Association of CREBRF variants with obesity and diabetes in Pacific Islanders from Guam and Saipan.

AIMS/HYPOTHESIS: Variants in CREBRF (rs12513649 and rs373863828) have been strongly associated with increased BMI and decreased risk of type 2 diabetes in Polynesian populations; the A allele at rs373863828 is common in Polynesians but rare in most other global populations. The aim of the present study was to assess the association of CREBRF variants with obesity and diabetes in Pacific Islander (largely Marianas and Micronesian) populations from Guam and Saipan. METHODS: CREBRF rs12513649 and rs373863828 were genotyped in 2022 participants in a community-based cross-sectional study designed to identify determinants of diabetes and end-stage renal disease (ESRD). Associations were analysed with adjustment for age, sex, ESRD and the first four genetic principal components from a genome-wide association study (to account for population stratification); a genomic control procedure was used to account for residual stratification. RESULTS: The G allele at rs12513649 had an overall frequency of 7.7%, which varied from 2.2% to 20.7% across different Marianas and Micronesian populations; overall frequency of the A allele at rs373863828 was 4.2% (range: 1.1-5.4%). The G allele at rs12513649 was associated with higher BMI (ß = 1.55 kg/m2 per copy; p = 0.0026) as was the A allele at rs373863828 (ß = 1.48 kg/m2, p = 0.033). The same alleles were associated with lower risk of diabetes (OR per copy: 0.63 [p = 0.0063] and 0.49 [p = 0.0022], respectively). Meta-analyses combining the current results with previous results in Polynesians showed a strong association between the A allele at rs373863828 and BMI (ß = 1.38 kg/m2; p = 2.5 × 10-29) and diabetes (OR 0.65, p = 1.5 × 10-13). CONCLUSIONS/INTERPRETATION: These results confirm the associations of CREBRF variants with higher BMI and lower risk of diabetes and, importantly, they suggest that these variants contribute to the risk of obesity and diabetes in Oceanic populations.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.

BACKGROUND: Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. METHODS: In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. RESULTS: The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS: An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.).

Variants associated with type 2 diabetes identified by the transethnic meta-analysis study: assessment in American Indians and evidence for a new signal in LPP.

AIM/HYPOTHESIS: A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians. METHODS: Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed. Previous genome-wide association study (GWAS) data from these individuals were used to screen for additional type 2 diabetes signals at these loci. A variant independent of the trans-ancestry meta-analysis was identified within LPP, and its replication was assessed in an additional 3,106 urban American Indians. RESULTS: SNP rs6813195 near to TMEM154 was nominally associated with type 2 diabetes (p = 0.01, OR 1.12 [95% CI 1.03, 1.22]) and adiposity: the type 2 diabetes risk allele was associated with a lower percentage body fat (ß = -1.451%, p = 4.8 × 10(-4)). Another SNP, rs3130501 near to POU5F1-TCF19, was associated with BMI (ß = -0.012, p = 0.004), type 2 diabetes adjusted for BMI (p = 0.02, OR 1.11 [95% CI 1.02, 1.22]), 2 h glucose concentrations (ß = 0.080 mmol/l, p = 0.02) and insulin resistance estimated by homeostatic model (ß = 0.039, p = 0.009). The independent variant identified at the LPP locus in our American Indian GWAS for type 2 diabetes was replicated in the additional samples (all American Indian meta-analysis, p = 8.9 × 10(-6), OR 1.29 [95% CI 1.15, 1.45]). CONCLUSIONS/INTERPRETATION: For two of the seven newly identified variants, there was nominal evidence for association with type 2 diabetes and related traits in American Indians. Identification of an independent variant at the LPP locus suggests the existence of more than one type 2 diabetes signal at this locus.

Cardiorespiratory Fitness, BMI, Mortality, and Cardiovascular Disease in Adults with Overweight/Obesity and Type 2 Diabetes.

