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Aims/hypothesis To investigate racial/ethnic disparities in diabetes risk after gestational diabetes mellitus (GDM). Methods This is a retrospective cohort study of women enrolled in the Kaiser Permanente Southern California health plan from 1995 to 2009. GDM status was identified on the basis of plasma glucose levels during pregnancy. The incidence of diabetes after the first delivery complicated by GDM before 31 December 2009 ( n  = 12,998) was compared with the experience for women without GDM ( n  = 64,668) matched on maternal age at delivery, race/ethnicity and year of delivery (1:5 ratio). Matched Cox regression was used to compare the RRs of diabetes associated with GDM within and across racial/ethnic groups. Results Compared with the women without GDM, the HRs (95% CI) of diabetes for women after GDM were 6.5 (5.2, 8.0) in non-Hispanic white, 7.7 (6.8, 8.7) in Hispanic, 9.9 (7.5, 13.1) in black and 6.3 (5.0, 7.9) in Asian/Pacific Islanders after adjustment for parity, maternal education, comorbidity and number of outpatient visits before the index pregnancy. The HR of diabetes for black women was significantly higher than that for non-Hispanic white women ( p  = 0.032). Further adjustment for prepregnancy BMI reduced the diabetes risk association with GDM for each racial/ethnic group, but did not explain the risk differences across groups. Conclusions/interpretations Racial/ethnic disparities exist in risk of diabetes after GDM. Black women with GDM had the highest risk of developing diabetes. This highlights the importance of developing an effective diabetes screening and prevention programme in women with GDM, particularly black women with GDM.

Aims/hypothesis Little is known about the performance of surrogates in assessing changes in insulin sensitivity over time. This report compared updated HOMA of insulin sensitivity (HOMA2-%S) and the Matsuda index from OGTTs with minimal model-based estimates of insulin sensitivity (SI) from frequently sampled IVGTTs (FSIGTs) in longitudinal settings and cross-sectional settings. Methods Two longitudinal studies were used: one a natural observational study in which 338 individuals were followed for a median of 4 years; one a clinical treatment study in which 97 individuals received pioglitazone treatment and were followed for 1 year. Pairs of OGTTs and FSIGTs were performed at baseline and follow-up. Correlations were computed. Impact of measurement uncertainty was investigated through simulation studies. Results Correlations between HOMA2-%S and SI from baseline or follow-up data were in the range reported previously (0.61–0.69). By contrast, correlations for changes over time were only 0.35–0.39. The corresponding correlations between the Matsuda index and SI were 0.66–0.72 for cross-sectional data and 0.40–0.48 for longitudinal change. Correlations for changes were significantly lower than the cross-sectional correlations in both studies ( p  < 0.03). Simulation results demonstrated that the reduced correlations for change were not explained by error propagation, supporting a real limitation of surrogates to fully capture longitudinal changes in insulin sensitivity. Conclusions/interpretation HOMA and Matsuda indices derived from cross-sectional data should be used cautiously in assessing longitudinal changes in insulin sensitivity.

Aims/hypothesis The aim of the study was to examine the determinants of oral glucose tolerance in 602 persons with impaired glucose tolerance (IGT) who participated in the Actos Now for Prevention of Diabetes (ACT NOW) study. Methods In addition to the 602 IGT participants, 115 persons with normal glucose tolerance (NGT) and 50 with impaired fasting glucose (IFG) were identified during screening and included in this analysis. Insulin secretion and insulin sensitivity indices were derived from plasma glucose and insulin during an OGTT. The acute insulin response (AIR) (0-10 min) and insulin sensitivity (SI) were measured with the frequently sampled intravenous glucose tolerance test (FSIVGTT) in a subset of participants. Results At baseline, fasting plasma glucose, 2 h postprandial glucose (OGTT) and HbA₁c were 5.8 ± 0.02 mmol/l, 10.5 ± 0.05 mmol/l and 5.5 ± 0.04%, respectively, in participants with IGT. Participants with IGT were characterised by defects in early (∆I ₀₋₃₀/∆G ₀₋₃₀ × Matsuda index, where ∆I is change in insulin in the first 30 min and ∆G is change in glucose in the first 30 min) and total (∆I₀₋₁₂₀/∆G₀₋₁₂₀ × Matsuda index) insulin secretion and in insulin sensitivity (Matsuda index and SI). Participants with IGT in whom 2 h plasma glucose was 7.8-8.3 mmol/l had a 63% decrease in the insulin secretion/insulin resistance (disposition) index vs participants with NGT and this defect worsened progressively as 2 h plasma glucose rose to 8.9-9.94 mmol/l (by 73%) and 10.0-11.05 mmol/l (by 80%). The Matsuda insulin sensitivity index was reduced by 40% in IGT compared with NGT (p < 0.005). In multivariate analysis, beta cell function was the primary determinant of glucose AUC during OGTT, explaining 62% of the variance. Conclusion Our results strongly suggest that progressive beta cell failure is the main determinant of progression of NGT to IGT.

