Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

The association between gender-related characteristics and type 2 diabetes risk in a multi-ethnic population: The HELIUS study.

BACKGROUND AND AIMS: Men and women have different type 2 diabetes mellitus (T2DM) risks, which have been reported across populations of different ethnicity. Where differences in T2DM risk for sex (biological) have been studied, research on gender (socio-cultural) and T2DM risk is lacking. We explored, in a multi-ethnic population, the association of six gender-related characteristics with incident T2DM over 3 years, and the mediation by known risk factors for T2DM. METHODS AND RESULTS: We included 9605 women and 7080 men of the multi-ethnic HELIUS study (Amsterdam, the Netherlands). We studied associations between gender-related characteristics and incident T2DM, using Cox regression. After a median of 3.0 years (IQR 2.0; 4.0), 198 (2.1%) women and 137 (1.9%) men developed T2DM. A lower T2DM risk was observed in those not being the primary earner (HR 0.67; 95% CI 0.47; 0.93) and a higher desired level of social support (HR 0.62; 95% CI 0.44; 0.87). Hours spent on household work, home repairs, type of employment and male- or female-dominated occupation were not associated with T2DM incidence. No evidence for effect modification by biological sex or ethnicity was found. Known risk factors of T2DM did not mediate the observed associations. CONCLUSION: Gender-related characteristics, not being the primary earner and a higher desired social support were associated with reduced T2DM risk, and this was not mediated by known risk factors for T2DM.

Lifestyle clusters related to type 2 diabetes and diabetes risk in a multi-ethnic population: The HELIUS study.

Little is known about how health-related behaviours cluster across different populations and how lifestyle clusters are associated with type 2 diabetes (T2D) risk. We investigated lifestyle clusters and their association with T2D in a multi-ethnic population. 4396 Dutch, 2850 South-Asian Surinamese, 3814 African Surinamese, 2034 Ghanaian, 3328 Turkish, and 3661 Moroccan origin participants of the HELIUS study were included (2011-2015). K-medoids cluster analyses were used to identify lifestyle clusters. Logistic and cox regression analyses were performed to investigate the association of clusters with prevalent and incident T2D, respectively. Pooled analysis revealed three clusters: a 'healthy', 'somewhat healthy', and 'unhealthy' cluster. Most ethnic groups were unequally distributed: Dutch participants were mostly present in the 'healthy' cluster, Turkish and Moroccan participants in the 'somewhat healthy' cluster, while the Surinamese and Ghanaian participants were equally distributed across clusters. When stratified for ethnicity, analysis revealed three clusters per ethnic group. While the 'healthy' and 'somewhat healthy' clusters were similar to those of the pooled analysis, we observed considerable differences in the ethnic-specific 'unhealthy' clusters. Fruit consumption (3-4 days/week) was the only behaviour that was consistent across all ethnic-specific 'unhealthy' clusters. The pooled 'unhealthy' cluster was positively associated with prediabetes (OR: 1.34, 95%CI 1.21-1.48) and incident T2D (OR: 1.23, 95%CI 0.89-1.69), and negatively associated with prevalent T2D (OR: 0.80, 95%CI 0.69-0.93). Results were similar for most, but not all, ethnic-specific clusters. This illustrates that targeting multiple behaviours is relevant in prevention of T2D but that ethnic differences in lifestyle clusters should be taken into account.

Effects of dietary and physical activity interventions on the risk of type 2 diabetes in South Asians: meta-analysis of individual participant data from randomised controlled trials.

