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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/m(2).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. [ABSTRACT FROM AUTHOR]

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 (S(I)).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. S(I) 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 S(I) 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 S(I) attenuated this relationship, however, suggesting that the link between adiponectin and diabetes may operate at least in part through insulin resistance. [ABSTRACT FROM AUTHOR]

Objective: Glucose effectiveness (S(G)), 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 S(G) and its components, basal insulin effect on S(G) (BIE) and S(G) at zero insulin (GEZI), but the natural course of S(G) has not been described in a large population.Research Design and Methods: S(G) 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, S(G), 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, S(G), 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 S(G) (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: S(G), BIE, and GEZI decline in subjects whose glycemic status worsens. S(G) and GEZI deteriorate more in the initial stages of the disease process. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Disposition index (DI) and glucose effectiveness (S(G)) are risk factors for diabetes. However, the effect of DI and S(G) on future diabetes has not been examined in large epidemiological studies using direct measures.Research Design and Methods: Insulin sensitivity index (S(I)), acute insulin response (AIR), and S(G) 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 S(I) x 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 S(I) 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 S(G), conversion to diabetes was predicted by both S(G) (odds ratio x 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 S(G) and DI to incident diabetes.Conclusions: The predictive power of DI is comparable to that of its components, S(I) and AIR. S(G) and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The IKKbeta/NF-kappaB 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 IkappaBalpha gene (NFKBIA) or surrounding untranslated regions would be associated with insulin sensitivity (S(I)) in Hispanic-American families. We tested for association between 25 single-nucleotide polymorphisms (SNPs) in and near NFKBIA and S(I) 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 S(I) in the San Antonio (SA) sample after adjusting for age, gender, and admixture (uncorrected P = 1.69 x 10(-5); conservative Bonferroni correction P = 3.38 x 10(-4)). Subjects with at least one A allele for NFKBIA rs1951276 had approximately 29% lower S(I) 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 x 10(-4); presence of A allele associated with approximately 20% lower S(I)). In SA, when adjusted for subcutaneous adipose tissue area (SAT, cm(2)), the association was modestly attenuated (P = 1.25 x 10(-3)), but the association remained highly significant after adjustment for visceral adipose tissue area (VAT, cm(2); P = 4.41 x 10(-6)). These results provide corroborating evidence that the NF-kappaB/IKKbeta pathway may mediate obesity-induced insulin resistance in humans. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Insulin resistance and beta-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 [S(I)]) 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 S(I) (odds ratio x 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 S(I) 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 > or = 0.15).Conclusions: Both insulin sensitivity and beta-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. [ABSTRACT FROM AUTHOR]

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 (S(I)), 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; r(2) = 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 S(I)(beta(homozygous) = -0.16; P(meta-analysis) = 0.0024-0.0030), decreased DI (beta(homozygous) = -0.35 to -5.16; P(meta-analysis) = 0.0075-0.027), and increased FBG (beta(homozygous) = 2.30; P(meta-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 S(I)to modulate glucose homeostasis. [ABSTRACT FROM AUTHOR]

