabolic Syndrome in Men) study were included. Of these subjects, 2,168 had normal glucose tolerance, 2,859 isolated impaired fasting glucose (IFG), 217 isolated impaired glucose tolerance (IGT), 701 a combination of IFG and IGT, and 469 newly diagnosed type 2 diabetes.

RESULTS

The Matsuda index of insulin sensitivity decreased substantially within the normal range of FPG (−17%) and 2-h PG (−37%) and was approximately −65 and −53% in the diabetic range of FPG and 2-h PG, respectively, compared with the reference range (FPG and 2-h PG <5.0 mmol/l). Early-phase insulin release declined by only approximately −5% within the normal range of FPG and 2-h PG but decreased significantly in the diabetic range of FPG (by 32–70%) and 2-h PG (by 33–51%). Changes in insulin sensitivity and insulin secretion in relation to hyperglycemia were independent of obesity. The predominant feature of isolated IGT was impaired peripheral insulin sensitivity. Isolated IFG was characterized by impaired early and total insulin release.

CONCLUSIONS

Peripheral insulin sensitivity was already decreased substantially at low PG levels within the normoglycemic range, whereas impairment in insulin secretion was observed mainly in the diabetic range of FPG and 2-h PG. Obesity did not affect changes in insulin sensitivity or insulin secretion in relation to hyperglycemia.

OBJECTIVE

To compare different anthropometric measures in terms of their ability to predict type 2 diabetes and to determine whether predictive ability was modified by ethnicity.

RESEARCH DESIGN AND METHODS

Anthropometry was measured at baseline for 1,073 non-Hispanic white (nHW), African American (AA), and Hispanic (HA) subjects, of whom 146 developed type 2 diabetes after 5.2 years. Logistic regression models were used with areas under the receiver operator characteristic curve (AROCs) comparing the prediction of models.

RESULTS

Waist-to-height ratio (AROC 0.678) was the most predictive measure, followed by BMI (AROC 0.674). Results were similar in nHW and HA subjects, although in AA subjects, central adiposity measures appeared to best predict type 2 diabetes.

CONCLUSIONS

Measures of central and overall adiposity predicted type 2 diabetes to a similar degree, except in AA subjects, for whom results suggested that central measures were more predictive.