AIMS/HYPOTHESIS: Individuals of South Asian origin have a high risk of type 2 diabetes and of dying from a diabetes-attributable cause. Lifestyle modification intervention trials to prevent type 2 diabetes in high-risk South Asian adults have suggested more modest effects than in European-origin populations. The strength of the evidence of individual studies is limited, however. We performed an individual participant data meta-analysis of available RCTs to assess the effectiveness of lifestyle modification in South Asian populations worldwide. METHODS: We searched PubMed, EMBASE, Cochrane Library and Web of Science (to 24 September 2018) for RCTs on lifestyle modification interventions incorporating diet and/or physical activity in South Asian adults. Reviewers identified eligible studies and assessed the quality of the evidence. We obtained individual participant data on 1816 participants from all six eligible trials (four from Europe and two from India). We generated HR estimates for incident diabetes (primary outcome) and mean differences for fasting glucose, 2 h glucose, weight and waist circumference (secondary outcomes) using mixed-effect meta-analysis overall and by pre-specified subgroups. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence of the estimates. The study is registered with the International Prospective Register of Systematic Reviews ([PROSPERO] CRD42017078003). RESULTS: Incident diabetes was observed in 12.6% of participants in the intervention groups and in 20.0% of participants in the control groups. The pooled HR for diabetes incidence was 0.65 (95% CI 0.51, 0.81; I2 = 0%) in intervention compared with control groups. The absolute risk reduction was 7.4% (95% CI 4.0, 10.2), with no interactions for the pre-specified subgroups (sex, BMI, age, study duration and region where studies were performed). The quality of evidence was rated as moderate. Mean difference for lifestyle modification vs control groups for 2 h glucose was -0.34 mmol/l (95% CI -0.62, -0.07; I2 = 50%); for weight -0.75 kg (95% CI -1.34, -0.17; I2 = 71%) and for waist -1.16 cm (95% CI -2.16, -0.16; I2 = 75%). No effect was found for fasting glucose. Findings were similar across subgroups, except for weight for European vs Indian studies (-1.10 kg vs -0.08 kg, p = 0.02 for interaction). CONCLUSIONS/INTERPRETATION: Despite modest changes for adiposity, lifestyle modification interventions in high-risk South Asian populations resulted in a clinically important 35% relative reduction in diabetes incidence, consistent across subgroups. If implemented on a large scale, lifestyle modification interventions in high-risk South Asian populations in Europe would reduce the incidence of diabetes in these populations.

A comparison of the in vitro cyto- and neurotoxicity of brominated and halogen-free flame retardants: prioritization in search for safe(r) alternatives.

Brominated flame retardants (BFRs) are abundant persistent organic pollutants with well-studied toxicity. The toxicological and ecological concerns associated with BFRs argue for replacement by safe(r) alternatives. Though previous research identified the nervous system as a sensitive target organ for BFRs, the (neuro) toxic potential of alternative halogen-free flame retardants (HFFRs) is largely unknown. We therefore investigated the in vitro (neuro) toxicity of 13 HFFRs and three BFRs in dopaminergic pheochromocytoma (PC12) and neuroblastoma (B35) cells by assessing several cytotoxic and neurotoxic endpoints. Effects on cell viability and production of reactive oxygen species (ROS) were measured using a combined Alamar Blue and Neutral Red assay and a H2-DCFDA assay, respectively, whereas effects on calcium homeostasis were measured using single-cell fluorescent Ca(2+)-imaging. The majority of the tested flame retardants induced negligible cytotoxicity, except zinc hydroxystannate (ZHS) and zinc stannate (ZS). A considerable fraction of flame retardants affected ROS production (decabromodiphenyl ether (BDE-209), triphenylphosphate (TPP), aluminium trihydroxide (ATH), ammonium polyphosphate (APP), magnesium hydroxide (MHO), ZHS, ZS and melamine polyphosphate (MPP)). Interestingly, ATH, ZHS, ZS and montmorillonite (MMT) increased the basal intracellular calcium concentration ([Ca(2+)]i), whereas tetrabromobisphenol A (TBBPA), resorcinol bis (diphenylphosphate) (RDP), TPP, 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO), ATH, ZHS, ZS and MMT reduced depolarization-evoked increases in [Ca(2+)]i as a result of inhibition of voltage-gated calcium channels. These combined data on the in vitro (neuro) toxicity of HFFRs in comparison with BFRs are essential for prioritization of safe(r) flame retardants. Though additional data are required for a complete (toxic) risk assessment, our data demonstrate that several HFFRs could be suitable substitutes for BFRs.

