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Aims/hypothesis The single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity associated gene (FTO) and the rs7566605 SNP located 10 kb upstream of the insulin-induced gene 2 gene (INSIG2) have been proposed as risk factors for common obesity. Methods We tested for genotype-treatment interactions on changes in obesity-related traits in the Diabetes Prevention Program (DPP). The DPP is a randomised controlled trial of 3,548 high-risk individuals from 27 participating centres throughout the USA who were originally randomised to receive metformin, troglitazone, intensive lifestyle modification or placebo to prevent the development of type 2 diabetes. Measures of adiposity from computed tomography were available in a subsample (n = 908). This report focuses on the baseline and 1 year results. Results The minor A allele at FTO rs9939609 was positively associated with baseline BMI (p = 0.003), but not with baseline adiposity or the change at 1 year in any anthropometric trait. For the INSIG2 rs7566605 genotype, the minor C allele was associated with more subcutaneous adiposity (second and third lumbar vertebrae [L2/3]) at baseline (p = 0.04). During follow-up, CC homozygotes lost more weight than G allele carriers (p = 0.009). In an additive model, we observed nominally significant gene-lifestyle interactions on weight change (p = 0.02) and subcutaneous (L2/3 [p = 0.01] and L4/5 [p = 0.03]) and visceral (L2/3 [p = 0.02]) adipose areas. No statistical evidence of association with physical activity energy expenditure or energy intake was observed for either genotype. Conclusions/interpretation Within the DPP study population, common variants in FTO and INSIG2 are nominally associated with quantitative measures of obesity, directly and possibly by interacting with metformin or lifestyle intervention. Trial registration: ClinicalTrials.gov NCT00004992 Funding: The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), the National Institute of Child Health and Human Development (NICHD), the National Center on Minority Health and Health Disparities (NCMHD) and the Office of Research on Women's Health (ORWH).

Background: Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss. Methods: Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1. Results: No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene ( FTO ) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P =0.005), but not ILI ( P =0.761), resulting in SNP × treatment arm interaction ( P =0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance ( P =0.051). Conclusions: Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.

Aims/hypothesis The ability to measure insulin sensitivity across the phenotypic spectrum of diabetes may contribute to a more accurate characterisation of diabetes type. Our goal was to develop and validate an insulin sensitivity (IS) score using the euglycaemic-hyperinsulinaemic clamp in a subset (n = 85) of 12- to 19-year-old youths with diabetes participating in the SEARCH study in Colorado, USA. Methods Youths with a diagnosis of type 1 (n = 60) or type 2 diabetes (n = 25) underwent a 3 h clamp to measure glucose disposal rate (GDR, mg kg⁻¹ min⁻¹). Demographic (age, sex, race), clinical (BMI, waist, Tanner stage) and metabolic characteristics (HbA₁c, lipids, blood pressure, urine albumin:creatinine) were used to estimate logeIS score via stepwise linear regression on a model-development set (n = 53). Estimated IS score was evaluated for reproducibility on two validation sets: youths with diabetes (n = 33) and healthy control youths (n = 22). Results The best model included waist, triacylglycerol (TG) and HbA₁c levels (R ² = 0.74). Diabetes type did not enter the model and there were no significant interactions between diabetes type and other predictors. Estimated IS score correlated well (r = 0.65, p < 0.0001; r = 0.62, p = 0.002) with GDR on the two validation sets. Based on this analysis, we propose the following formula to estimate insulin sensitivity in youths with diabetes: [graphic removed] . Conclusions/interpretation Insulin sensitivity can be estimated in adolescents with diabetes using routinely collected measures. This score can be applied to epidemiological studies of youths with diabetes to characterise relationships between dimensions of diabetes type.

Objective: Following unblinding of the Diabetes Prevention Program (DPP) results, a 16-session lifestyle intervention program was offered to all study participants, including those who had initially been randomized to lifestyle treatment. This study compares the effects of the lifestyle program between participants who had previous exposure and those who had not. Design: A 16-session behavioral intervention was conducted in groups at each of the 27 DPP sites during a transitional (bridge) period from the DPP trial to the DPP Outcomes Study (DPPOS). Session participation for this 6-month behavioral weight loss program was confirmed by originally randomized treatment groups. Subjects and measurements: Independently assessed weight measurements were available within a 7-month period before and after the program for 2808 ethnically diverse participants. Results: Participants from the lifestyle group in the DPP were the least likely to attend a repeat offering of a 16-session behavioral weight loss program conducted in groups. Weight loss during the transitional lifestyle program was strongly related to the duration of attendance in the three groups that were participating in the program for the first time (metformin, placebo and troglitazone), but not related to amount of earlier weight loss. Conclusion: Individuals who were naive to the behavioral program lost a greater amount of weight and this was strongly related to their degree of participation. A second exposure to a behavioral weight loss program resulted in unsatisfactory low attendance rates and weight loss.