Aims/hypothesis Insulin clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with insulin clearance. Methods Hyperinsulinaemic–euglycaemic clamps were performed in two Hispanic-American family cohorts totalling 1329 participants in 329 families. The Metabochip was used to fine-map about 50 previously identified loci for type 2 diabetes, fasting glucose, fasting insulin, 2 h glucose or HbA 1c . This resulted in 17,930 variants, which were tested for association with clamp-derived insulin clearance via meta-analysis of the two cohorts. Results In the meta-analysis, 38 variants located within seven loci demonstrated association with insulin clearance ( p  < 0.001). The top signals for each locus were rs10241087 ( DGKB/TMEM195 [ TMEM195 also known as AGMO ]) ( p  = 4.4 × 10 −5 ); chr1:217605433 ( LYPLAL1 ) ( p  = 3.25 × 10 −4 ); rs2380949 ( GLIS3 ) ( p  = 3.4 × 10 −4 ); rs55903902 ( FADS1 ) ( p  = 5.6 × 10 −4 ); rs849334 ( JAZF1 ) ( p  = 6.4 × 10 −4 ); rs35749 ( IGF1 ) ( p  = 6.7 × 10 −4 ); and rs9460557 ( CDKAL1 ) ( p  = 6.8 × 10 −4 ). Conclusions/interpretation While the majority of validated loci for type 2 diabetes and related traits do not appear to influence insulin clearance in Hispanics, several of these loci do show evidence of association with this trait. It is therefore possible that these loci could have pleiotropic effects on insulin secretion, insulin sensitivity and insulin clearance.

Aims/hypothesis We have previously documented a high heritability of insulin clearance in a Hispanic cohort. Here, our goal was to confirm the high heritability in a second cohort and search for genetic loci contributing to insulin clearance. Methods Hyperinsulinaemic–euglycaemic clamps were performed in 513 participants from 140 Hispanic families. Heritability was estimated for clamp-derived insulin clearance and a two-phase genome-wide linkage scan was conducted using a variance components approach. Linkage peaks were further investigated by candidate gene association analysis in two cohorts. Results The covariate-adjusted heritability of insulin clearance was 73%, indicating that the majority of the phenotypic variance is due to genetic factors. In the Phase 1 linkage scan, no signals with a logarithm of odds (LOD) score >2 were detected. In the Phase 2 scan, two linkage peaks with an LOD >2 for insulin clearance were identified on chromosomes 15 (LOD 3.62) and 20 (LOD 2.43). These loci harbour several promising candidate genes for insulin clearance, with 12 single nucleotide polymorphisms (SNPs) on chromosome 15 and six SNPs on chromosome 20 being associated with insulin clearance in both Hispanic cohorts. Conclusions/interpretation In a second Hispanic cohort, we confirmed that insulin clearance is a highly heritable trait and identified chromosomal loci that harbour genes regulating insulin clearance. The identification of such genes may improve our understanding of how the body clears insulin, thus leading to improved risk assessment, diagnosis, prevention and therapy of diabetes, as well as of other hyperinsulinaemic disorders, such as the metabolic syndrome and polycystic ovary syndrome.

Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes. A H Xiang , R K Peters , E Trigo , S L Kjos , W P Lee and T A Buchanan Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, USA. Abstract Detailed metabolic studies were carried out to compare major regulatory steps in glucose metabolism in vivo between 25 normal pregnant Latino women without and 150 pregnant Latino women with gestational diabetes mellitus (GDM). The two groups were frequency-matched for age, BMI, and gestational age at testing in the third trimester. After an overnight fast, women with GDM had higher fasting plasma glucose (P = 0.0001) and immunoreactive insulin (P = 0.0003) concentrations and higher glucose production rates (P = 0.01) but lower glucose clearance rates (P = 0.001) compared with normal pregnant women. During steady-state hyperinsulinemia (approximately 600 pmol/l) and euglycemia (approximately 4.9 mmol/l), women with GDM had lower glucose clearance rates (P = 0.0001) but higher glucose production rates (P = 0.0001) and plasma free fatty acid (FFA) concentrations (P = 0.0002) than the normal women. These intergroup differences persisted when a subgroup of 116 women with GDM who were not diabetic < or = 6 months after pregnancy were used in the analysis. When all subjects were considered, there was a very close correlation between glucose production rates and plasma FFA concentrations throughout the glucose clamps in control (r = 0.996) and GDM (r = 0.995) groups. Slopes and intercepts of the relationships were nearly identical, suggesting that blunted suppression of FFA concentrations contributed to blunted suppression of glucose production in the GDM group. In addition to these defects in insulin action, women with GDM had a 67% impairment of pancreatic beta-cell compensation for insulin resistance compared with normal pregnant women. These results demonstrate that women with GDM have multiple defects in insulin action together with impaired compensation for insulin resistance. Our findings suggest that defects in the regulation of glucose clearance, glucose production, and plasma FFA concentrations, together with defects in pancreatic beta-cell function, precede the development of type 2 diabetes in these high-risk women.

Resistin is a peptide hormone produced by adipocytes that is present at high levels in sera of obese mice and may be involved in glucose homeostasis through regulation of insulin sensitivity. Several studies in humans have found associations between polymorphisms in the resistin gene and obesity, insulin sensitivity and blood pressure. An association between variation in the resistin gene and type 2 diabetes has been reported in some, but not all studies. The aim of this study was to analyse variants of the resistin gene for association with type 2 diabetes and related traits in a Finnish sample. In 781 cases with type 2 diabetes, 187 spouse controls and 222 elderly controls of Finnish origin, we genotyped four previously identified non-coding single-nucleotide polymorphisms (SNPs): -420C>G from the promoter region, +156C>T and +298G>A from intron 2, and +1084G>A from the 3' untranslated region. We then tested whether these SNPs were associated with type 2 diabetes and related traits. The SNPs were not significantly associated with type 2 diabetes. However, SNPs -420C>G, +156C>T and +298G>A and the common haplotype for these three markers were associated with increased values of weight-related traits and diastolic blood pressure in cases, lower weight in elderly control subjects, and lower insulin sensitivity and greater acute insulin response in spouses. Furthermore, the +1084G allele was associated with lower HDL cholesterol in both cases and controls, higher systolic blood pressure and waist circumference in cases, and greater acute insulin response in spouse controls. Our results add to growing evidence that resistin is associated with variation in weight, fat distribution and insulin resistance.

Response of pancreatic beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes. T A Buchanan , A H Xiang , R K Peters , S L Kjos , K Berkowitz , A Marroquin , J Goico , C Ochoa and S P Azen Department of Medicine, University of Southern California School of Medicine, Los Angeles, USA. buchanan@hsc.usc.edu Abstract The purpose of this study was to examine the response of pancreatic beta-cells to changes in insulin sensitivity in women at high risk for type 2 diabetes. Oral glucose tolerance tests (OGTTs) and frequently sampled intravenous glucose tolerance tests (FSIGTs) were conducted on Latino women with impaired glucose tolerance and a history of gestational diabetes before and after 12 weeks of treatment with 400 mg/day troglitazone (n = 13) or placebo (n = 12). Insulin sensitivity was assessed by minimal model analysis, and beta-cell insulin release was assessed as acute insulin responses to glucose (AIRg) and tolbutamide (AIRt) during FSIGTs and as the 30-min incremental insulin response (30-min dINS) during OGTTs. Beta-cell compensation for insulin resistance was assessed as the product (disposition index) of minimal model insulin sensitivity and each of the 3 measures of beta-cell insulin release. In the placebo group, there was no significant change in insulin sensitivity or in any measure of insulin release, beta-cell compensation for insulin resistance, or glucose tolerance. Troglitazone treatment resulted in a significant increase in insulin sensitivity, as reported previously. In response, AIRg did not change significantly, so that the disposition index for AIRg increased significantly from baseline (P = 0.004) and compared with placebo (P = 0.02). AIRt (P = 0.001) and 30-min dINS (P = 0.02) fell with improved insulin sensitivity during troglitazone treatment, so that the disposition index for each of these measures of beta-cell function did not change significantly from baseline (P > 0.20) or compared with placebo (P > 0.3). Minimal model analysis revealed that 89% of the change from baseline in insulin sensitivity during troglitazone treatment was accounted for by lowered plasma insulin concentrations. Neither oral nor intravenous glucose tolerance changed significantly from baseline or compared with placebo during troglitazone treatment. The predominant response of beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes was a reduction in insulin release to maintain nearly constant glucose tolerance.