Plasma sphingolipids mediate the association between gut microbiome composition and type 2 diabetes risk in the HELIUS cohort: a case-cohort study.

INTRODUCTION: The association between the gut microbiome and incident type 2 diabetes (T2D) is potentially partly mediated through sphingolipids, however these possible mediating mechanisms have not been investigated. We examined whether sphingolipids mediate the association between gut microbiome and T2D, using data from the Healthy Life in an Urban Setting study. RESEARCH DESIGN AND METHODS: Participants were of Dutch or South-Asian Surinamese ethnicity, aged 18-70 years, and without T2D at baseline. A case-cohort design (subcohort n=176, cases incident T2D n=36) was used. The exposure was measured by 16S rRNA sequencing (gut microbiome) and mediator by targeted metabolomics (sphingolipids). Dimensionality reduction was achieved by principle component analysis and Shannon diversity. Cox regression and procrustes analyses were used to assess the association between gut microbiome and T2D and sphingolipids and T2D, and between gut microbiome and sphingolipids, respectively. Mediation was tested familywise using mediation analysis with permutation testing and Bonferroni correction. RESULTS: Our study confirmed associations between gut microbiome and T2D and sphingolipids and T2D. Additionally, we showed that the gut microbiome was associated with sphingolipids. The association between gut microbiome and T2D was partly mediated by a sphingolipid principal component, which represents a dominance of ceramide species over more complex sphingolipids (HR 1.17; 95% CI 1.08 to 1.28; proportional explained 48%), and by Shannon diversity (HR 0.97; 95% CI 0.95 to 0.99; proportional explained 24.8%). CONCLUSIONS: These data suggest that sphingolipids mediate the association between microbiome and T2D risk. Future research is needed to confirm observed findings and elucidate causality on a molecular level.

The Association of Cardiometabolic, Diet and Lifestyle Parameters With Plasma Glucagon-like Peptide-1: An IMI DIRECT Study.

CONTEXT: The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood. OBJECTIVE: We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. METHODS: We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D. RESULTS: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. CONCLUSION: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D.

The contribution of smoking to differences in cardiovascular disease incidence between men and women across six ethnic groups in Amsterdam, the Netherlands: The HELIUS study.

It is unclear to what extent differences in cardiovascular disease (CVD) risk between men and women are explained by differences in smoking, and whether this contribution to risk is consistent across ethnic groups. In this prospective study, we determined the contribution of smoking to differences in CVD incidence between men and women, also in various ethnic groups. We linked baseline data of 18,058 participants of six ethnic groups from the HELIUS study (Amsterdam, the Netherlands) to CVD incidence data, based on hospital admission and death records from Statistics Netherlands (2013-2019). The contribution of smoking to CVD incidence, as estimated by the population attributable fraction, was higher in men than in women, overall (24.1% versus 15.6%) and across most ethnic groups. Among Dutch participants, however, the contribution of smoking was higher among women (21.0%) than men (16.2%). Using Cox regression analyses, we observed that differences in smoking prevalence explained 22.0% of the overall lower hazard for CVD in women compared to men. Smoking contributed minimally to the lower hazards for CVD in women among participants of Dutch (0%), Ghanaian (4.9%) and Moroccan origin (0%), but explained 28.6% and 48.6% of the lower hazards in women in South-Asian Surinamese and African Surinamese groups, respectively. While smoking prevention and cessation may lead to lower CVD incidence in most groups of men and women, it may not substantially reduce disparities in CVD risk between men and women in most ethnic groups.