The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. M M Gabir , R L Hanson , D Dabelea , G Imperatore , J Roumain , P H Bennett and W C Knowler National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85014, USA. Abstract OBJECTIVE: The 1997 American Diabetes Association (ADA) and the 1985 and 1999 World Health Organization (WHO) criteria for diabetes and hyperglycemia differ. The appropriateness of these diagnostic criteria in terms of individuals identified as abnormal and their prognosis has been debated. The purpose of this study is to compare the classifications of people by these criteria and to compare fasting and postload plasma glucose concentrations in the prediction of diabetes. RESEARCH DESIGN AND METHODS: The frequencies of diabetes by the 3 sets of criteria were compared in 5,023 adult Pima Indians not taking hypoglycemic drugs. Among nondiabetic subjects, fasting plasma glucose (FPG) and 2-h postload plasma glucose (2-h PG) concentrations and categories of impaired glucose regulation or diabetes were evaluated as predictors of diabetes defined by 1999 WHO criteria. RESULTS: The frequency of diabetes was 12.5% by 1997 ADA criteria, 14.6% by 1985 WHO criteria, and 15.3% by 1999 WHO criteria. The incidence of diabetes was strongly related to higher FPG and 2-h PG, each of which had very similar predictive powers. Impaired glucose tolerance (IGT) was more common than impaired fasting glucose (IFG) (15 vs. 5%), but the 5-year incidence of diabetes was higher in IFG than IGT (37 vs. 24%). CONCLUSIONS: The prevalence and incidence of diabetes are somewhat lower with the ADA criteria than with the 1985 or 1999 WHO criteria. The intermediate categories of glycemia differ substantially IFG defines a smaller number of people who are at higher risk of developing diabetes than those with IGT. More people at high risk of diabetes could be identified by using either IFG or IGT, as recommended by the 1999 WHO criteria, or by using the FPG concentration alone, but with a lower cutoff value.

Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. D Dabelea , R L Hanson , R S Lindsay , D J Pettitt , G Imperatore , M M Gabir , J Roumain , P H Bennett and W C Knowler Diabetes and Arthritis Epidemiology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85014, USA. Abstract Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone.

Aims/hypothesis Peroxisome proliferator-activated receptor γ (PPARγ), encoded by the PPARG gene, regulates insulin sensitivity and adipogenesis, and may bind polyunsaturated fatty acids (PUFA) and thiazolidinediones in a ligand-dependent manner. The PPARG proline for alanine substitution at position 12 (Pro12Ala polymorphism) has been related with obesity directly and via interaction with PUFA. Methods We tested the effect-modifying role of Pro12Ala on the 1 year change in obesity-related traits in a randomised clinical trial of treatment with metformin (n = 989), troglitazone (n = 363) or lifestyle modification (n = 1,004) vs placebo (n = 1,000) for diabetes prevention in high-risk individuals. Results At baseline, Ala12 carriers had larger waists (p < 0.001) and, in a subset, more subcutaneous adipose tissue (SAT; lumbar 2/3; p = 0.04) than Pro12 homozygotes. There was a genotype-by-intervention interaction on 1-year weight change (p = 0.01); in the placebo arm, Pro12 homozygotes gained weight and Ala12 carriers lost weight (p = 0.001). In the metformin and lifestyle arms, weight loss occurred across genotypes, but was greatest in Ala12 carriers (p < 0.05). Troglitazone treatment induced weight gain, which tended to be greater in Ala12 carriers (p = 0.08). In the placebo group, SAT (lumbar 2/3, lumbar 4/5) decreased in Ala12 allele carriers, but was unchanged in Pro12 homozygotes (p <= 0.005). With metformin treatment, SAT decreased independently of genotype. In the lifestyle arm, SAT (lumbar 2/3) reductions occurred across genotypes, but were greater in Ala12 carriers (p = 0.03). A genotype-by-PUFA intake interaction on reduction in visceral fat (lumbar 4/5; p = 0.04) was also observed, which was most evident with metformin treatment (p < 0.001). Conclusions/interpretation Within the Diabetes Prevention Program, the Ala12 allele influences central obesity, an effect which may differ by treatment group and dietary PUFA intake (ClinicalTrials.gov ID no: NCT00004992).