Hypertensive patients with the cardiometabolic syndrome (CMS) are at increased risk for type 2 diabetes and cardiovascular disease. The authors examined effects of valsartan and hydrochlorothiazide (HCTZ) combined and alone on insulin sensitivity (using homeostasis model assessment-insulin resistance [HOMA-IR]), and inflammatory/metabolic biomarkers in prediabetic hypertensive persons with CMS. Eligible patients entered 16-week therapy with valsartan 320 mg/d (n=189), HCTZ 25 mg/d (n=190), or valsartan/HCTZ 320/25 mg/d (n=187). At the end point, there were no statistically significant differences in HOMA-IR among the 3 groups. HCTZ significantly increased hemoglobin A(1c) and triglyceride concentrations and lowered serum potassium levels vs valsartan. HCTZ also increased plasma aldosterone and C-reactive protein levels. Blood pressure reduction and blood pressure control rates were highest with valsartan/HCTZ. There were no differences between combination valsartan/HCTZ or monotherapies on a measure of insulin sensitivity; however, the negative metabolic effects of HCTZ (increase in triglyceride and hemoglobin A(1c) values) were absent with valsartan/HCTZ, indicating an ameliorating effect of valsartan on these measures. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Methods to assess beta-cell function in clinical studies are limited. The aim of the current study was to compare a direct measure of insulin secretion with fasting surrogate markers in relation to glucose tolerance status. RESEARCH DESIGN AND METHODS: In 1,380 individuals from the Insulin Resistance Atherosclerosis Study, beta-cell function was assessed using a frequently sampled intravenous glucose tolerance test (first-phase insulin secretion; acute insulin response [AIR]), homeostasis model assessment of beta-cell function (HOMA-B), proinsulin levels, and the proinsulin-to-insulin ratio. Beta-cell function was cross-sectionally analyzed by glucose tolerance categories (normal glucose tolerance [NGT], n = 712; impaired glucose tolerance [IGT], n = 353; newly diagnosed diabetes by 2-h glucose from an oral glucose tolerance test [OGTT] [DM2h], n = 80; newly diagnosed diabetes by fasting glucose [DMf], n = 135; or newly diagnosed diabetes by fasting and 2-h glucose and established diabetes on diet/exercise only [DM], n = 100). RESULTS: In Spearman correlation analyses, proinsulin and the proinsulin-to-insulin ratio were only modestly inversely related to AIR (r values from -0.02 to -0.27), and AIR was strongly related to HOMA-B (r values 0.56 and 0.58). HOMA-B markedly underestimated the magnitude of the beta-cell defect across declining glucose tolerance, especially for IGT and new DM by OGTT compared with AIR. Analyses adjusting for insulin sensitivity showed that beta-cell function was compromised in IGT, DM2h, DMf, and DM, relative to NGT, by 13, 12, 59, and 62% (HOMA-B) and by as much as 40, 60, 80, and 75%, using AIR. CONCLUSIONS: Subjects with IGT and early-stage, asymptomatic type 2 diabetic patients have more pronounced beta-cell defects than previously estimated from epidemiological studies using homeostasis model assessment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS: In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS: Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of the present analysis was to evaluate the association of alanine aminotransferase (ALT) with directly measured insulin sensitivity (S(i)) in a large, multiethnic cohort of U.S. adults and to determine whether ALT adds to existing metabolic risk definitions in identifying subjects with insulin resistance. RESEARCH DESIGN AND METHODS: S(i) was directly measured from frequently sampled intravenous glucose tolerance tests among 999 nondiabetic African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years who were participating in the Insulin Resistance Atherosclerosis Study. Subjects also received an oral glucose tolerance test, and fasting insulin, ALT, and alcohol intake were determined. RESULTS: ALT was associated with S(i) after adjustment for age, sex, ethnicity, impaired fasting glucose, triglycerides, HDL, blood pressure, and waist (clinical model) (P < 0.0001). The association remained significant after further adjustment for fasting insulin and impaired glucose tolerance (P = 0.004). In logistic regression analysis, elevated ALT (upper quartile) was associated with insulin resistance (lowest quartile of S(i)) after adjustment for age, sex, and ethnicity (odds ratio 3.0 [95% CI 2.2-4.1]). Elevated ALT was independently associated with insulin resistance when included in models with waist circumference, National Cholesterol Education Program criteria for metabolic syndrome, hypertriglyceridemic waist, elevated triglyceride-to-HDL ratio, or homeostasis model assessment of insulin resistance (HOMA-IR) (all P < 0.01). Finally, the addition of elevated ALT improved classification of insulin resistance by area under the receiver operating characteristic curve criteria for all models except HOMA-IR. CONCLUSIONS: ALT was associated with insulin resistance independently of conventional and more detailed metabolic measures. These findings suggest that the addition of ALT to existing clinically based metabolic risk definitions is an inexpensive way to improve the identification of subjects with insulin resistance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The clinical value of metabolic syndrome is uncertain. Thus, we examined cardiovascular disease (CVD) and diabetes risk prediction by the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATPIII), International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome. RESEARCH DESIGN AND METHODS: We analyzed the risks associated with metabolic syndrome, the NCEP multiple risk factor categories, and 2-h glucose values in the San Antonio Heart Study (n = 2,559; age range 25-64 years; 7.4 years of follow-up). RESULTS: Both ATPIII metabolic syndrome plus age >/=45 years (odds ratio 9.25 [95% CI 4.85-17.7]) and multiple (two or more) risk factors plus a 10-year coronary heart disease (CHD) risk of 10-20% (11.9 [6.00-23.6]) had similar CVD risk in men without CHD, as well as CHD risk equivalents. In women counterparts, multiple (two or more) risk factors plus a 10-year CHD risk of 10-20% was infrequent (10 of 1,254). However, either a 10-year CHD risk of 5-20% (7.72 [3.42-17.4]) or ATPIII metabolic syndrome plus age >/=55 years (4.98 [2.08-12.0]) predicted CVD. ATPIII metabolic syndrome increased the area under the receiver operating characteristic curve of a model containing age, sex, ethnic origin, family history of diabetes, and 2-h and fasting glucose values (0.857 vs. 0.842, P = 0.013). All three metabolic syndrome definitions imparted similar CVD and diabetes risks. CONCLUSIONS: Metabolic syndrome is associated with a significant CVD risk, particularly in men aged >/=45 years and women aged >/=55 years. The metabolic syndrome predicts diabetes beyond glucose intolerance alone. [ABSTRACT FROM AUTHOR]