The entero-endocrine response following a mixed-meal tolerance test with a non-nutritive pre-load in participants with pre-diabetes and type 2 diabetes: A crossover randomized controlled trial proof of concept study.

INTRODUCTION: This crossover randomized controlled trial (RCT) investigated differences in short-term entero-endocrine response to a mixed-meal tolerance test preceded by nutrient sensing between participants with pre-diabetes (pre-T2D) and type 2 diabetes (T2D). Additionally, differences in gut and oral microbiome composition between participants with a high and low entero-endocrine response were investigated. RESEARCH DESIGN AND METHODS: Ten participants with pre-T2D and ten with T2D underwent three test days with pre-loads consisting of either swallowing water (control), or rinsing with a non-nutritive sweetener solution, or swallowing the sweetener solution before a mixed-meal tolerance test. Blood glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon, glucose, insulin and peptide YY (PYY) were determined at t = -20, 0, 15, 30, 60, 120 and 240 minutes. The composition of the oral and gut microbiome at baseline were also determined. RESULTS: The entero-endocrine response differed by pre-loads, e.g. a lower PYY response after swallowing the non-nutritive sweetener (-3585.2pg/mL [95% CI: -6440.6; -729.8]; p = 0.01). But it also differed by T2D status, e.g. a higher glucose, glucagon and PYY response was found in participants with T2D, compared to those with pre-T2D. Evidence for associations between the oral and gut microbiome composition and the entero-endocrine response was limited. Still, the level of entero-endocrine response was associated with several oral microbiome measures. Higher oral anterior α-diversity was associated with a lower PYY response (e.g. Inverse Simpson index -1357pg/mL [95% CI -2378; -336; 1.24]), and higher oral posterior α-diversitywith a higher GIP response (e.g. Inverse Simpson index 6773pg/mL [95% CI 132; 13414]) in models adjusted for sex, age and T2D status. CONCLUSIONS: Non-nutritive pre-loads influence the entero-endocrine response to a mixed-meal, and this effect varies based on (pre-)T2D status. The entero-endocrine response is likely not associated with the gut microbiome, and there is limited evidence for association with the α-diversity of the oral microbiome composition. TRIAL REGISTRATION: Trial register: Netherlands Trial Register NTR7212, accessible through International Clinical Trials Registry Platform: ICTRP Search Portal (who.int).

Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

The acceptability and effect of a culturally-tailored dance intervention to promote physical activity in women of South Asian origin at risk of diabetes in the Netherlands-A mixed-methods feasibility study.

OBJECTIVE: Populations of South Asian (SA) origin are at high risk of type 2 diabetes (T2D) and related complications. Analysis of T2D prevention interventions for these populations show that limited attention has been given to facilitating increased physical activity (PA) in a culturally appropriate manner. The aim of this feasibility study was to identify whether culturally tailored dance is acceptable to women of SA origin, and whether it may have an effect on PA and PA-related social cognitive determinants. METHODS: A community-based culturally tailored dance intervention choreographed to Bollywood music was evaluated among 26 women of SA origin in the Netherlands for 10 weeks, 2 times per week. This feasibility study was conducted as a before-after, mixed-methods study, combining data from focus groups, individual interviews, questionnaires and accelerometers. RESULTS: The majority of participants were in the age of 50-59 years and at moderate-to-high T2D risk. There was high attendance (73%), low drop out (12%) and high satisfaction scores for various program components. Key reasons for participation were the cultural appropriateness, in particular the combination of historically and emotionally embedded Indian music and dance, and the non-competitive nature of the intervention. On average, in each of the 19 one-hour sessions, participants spent 30.8 minutes in objectively assessed light intensity PA, 14.1 minutes in moderate intensity PA and 0.3 minutes in vigorous PA, and took 2,100 steps during a session. At follow-up, total moderate-to-vigorous PA increased by 7.8 minutes per day (95%CI: 3.1, 12.5) and daily steps increased by 784 (95%CI: 173, 1394), with a concomitant reduction in light PA of 12 minutes per day (95%CI: -21.9, -2.2). Positive shifts in some PA-behavioral social cognitive determinants and no negative side-effects were observed. CONCLUSIONS: Bollywood Dance appears to be a feasible, culturally acceptable and potentially effective approach to increase PA in SA women in the Netherlands. A pilot cluster RCT is needed to confirm these initial findings on effectiveness.