INTRODUCTION: We estimated the effects of cardiorespiratory fitness (CRF) and body mass index (BMI) at baseline on mortality and cardiovascular disease events in people with type 2 diabetes who participated in the Look AHEAD randomized clinical trial. METHODS: Look AHEAD compared effects of an intensive lifestyle intervention with diabetes support and education on cardiovascular disease events in 5145 adults age 45-76 yr with overweight/obesity and type 2 diabetes. In 4773 participants, we performed a secondary analysis of the association of baseline CRF during maximal treadmill test (expressed as metabolic equivalents (METs)) on mortality and cardiovascular disease events during a mean follow-up of 9.2 yr. RESULTS: The mean (SD) CRF was 7.2 (2.0) METs. Adjusted for age, sex, race/ethnicity, BMI, intervention group, and ß-blocker use, all-cause mortality rate was 30% lower per SD greater METs (hazard ratio (HR) = 0.70 (95% confidence interval, 0.60 to 0.81); rate difference (RD), -2.71 deaths/1000 person-years (95% confidence interval, -3.79 to -1.63)). Similarly, an SD greater METs predicted lower cardiovascular disease mortality (HR, 0.45; RD, -1.65 cases/1000 person-years) and a composite cardiovascular outcome (HR, 0.72; RD, -6.38). Effects of METs were homogeneous on the HR scale for most baseline variables and outcomes but heterogeneous for many on the RD scale, with greater RD in subgroups at greater risk of the outcomes. For example, all-cause mortality was lower by 7.6 deaths/1000 person-years per SD greater METs in those with a history of cardiovascular disease at baseline but lower by only 1.6 in those without such history. BMI adjusted for CRF had little or no effect on these outcomes. CONCLUSIONS: Greater CRF is associated with reduced risks of mortality and cardiovascular disease events.

Abnormal Exercise Test or CVD History on Weight Loss or Fitness: the Look AHEAD Trial.

PURPOSE: Obesity and type 2 diabetes are associated with an increased risk of cardiovascular disease (CVD) and the combination of weight loss and increased physical exercise are commonly recommended to reduce CVD. This study examined whether people with obesity and type 2 diabetes with an abnormal graded exercise tolerance test (GXT) or a history of CVD would have less success in achieving weight loss and improved fitness, compared to adults without these conditions. METHODS: The Look AHEAD Study examined whether an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) reduced cardiovascular events in adults with overweight/obesity and type 2 diabetes. Participants underwent a baseline maximal GXT and provided medical history data. Weight loss and fitness change were examined in 5011 participants over four years in those with or without an abnormal baseline GXT and/or history of CVD. RESULTS: After four years, weight loss in both ILI and DSE were significantly greater in those without a prior history of CVD than in those with a CVD history (6.69% vs 5.98%, p=0.02, in ILI and 0.73 vs -.07% (weight gain), p=0.01, in DSE). Likewise, those without a prior history of CVD experienced greater improvements in fitness in both ILI and DSE relative to those with a history of CVD. Having an abnormal GXT at baseline did not affect weight loss or fitness. CONCLUSIONS: A history of CVD at baseline modestly lessened weight loss and fitness changes at 4 years, whereas having any abnormality on the baseline GXT did not affect these outcomes. Thus, weight loss and improved fitness are achievable in adults with a history of CVD or ECG abnormalities.

Weight Change 2 Years After Termination of the Intensive Lifestyle Intervention in the Look AHEAD Study.

OBJECTIVE: This study evaluated weight changes after cessation of the 10-year intensive lifestyle intervention (ILI) in the Look AHEAD (Action for Health in Diabetes) study. It was hypothesized that ILI participants would be more likely to gain weight during the 2-year observational period following termination of weight-loss-maintenance counseling than would participants in the diabetes support and education (DSE) control group. METHODS: Look AHEAD was a randomized controlled trial that compared the effects of ILI and DSE on cardiovascular morbidity and mortality in participants with overweight/obesity and type 2 diabetes. Look AHEAD was converted to an observational study in September 2012. RESULTS: Two years after the end of the intervention (EOI), ILI and DSE participants lost a mean (SE) of 1.2 (0.2) kg and 1.8 (0.2) kg, respectively (P = 0.003). In addition, 31% of ILI and 23.9% of DSE participants gained ≥ 2% (P < 0.001) of EOI weight, whereas 36.3% and 45.9% of the respective groups lost ≥ 2% of EOI weight (P = 0.001). Two years after the EOI, ILI participants reported greater use of weight-control behaviors than DSE participants. CONCLUSIONS: Both groups lost weight during the 2-year follow-up period, but more ILI than DSE participants gained ≥ 2% of EOI weight. Further understanding is needed of factors that affected long-term weight change in both groups.