Background: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known.Methods: We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function.Results: Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons).Conclusions: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Context: Carotid artery intima-media thickness (CIMT) is a marker of coronary atherosclerosis and independently predicts cardiovascular events, which are increased in type 2 diabetes mellitus (DM). While studies of relatively short duration have suggested that thiazolidinediones such as pioglitazone might reduce progression of CIMT in persons with diabetes, the results of longer studies have been less clear.Objective: To evaluate the effect of pioglitazone vs glimepiride on changes in CIMT of the common carotid artery in patients with type 2 DM.Design, Setting, and Participants: Randomized, double-blind, comparator-controlled, multicenter trial in patients with type 2 DM conducted at 28 clinical sites in the multiracial/ethnic Chicago metropolitan area between October 2003 and May 2006. The treatment period was 72 weeks (1-week follow-up). CIMT images were captured by a single ultrasonographer at 1 center and read by a single treatment-blinded reader using automated edge-detection technology. Participants were 462 adults (mean age, 60 [SD, 8.1] years; mean body mass index, 32 [SD, 5.1]) with type 2 DM (mean duration, 7.7 [SD, 7.2] years; mean glycosylated hemoglobin [HbA1c] value, 7.4% [SD, 1.0%]), either newly diagnosed or currently treated with diet and exercise, sulfonylurea, metformin, insulin, or a combination thereof.Interventions: Pioglitazone hydrochloride (15-45 mg/d) or glimepiride (1-4 mg/d) as an active comparator.Main Outcome Measure: Absolute change from baseline to final visit in mean posterior-wall CIMT of the left and right common carotid arteries.Results: Mean change in CIMT was less with pioglitazone vs glimepiride at all time points (weeks 24, 48, 72). At week 72, the primary end point of progression of mean CIMT was less with pioglitazone vs glimepiride (-0.001 mm vs +0.012 mm, respectively; difference, -0.013 mm; 95% confidence interval, -0.024 to -0.002; P = .02). Pioglitazone also slowed progression of maximum CIMT compared with glimepiride (0.002 mm vs 0.026 mm, respectively, at 72 weeks; difference, -0.024 mm; 95% confidence interval, -0.042 to -0.006; P = .008). The beneficial effect of pioglitazone on mean CIMT was similar across prespecified subgroups based on age, sex, systolic blood pressure, duration of DM, body mass index, HbA(1c) value, and statin use.Conclusion: Over an 18-month treatment period in patients with type 2 DM, pioglitazone slowed progression of CIMT compared with glimepiride.Trial Registration: clinicaltrials.gov Identifier: NCT00225264 [ABSTRACT FROM AUTHOR]