Antepartum predictors of the development of type 2 diabetes in Latino women 11-26 months after pregnancies complicated by gestational diabetes. T A Buchanan , A H Xiang , S L Kjos , E Trigo , W P Lee and R K Peters Department of Medicine, University of Southern California School of Medicine, Los Angeles, USA. buchanan@hsc.usc.edu Abstract In this study, we sought to identify antepartum characteristics that predict the de novo development of diabetes 11-26 months after the index pregnancy in a carefully characterized cohort of women with gestational diabetes mellitus (GDM). Oral and frequently sampled intravenous glucose tolerance tests (OGTTs and FSIGTs), hyperinsulinemic-euglycemic clamps with labeled glucose, and body composition studies were performed on 91 islet cell antibody-negative Latino women with GDM during the third trimester of pregnancy. The women were documented to be diabetes-free within 6 months postpartum. Their diabetes status was ascertained again between 11 and 26 months postpartum. Logistic regression analysis was used to identify independent predictors of the development of diabetes within that interval. Fourteen of the women developed diabetes by World Health Organization criteria 11-26 months after delivery of the index pregnancy. Three antepartum variables were independent predictors of diabetes: the 1-h postchallenge plasma glucose concentration from the 100-g OGTT at which GDM was diagnosed (higher = increased risk; P = 0.003); an index of pancreatic beta-cell compensation for insulin resistance, defined as the product of the 30-min incremental plasma insulin:glucose ratio on a 75-g OGTT and the insulin sensitivity index from a hyperinsulinemic-euglycemic clamp (lower = increased risk, P = 0.009); and the basal glucose production rate after an overnight fast (higher = increased risk; P = 0.04). We conclude that postchallenge hyperglycemia, poor pancreatic beta-cell compensation for insulin resistance, and elevated endogenous glucose production during pregnancy precede the development of type 2 diabetes in young Latino women by at least 1-2 years.

Summary We hypothesized that chronic exposures to traffic combustion products may lower bone mineral density (BMD). We found that proximity to freeways was associated with reduced BMD. Our findings suggest that traffic-related pollution may contribute to the occurrence of osteopenia and osteoporosis. Introduction Adults residing in rural areas have been linked with higher BMD. We aimed to determine if this difference is due in part to air pollution by examining the relationships between traffic metrics and ambient air pollution with total body and pelvic BMD. Methods Mexican American adults ( n  = 1,175; mean 34 years; 72 % female) who had participated in the BetaGene study of air pollution, obesity, and insulin resistance were included in this analysis. Total body and pelvic BMD were estimated using dual-energy X-ray absorptiometry. Traffic and ambient air pollutant exposures were estimated at residences using location and ambient monitoring data. Variance component models were used to analyze the associations between residential distance to the nearest freeway and ambient air pollutants with BMD. Results Residential proximity to a freeway was associated with lower total body BMD (p-trend = 0.01) and pelvic BMD (p-trend = 0.03) after adjustment for age, sex, weight, and height. The adjusted mean total body and pelvic BMD in participants living within 500 m of a freeway were 0.02 and 0.03 g/cm 2 lower than participants living greater than 1,500 m from a freeway. These associations did not differ significantly by age, sex, or obesity status. Results were similar after further adjustment for body fat and weekly physical activity minutes. Ambient air pollutants (NO 2 , O 3 , and PM 2.5 ) were not significantly associated with BMD. Conclusions Traffic-related exposures in overweight and obese Mexican Americans may adversely affect BMD. Our findings indicate that long-term exposures to traffic may contribute to the occurrence of osteoporosis and its consequences.