History of Cardiovascular Disease, Intensive Lifestyle Intervention, and Cardiovascular Outcomes in the Look AHEAD Trial.

OBJECTIVE: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). METHODS: This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. RESULTS: Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. CONCLUSIONS: Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

Effect of periodontitis on overt nephropathy and end-stage renal disease in type 2 diabetes.

OBJECTIVE: The purpose of this study was to investigate the effect of periodontitis on development of overt nephropathy, defined as macroalbuminuria, and end-stage renal disease (ESRD) in type 2 diabetes. RESEARCH DESIGN AND METHODS: Individuals residing in the Gila River Indian Community aged > or =25 years with type 2 diabetes, one or more periodontal examination, estimated glomerular filtration rate > or =60 ml/min per 1.73 m(2), and no macroalbuminuria (urinary albumin-to-creatinine ratio > or =300 mg/g) were identified. Periodontitis was classified as none/mild, moderate, severe, or edentulous using number of teeth and alveolar bone score. Subjects were followed to development of macroalbuminuria or ESRD, defined as onset of renal replacement therapy or death attributed to diabetic nephropathy. RESULTS: Of the 529 individuals, 107 (20%) had none/mild periodontitis, 200 (38%) had moderate periodontitis, 117 (22%) had severe periodontitis, and 105 (20%) were edentulous at baseline. During follow-up of up to 22 years, 193 individuals developed macroalbuminuria and 68 developed ESRD. Age- and sex-adjusted incidence of macroalbuminuria and ESRD increased with severity of periodontitis. After adjustment for age, sex, diabetes duration, BMI, and smoking in a proportional hazards model, the incidences of macroalbuminuria were 2.0, 2.1, and 2.6 times as high in individuals with moderate or severe periodontitis or those who were edentulous, respectively, compared with those with none/mild periodontitis (P = 0.01). Incidences of ESRD in individuals with moderate or severe periodontitis or in those who were edentulous were 2.3, 3.5, and 4.9 times as high, respectively, compared with those with none/mild periodontitis (P = 0.02). CONCLUSIONS: Periodontitis predicts development of overt nephropathy and ESRD in individuals with type 2 diabetes. Whether treatment of periodontitis will reduce the risk of diabetic kidney disease remains to be determined.

Role of Established Type 2 Diabetes-Susceptibility Genetic Variants in a High Prevalence American Indian Population.

Several single nucleotide polymorphisms (SNPs) associated with type 2 diabetes mellitus (T2DM) have been identified, but there is little information on their role in populations at high risk for T2DM. We genotyped SNPs at 63 T2DM loci in 3,421 individuals from a high-risk American Indian population. Nominally significant (P < 0.05) associations were observed at nine SNPs in a direction consistent with the established association. A genetic risk score derived from all loci was strongly associated with T2DM (odds ratio 1.05 per risk allele, P = 6.2 × 10(-6)) and, in 292 nondiabetic individuals, with lower insulin secretion (by 4% per copy, P = 4.1 × 10(-6)). Genetic distances between American Indians and HapMap populations at T2DM markers did not differ significantly from genomic expectations. Analysis of U.S. national survey data suggested that 66% of the difference in T2DM prevalence between African Americans and European Americans, but none of the difference between American Indians and European Americans, was attributable to allele frequency differences at these loci. These analyses suggest that, in general, established T2DM loci influence T2DM in American Indians and that risk is mediated in part through an effect on insulin secretion. However, differences in allele frequencies do not account for the high population prevalence of T2DM.

Impact of an intensive lifestyle intervention on use and cost of medical services among overweight and obese adults with type 2 diabetes: the action for health in diabetes.

OBJECTIVE: To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial. RESEARCH DESIGN AND METHODS: A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years. RESULTS: ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385-7,175); however, these were not evident among individuals with a history of cardiovascular disease. CONCLUSIONS: Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs.

Impact of intensive lifestyle intervention on depression and health-related quality of life in type 2 diabetes: the Look AHEAD Trial.

