OBJECTIVE -The oral glucose tolerance test identifies high-risk subjects for diabetes, but it is costly and inconvenient. To find better predictors of type 2 diabetes, we evaluated two different definitions of the metabolic syndrome because insulin resistance, which is commonly associated with this clustering of metabolic factors, frequently precedes the onset of type 2 diabetes. RESEARCH DESIGN AND METHODS-We compared the ability of the National Cholesterol Education Program (NCEP) definition, a modified version of the 1999 World Health Organization (WHO) definition that excludes the 2-h glucose requirement, and impaired glucose tolerance (IGT) to predict incident type 2 diabetes. In the San Antonio Heart Study, 1,734 participants completed a 7-to 8-year follow-up examination.RESULTS -IGT and the NCEP definition had higher sensitivity than the modified WHO definition (51.9, 52.8, and 42.8%, respectively). IGT had a higher positive predictive value than the NCEP and modified WHO definitions (43.0, 30.8, and 30.4%, respectively). The combination of the IGT and NCEP definitions increased the sensitivity to 70.8% with an acceptable positive predictive value of 29.7%. Risk for incidence of type 2 diabetes using the NCEP definition was independent of other risk factors, including IGT and fasting insulin (odds ratio 3.30, 95% CI 2.27-4.80). The NCEP definition performed better with fasting glucose Ն5.4 mmol/l (sensitivity 62.0% and positive predictive value 30.9%). The OGTT is the standard method for identifying subjects at increased risk for developing type 2 diabetes in clinical research. However, OGTT is not widely used in clinical practice because it is inconvenient and costly. Identifying subjects at risk for diabetes has become more relevant because of the positive results seen with lifestyle modification and medication in the prevention (or delay) of type 2 diabetes (5-9). CONCLUSIONSIn seeking better predictors of type 2 diabetes, we evaluated two different definitions of the metabolic syndrome because insulin resistance, which is commonly associated with this clustering of metabolic factors, frequently precedes the onset of type 2 diabetes. We compared the ability of the NCEP definition, a modified version of the 1999 WHO definition of the metabolic syndrome, and IGT to predict the incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS SubjectsThe San Antonio Heart Study (SAHS) is a population-based, epidemiological study of type 2 diabetes and cardiovascular disease (initial response rate 65.3%). A total of 2,941 Mexican Americans and nonHispanic whites aged 25-68 years were enrolled in phase 2 (10,11). We excluded participants in phase 1 (waist circumference was not measured) and those in phase 2 with diabetes at baseline (baseline prevalence of type 2 diabetes 10.6%). From a total of 2,569 eligible participants, 1,734 subjects completed a 7-to 8-year follow-up examination. Survey protocols at baseline and follow-up were identical and were approved by the Institutional Review Board of the University of T...

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 ϭ 2,559; age range 25-64 years; 7.4 years of follow-up).RESULTS -Both ATPIII metabolic syndrome plus age Ն45 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 Ն55 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 ϭ 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 Ն45 years and women aged Ն55 years. The metabolic syndrome predicts diabetes beyond glucose intolerance alone. Diabetes Care 30:8 -13, 2007S ixty-four of 201 million U.S. individuals aged Ն20 years have the metabolic syndrome (1). The metabolic syndrome increases the risk for future cardiovascular disease (CVD), as well as diabetes (2). However, its clinical value has been questioned in a recent joint statement from the American Diabetes Association and the European Association for the Study of Diabetes (3). First, this statement points out that the metabolic syndrome is an ill-characterized entity with no proven value as a risk assessment tool for future CVD. Second, it brings up a concern: the possibility of misleading practitioners in the treatment of individuals who had one or two CVD risk factors. Finally, it acknowledges that this syndrome is effective in predicting future diabetes but questions its predictive value beyond that of glucose intolerance.To shed some light to these questions, we examined the predictive discrimination of the metabolic syndrome in the context of other readily available risk factors (such as age, sex, ethnic origin, and family, as well as past medical history of diabetes and CVD). Particularly, we took into account the higher CVD risk of men aged Ն45 years and women aged Ն55 years (4) and hypothesized that metabolic syndrome plus age Ն45/55 years in men/ women would be a good CVD marker. We also considered the high diabetes risk associated with impaired fa...

Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P <5x10 -8 ), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

The risk of developing DM and CVD is increased in MUH-NW and MHO individuals. Screening for obesity and other metabolic abnormalities should be routinely performed in clinical practice to institute appropriate preventive measures.

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

OBJECTIVERecent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort.RESEARCH DESIGN AND METHODSIn 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests.RESULTSElevated plasma BCAAs were inversely associated with SI and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = −0.0012 [95% CI −0.0018, −0.00059], P < 0.001 for SI; β = −0.0013 [95% CI −0.0018, −0.00082], P < 0.001 for MCRI; and β = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR.CONCLUSIONSPlasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.

OBJECTIVEA1C 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 METHODSA 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).RESULTSIFG 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).CONCLUSIONSA1C 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.

OBJECTIVEDisposition 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 METHODSInsulin 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.RESULTSThe 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.CONCLUSIONSThe 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.