Aims/hypothesis Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is caused by mutations in the WFS1 gene. Recently, single nucleotide polymorphisms (SNPs) in WFS1 have been reproducibly associated with type 2 diabetes. We therefore examined the effects of these variants on diabetes incidence and response to interventions in the Diabetes Prevention Program (DPP), in which a lifestyle intervention or metformin treatment was compared with placebo. Methods We genotyped the WFS1 SNPs rs10010131, rs752854 and rs734312 (H611R) in 3,548 DPP participants and performed Cox regression analysis using genotype, intervention and their interactions as predictors of diabetes incidence. We also evaluated the effect of these SNPs on insulin resistance and beta cell function at 1 year. Results Although none of the three SNPs was associated with diabetes incidence in the overall cohort, white homozygotes for the previously reported protective alleles appeared less likely to develop diabetes in the lifestyle arm. Examination of the publicly available Diabetes Genetics Initiative genome-wide association dataset revealed that rs10012946, which is in strong linkage disequilibrium with the three WFS1 SNPs (r ² = 0.88-1.0), was associated with type 2 diabetes (allelic odds ratio 0.85, 95% CI 0.75-0.97, p = 0.026). In the DPP, we noted a trend towards increased insulin secretion in carriers of the protective variants, although for most SNPs this was seen as compensatory for the diminished insulin sensitivity. Conclusions/interpretation The previously reported protective effect of select WFS1 alleles may be magnified by a lifestyle intervention. These variants appear to confer an improvement in beta cell function.

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus * From the American Diabetes Association, Alexandria, Virginia ACOG, American College of Obstetricians and Gynecologists FPG, fasting plasma glucose GCT, glucose challenge test GDM, gestational diabetes mellitus HNF, hepatocyte nuclear factor, IFG, impaired fasting glucose IGT, impaired glucose tolerance MODY, maturity-onset diabetes of the young NDDG, National Diabetes Data Group NHANES III, Third National Health and Nutrition Examination Survey OGTT, oral glucose tolerance test PAI-1, plasminogen activator inhibitor-1 WHO, World Health Organization 2-h PG, 2-h postload glucose The current classification and diagnosis of diabetes used in the U.S. was developed by the National Diabetes Data Group (NDDG) and published in 1979 (1). The impetus for the classification and diagnosis scheme proposed then holds true today. That is, the growth of knowledge regarding the etiology and pathogenesis of diabetes has led many individuals and groups in the diabetes community to express the need for a revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a consequence, it was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease. (1) It is now considered to be particularly important to move away from a system that appears to base the classification of the disease, in large part, on the type of pharmacological treatment used in its management toward a system based on disease etiology where possible. An international Expert Committee, working under the sponsorship of the American Diabetes Association, was established in May 1995 to review the scientific literature since 1979 and to decide if changes to the classification and diagnosis of diabetes were warranted. The Committee met on multiple occasions and widely circulated a draft report of their findings and preliminary recommendations to the international diabetes community. Based on the numerous comments and suggestions received, including the opportunity to review unpublished data in detail, the Committee discussed and revised numerous drafts of a manuscript that culminated in this published document. This report is divided into four sections: definition and description of diabetes, classification of the disease, diagnostic criteria, and testing for diabetes. The aim of this document is to define and describe diabetes as we know it today, present a classification scheme that reflects its etiology and/or pathogenesis, provide guidelines for the diagnosis … [Full Text of this Article]

Aims/hypothesis To determine the associations of baseline depression symptoms and use of antidepressant medicines (ADMs) with baseline cardiovascular disease (CVD) risk factors in Look AHEAD (Action for Health in Diabetes) trial participants. Methods Look AHEAD participants (n = 5,145; age 58.7 ± 6.8 years; BMI 35.8 ± 5.8 kg/m²) were assessed for CVD risk factors (elevated HbA₁c or insulin use, elevated BP or antihypertensive use, elevated lipid levels or lipid-lowering medication, current smoking, BMI ≥30 kg/m², lower peak exercise capacity assessed as metabolic equivalents [METs], and ankle-brachial index <0.9 or >1.3). Participants also completed the Beck Depression Inventory (BDI) and reported their use of ADMs. Results Of the participants, 14.7% had BDI scores ≥11, consistent with mild-moderate depression, and 16.5% took ADMs; 4.4% had both depression markers (i.e. elevated symptom scores and took ADMs). In logistic regression analyses of CVD risk (elevated risk factor or use of medication to control the risk factor), controlled for demographic factors, continuous BDI scores and ADM use were each independently associated with elevated BP (or medication), current smoking, BMI ≥30 kg/m² and lower MET values. ADM use was also associated with elevated serum lipids or use of lipid-lowering medication. Conclusions/interpretation Among Look AHEAD participants, depression symptoms or ADM use on entry to the study were each independently associated with a wide range of CVD risk factors. Future research should assess the temporal dynamics of the relationships of depression symptoms and ADM use with CVD risk factors. Trial registration Clinicaltrials.gov NCT00017953 Funding This study is funded by the National Institutes of Health with additional support from the Centers for Disease Control and Prevention.