OBJECTIVE: We examined the effects of an intensive lifestyle intervention (ILI), compared with a diabetes support and education (DSE) control intervention, on long-term changes in depression symptoms, antidepressant medication (ADM) use, and health-related quality of life (HRQoL) in overweight/obese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Look AHEAD was a multisite randomized controlled trial of 5,145 overweight/obese participants assigned to ILI (designed to produce weight loss) or DSE and followed for a median of 9.6 years. The Beck Depression Inventory (BDI) was administered at baseline, annually at years 1-4, and again at year 8. Mean BDI scores and incidence of BDI scores ≥10, indicative of likely mild or greater depression, were examined. Annually through year 10, participants reported their ADM use and completed the Medical Outcomes Study Short Form 36 (SF-36) questionnaire, which yields physical component summary (PCS) and mental component summary (MCS) scores. RESULTS: ILI significantly reduced the incidence of mild or greater depression symptoms (BDI scores ≥10) compared with DSE (hazard ratio [HR] = 0.85; 95% CI 0.75-0.97; P = 0.0145). Although SF-36 PCS scores worsened over time in both groups, ILI participants reported better physical function than DSE throughout the first 8 years (all P values <0.01). There were no significant differences between treatment arms in the proportion of participants who used ADMs or in SF-36 MCS scores. CONCLUSIONS: ILI for overweight/obese patients with type 2 diabetes may reduce the risk of developing clinically significant symptoms of depression and preserve physical HRQoL. These findings should be considered when evaluating the potential benefits of ILIs.

Between-monitor differences in step counts are related to body size: implications for objective physical activity measurement.

BACKGROUND: The quantification of the relationships between walking and health requires that walking is measured accurately. We correlated different measures of step accumulation to body size, overall physical activity level, and glucose regulation. METHODS: Participants were 25 men and 25 women American Indians without diabetes (Age: 20-34 years) in Phoenix, Arizona, USA. We assessed steps/day during 7 days of free living, simultaneously with three different monitors (Accusplit-AX120, MTI-ActiGraph, and Dynastream-AMP). We assessed total physical activity during free-living with doubly labeled water combined with resting metabolic rate measured by expired gas indirect calorimetry. Glucose tolerance was determined during an oral glucose tolerance test. FINDINGS: Based on observed counts in the laboratory, the AMP was the most accurate device, followed by the MTI and the AX120, respectively. The estimated energy cost of 1000 steps per day was lower in the AX120 than the MTI or AMP. The correlation between AX120-assessed steps/day and waist circumference was significantly higher than the correlation between AMP steps and waist circumference. The difference in steps per day between the AX120 and both the AMP and the MTI were significantly related to waist circumference. INTERPRETATION: Between-monitor differences in step counts influence the observed relationship between walking and obesity-related traits.

Predictive value of albuminuria in American Indian youth with or without type 2 diabetes.

OBJECTIVE: To examine the prognostic significance of elevated albuminuria in youth with type 2 diabetes. PATIENTS AND METHODS: Cross-sectional and prospective studies were conducted on Pima Indian youth aged 5 to 19 years at baseline who were examined between July 1, 1982, and December 31, 2007. Prevalence and sequential changes in the level of microalbuminuria (30 < or = albumin-to-creatinine ratio [ACR] < 300 mg/g) and macroalbuminuria (ACR > or = 300 mg/g) and incidence of macroalbuminuria were computed according to the presence or absence of type 2 diabetes. RESULTS: The prevalence of microalbuminuria and macroalbuminuria was 6.5% and 0.6% in the 3856 nondiabetic youth and 18.5% and 2.9% in the 103 youth with diabetes, respectively. One hundred forty-one of 187 (75.4%) nondiabetic youth, but only 1 of 14 (7.1%) diabetic youth with an elevated ACR (> or =30 mg/g) regressed to an undetectable or normal ACR (<30 mg/g) on subsequent examination. In a subset of 2666 youth with a median follow-up of 8.1 years, 36 nondiabetic and 30 diabetic youth with baseline ACRs of <300 mg/g developed macroalbuminuria. For a given ACR, the incidence of macroalbuminuria was 15.9-fold (95% confidence interval: 11.1-22.6) higher in the diabetic than in the nondiabetic youth. CONCLUSIONS: Elevated albuminuria is infrequent and largely transient in nondiabetic youth, but it is relatively frequent and largely persistent in those with diabetes. Microalbuminuria in youth with type 2 diabetes strongly predicts progression to macroalbuminuria, which supports annual screening for albuminuria.