Data from the UKPDS (U.K. Prospective Diabetes Study) indicate a continuous decline in beta-cell function in patients with type 2 diabetes. We studied longitudinal changes in beta-cell function (follow-up of 5.2 years) in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes, using acute insulin response (AIR) and insulin sensitivity index (S(i)) from a frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years. At baseline, decreasing levels of both S(i) and AIR (either unadjusted or adjusted for S(i)) mirrored deteriorating glucose tolerance status at baseline and at follow-up. A different pattern was found with respect to longitudinal changes; S(i) declined in each glucose tolerance category, ranging from -0.81 x10(-4) min(-1) x muU(-1) x ml(-1) in NGT at baseline and NGT at follow-up (NGT/NGT) to -1.06 x10(-4) in NGT/diabetes, whereas the directional change in AIR principally determined the glucose tolerance status at follow-up. In NGT/NGT S(i) decreased by 35% and AIR increased by 34%. Results were similar in each of the three ethnic groups. These data shed light on the natural course of beta-cell function; over 5.2 years, mean insulin sensitivity declined in each glucose tolerance category. The change in AIR, however, principally determined glucose tolerance status at follow-up; NGT was maintained by a compensatory increase in insulin secretion. Failure to increase insulin secretion led to IGT, and a decrease in insulin secretion led to overt diabetes. This data may have important implications for the prevention and treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Glucose homeostasis, a defining characteristic of physiological glucose metabolism, is the result of complex feedback relationships with both genetic and environmental determinants that influence insulin sensitivity and beta-cell function. Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes. Our group previously published a genome scan for glucose homeostasis traits in 284 African-American subjects from 21 pedigrees in the Insulin Resistance Atherosclerosis Study Family Study (IRASFS) and presented evidence for linkage to disposition index (DI) on chromosome 11q with a logarithm of odds (LOD) of 3.21 at 81 cM flanked by markers D11S2371 and D11S2002 (support interval from 71 to 96 cM). In this study, genotyping and analysis of an additional 214 African-American subjects in 21 pedigrees from the IRASFS yielded independent evidence of linkage to DI. When these two datasets were combined, a DI linkage peak was observed with an LOD of 3.89 at 78 cM (support interval from 67 to 89 cM). Fine mapping with 15 additional microsatellite markers in this 11q region for the entire 42 pedigrees resulted in an LOD score of 4.80 at 80 cM near marker D11S937 (support interval from 76 to 84 cM). In these 42 pedigrees, there was also suggestive evidence for linkage to acute insulin response (AIR) at two separate locations flanking the DI peak (64 cM, LOD 2.77, flanked by markers D11S4076 and D11S981; and 85 cM, LOD 2.54, flanked by markers D11S4172 and D11S2002). No evidence of linkage to the insulin sensitivity index (S(i)) was observed. Nine positional candidate genes were evaluated for association to DI and AIR. Among these candidates, single nucleotide polymorphisms (SNPs) in muscle glycogen phosphorylase showed evidence of association with DI (P < 0.011). In addition, SNPs in the pyruvate carboxylase gene showed evidence of association (P < 0.002) with AIR. Further analysis of these candidate genes, however, did not provide evidence that these SNPs accounted for the evidence of linkage to either DI or AIR. These detailed genetic analyses provide strong evidence of a DI locus on 11q in African-American pedigrees, with additional suggestive evidence of independent AIR loci in the same region. [ABSTRACT FROM AUTHOR]

Objective: With the current obesity epidemic, one would expect a prevalence increase in the metabolic syndrome. Therefore, in the San Antonio Heart Study, a population-based study with worsening obesity, we examined the metabolic syndrome and its effect on incident cardiovascular disease (CVD).Research Design and Methods: We enrolled 5,158 subjects in two cohorts: 1979-1982 and 1984-1988. We reexamined 3,682 (71.4%) subjects in 1987-1990 (cohort 1) and 1991-1996 (cohort 2) and assessed a 7.5-year incidence of CVD in 4,635 (90.0%) participants. We used the metabolic syndrome definition of the National Cholesterol Education Program-Adult Treatment Panel III.Results: At baseline, the metabolic syndrome was less prevalent in cohort 1 than in cohort 2: in men, 20.4 vs. 29.3% (P < 0.001); in women, 16.3 vs. 26.3% (P < 0.001). The prevalence increased in men and women of both Mexican-American and non-Hispanic white ethnic groups between 1979-1982 and 1991-1996 (P for trend <0.001 for each of the groups). There was an excess of incident CVD in cohort 2 relative to cohort 1 (odds ratio 1.37 [95% CI 1.02-1.84]) after adjustment for age, sex, ethnic origin, socioeconomic status, history of CVD, diabetes, total cholesterol, smoking, and family history of heart attack. Further adjustment for the metabolic syndrome reduced this difference (1.26 [0.93-1.71]) because the metabolic syndrome predicted incident CVD (1.58 [1.14-2.18]).Conclusions: In San Antonio, Texas, an increase in the prevalence of the metabolic syndrome between 1979-1982 and 1984-1988 contributes to explain a higher CVD incidence. [ABSTRACT FROM AUTHOR]

The Analysis and Understanding of Diabetes and Dyslipidaemia: Improving Treatment (AUDIT) study was a confidential, web-based, cross-sectional survey involving 2,043 diabetes specialists in 50 countries. The study investigated the attitudes of physicians specialising in the treatment of patients with type 2 diabetes mellitus towards the management of dyslipidaemia and other cardiovascular risk factors in these patients. Physicians reported obtaining lipid profiles in 91% of patients with type 2 diabetes and estimated that 62% of type 2 diabetic patients have dyslipidaemia. Across all regions, stated low-density lipoprotein cholesterol (LDL-C), triglyceride and total cholesterol targets were lower for type 2 diabetic patients with than without cardiovascular disease (CVD). Fewer physicians reported having an LDL-C target of

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