The separate and joint effects of prolonged QT interval and heart rate on mortality.

OBJECTIVES: Understanding why prolonged Bazett-corrected QT interval (QTc) is a risk factor for mortality is difficult, because QTc is positively correlated with heart rate. To optimally distinguish the effects of QT interval and heart rate on mortality, QT interval and heart rate were modeled separately and jointly in Pima Indians. METHODS: The effects of QT and heart rate on all-cause and cause-specific mortality were assessed in the overall study population and according to the presence or absence of diabetes using multivariable time-dependent proportional hazards models. RESULTS: Among 1488 nondiabetic and 990 diabetic subjects > or =25 years old, 81 nondiabetic and 149 diabetic subjects died during a median follow-up of 7.3 years. When included in the same regression model, QT and heart rate each predicted all-cause mortality [hazard ratios per standard deviation (SD) (95% confidence interval)=1.31 (1.10-1.57) and 1.57 (1.32-1.87) respectively]. In nondiabetic subjects, hazard ratios for all-cause mortality were 1.54 (1.19-1.99) for QT and 1.86 (1.46-2.37) for heart rate. In diabetic subjects, hazard ratios for all-cause mortality were lower, 1.27 (1.00-1.62) for QT and 1.41 (1.12-1.78) for heart rate. In the overall study population, neither QT nor heart rate significantly predicted cardiovascular disease (CVD) mortality [hazard ratios=1.13 (0.77-1.64) and 1.46 (0.98-2.19)] when adjusted for each other. Heart rate unadjusted for QT, however, predicted CVD mortality [hazard ratio=1.34 (1.00-1.79)] in a separate model. CONCLUSIONS: QT prolongation and high heart rate both predict all-cause mortality in Pima Indians, but heart rate was consistently the stronger predictor of the two.

Prevalence and predictors of abnormal cardiovascular responses to exercise testing among individuals with type 2 diabetes: the Look AHEAD (Action for Health in Diabetes) study.

OBJECTIVE: We examined maximal graded exercise test (GXT) results in 5,783 overweight/obese men and women, aged 45-76 years, with type 2 diabetes, who were entering the Look AHEAD (Action for Health in Diabetes) study, to determine the prevalence and correlates of exercise-induced cardiac abnormalities. RESEARCH DESIGN AND METHODS: Participants underwent symptom-limited maximal GXTs. Questionnaires and physical examinations were used to determine demographic, anthropometric, metabolic, and health status predictors of abnormal GXT results, which were defined as an ST segment depression > or =1.0 mm, ventricular arrhythmia, angina pectoris, poor postexercise heart rate recovery (<22 bpm reduction 2 min after exercise), or maximal exercise capacity less than 5.0 METs. Systolic blood pressure response to exercise was examined as a continuous variable, without a threshold to define abnormality. RESULTS: Exercise-induced abnormalities were present in 1,303 (22.5%) participants, of which 693 (12.0%) consisted of impaired exercise capacity. ST segment depression occurred in 440 (7.6%), abnormal heart rate recovery in 206 (5.0%), angina in 63 (1.1%), and arrhythmia in 41 (0.7%). Of potential predictors, only greater age was associated with increased prevalence of all abnormalities. Other predictors were associated with some, but not all, abnormalities. Systolic blood pressure response decreased with greater age, duration of diabetes, and history of cardiovascular disease. CONCLUSIONS: We found a high rate of abnormal GXT results despite careful screening for cardiovascular disease symptoms. In this cohort of overweight and obese individuals with type 2 diabetes, greater age most consistently predicted abnormal GXT. Long-term follow-up of these participants will show whether these abnormalities are clinically significant.

Change in the distribution of albuminuria according to estimated glomerular filtration rate in Pima Indians with type 2 diabetes.

OBJECTIVE: We examined secular trends in the frequency distribution of albuminuria and estimated glomerular filtration rate (eGFR) in subjects with type 2 diabetes in 1982-1988 and 2001-2006, two periods associated with major changes in the management of diabetes. RESEARCH DESIGN AND METHODS: The cross-sectional study included Pima Indians > or =15 years old with type 2 diabetes and measures of serum creatinine and urinary albumin-to-creatinine ratios (ACR). The continuous probability density distributions of ACR and eGFR were compared for the two time periods. eGFR was calculated using the Modification of Diet in Renal Disease Study equation. RESULTS: The overall standardized distribution of ACR shifted toward lower values between time periods (P = 0.001), whereas the standardized distribution of eGFR did not (P = 0.45). In the first period, eGFR was <60 ml/min per 1.73 m(2) in 6.5% of the 837 subjects. Of these, 9.3% had normal ACR, 7.4% had microalbuminuria, and 83.3% had macroalbuminuria. In the second period, the prevalence of low eGFR was similar (6.6% of the 1,310 subjects). Among those with low eGFR, normal ACR prevalence doubled to 17.2%, microalbuminuria prevalence nearly tripled to 19.5%, and macroalbuminuria prevalence declined to 63.2%. Twice as many subjects in the second period received antihypertensive medicines and 30% more received hypoglycemic medicines than in the first period. CONCLUSIONS: The distribution of albuminuria changed significantly among diabetic Pima Indians over the past 20 years, as treatment with medicines to control hyperglycemia and hypertension increased. The distribution of eGFR, however, remained unchanged. Consequently, the frequency of chronic kidney disease characterized by normoalbuminuria and low eGFR doubled.

Plasma glucose regulation and mortality in pima Indians.

OBJECTIVE: To evaluate whether impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are associated with increased risk of mortality and prevalent ischemic heart disease (IHD) and to analyze if the increased risk of death is dependent on subsequent development of diabetes in Pima Indians. RESEARCH DESIGN AND METHODS: A total of 2,993 Pima Indians aged >or=35 years were included. Prevalent IHD, defined by major ischemic electrocardiogram changes, was evaluated according to the following glucose/diabetes categories: normal glucose regulation (NGR), IFG and/or IGT, and diabetic groups by duration. During a median follow-up of 10.4 years, 780 subjects died from natural causes and 156 of these died from IHD. Mortality was analyzed according to the same glucose/diabetes categories at baseline and then as time-dependent variables. RESULTS: Only subjects with diabetes >or=15 years of duration have a higher prevalence of IHD (odds ratio 1.9 [95% CI 1.4-2.5]) relative to NGR. In baseline and time-dependent models, age- and sex-adjusted death rates from natural causes and from IHD were similar among the nondiabetic groups. Among diabetic subjects, natural mortality was higher in those with >or=15 years diabetes duration (death rate ratio [DRR] relative to NGR = 2.6 [95% CI 2.1-3.3]). IHD mortality was higher in subjects with long diabetes duration (DRR for diabetes 10-15 years = 3.8 [1.5-9.5]; DRR for diabetes >or=15 years = 8.6 [3.8-19.4]) in the time-dependent model. CONCLUSIONS: Natural and IHD mortality are not increased in Pima Indians with IFG and/or IGT. Only after the onset of diabetes do the rates of these events increase relative to NGR.

Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial.

OBJECTIVE: The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes 1-year changes in CVD risk factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on the incidence of major CVD events. RESEARCH DESIGN AND METHODS: This study consisted of a multicentered, randomized, controlled trial of 5,145 individuals with type 2 diabetes, aged 45-74 years, with BMI >25 kg/m2 (>27 kg/m2 if taking insulin). An intensive lifestyle intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared with a diabetes support and education (DSE) condition. RESULTS: Participants assigned to ILI lost an average 8.6% of their initial weight vs. 0.7% in DSE group (P < 0.001). Mean fitness increased in ILI by 20.9 vs. 5.8% in DSE (P < 0.001). A greater proportion of ILI participants had reductions in diabetes, hypertension, and lipid-lowering medicines. Mean A1C dropped from 7.3 to 6.6% in ILI (P < 0.001) vs. from 7.3 to 7.2% in DSE. Systolic and diastolic pressure, triglycerides, HDL cholesterol, and urine albumin-to-creatinine ratio improved significantly more in ILI than DSE participants (all P < 0.01). CONCLUSIONS: At 1 year, ILI resulted in clinically significant weight loss in people with type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine whether these changes are maintained and will reduce CVD risk.