The iHealth-T2D study: a cluster randomised trial for the prevention of type 2 diabetes amongst South Asians with central obesity and prediabetes-a statistical analysis plan.

BACKGROUND: South Asians are at high risk of type 2 diabetes (T2D). Lifestyle modification is effective at preventing T2D amongst South Asians, but the approaches to screening and intervention are limited by high costs, poor scalability and thus low impact on T2D burden. An intensive family-based lifestyle modification programme for the prevention of T2D was developed. The aim of the iHealth-T2D trial is to compare the effectiveness of this programme with usual care. METHODS: The iHealth-T2D trial is designed as a cluster randomised controlled trial (RCT) conducted at 120 sites across India, Pakistan, Sri Lanka and the UK. A total of 3682 South Asian men and women with age between 40 and 70 years without T2D but at elevated risk for T2D [defined by central obesity (waist circumference ≥ 95 cm in Sri Lanka or ≥ 100 cm in India, Pakistan and the UK) and/or prediabetes (HbA1c ≥ 6.0%)] were included in the trial. Here, we describe in detail the statistical analysis plan (SAP), which was finalised before outcomes were available to the investigators. The primary outcome will be evaluated after 3 years of follow-up after enrolment to the study and is defined as T2D incidence in the intervention arm compared to usual care. Secondary outcomes are evaluated both after 1 and 3 years of follow-up and include biochemical measurements, anthropometric measurements, behavioural components and treatment compliance. DISCUSSION: The iHealth-T2D trial will provide evidence of whether an intensive family-based lifestyle modification programme for South Asians who are at high risk for T2D is effective in the prevention of T2D. The data from the trial will be analysed according to this pre-specified SAP. ETHICS AND DISSEMINATION: The trial was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and in conference presentations. TRIAL REGISTRATION: EudraCT 2016-001,350-18 . Registered on 14 April 2016. CLINICALTRIALS: gov NCT02949739 . Registered on 31 October 2016.

Sex differences in the association of sphingolipids with age in Dutch and South-Asian Surinamese living in Amsterdam, the Netherlands.

BACKGROUND: Men have a higher risk for cardiovascular disease (CVD) early in life, while women have a higher risk later in life. The sex-related differences in CVD risk, especially by age, could be related to sphingolipid metabolism. We compared plasma sphingolipid concentrations and its increase by age in men and women. METHODS: Plasma concentrations of 13 types of sphingolipids were measured by liquid chromatography-tandem mass spectrometry in a random subsample of 328 men and 372 women of Dutch and South-Asian Surinamese ethnic origin, participating in the HELIUS study. Sphingolipid concentrations were compared between men and women by age group (18-39, 40-55, and 56-70 years). Multiple linear regression was used to determine sex differences in age trends in sphingolipids stratified by ethnicity. Analyses were performed without adjustment and adjusted for body mass index (BMI) and waist circumference. RESULTS: At age 18-39 years, sphingolipid concentrations were lower in women than those in men, but at age 56-70 years this was reversed. At higher age, women showed higher concentrations than men. In line, we observed a more rapid increase of sphingolipid concentrations by age in women than in men. The observed sex differences were not explained by BMI or waist circumference. Patterns of sex differences were similar across ethnic groups, although the strength of associations differed. CONCLUSIONS: Mean sphingolipid concentrations increase more rapidly with age in women than in men. Therefore, plasma lipid concentrations of sphingolipids, although lower in women than in men at younger age, are higher in women than in men at older age.

The iHealth-T2D study, prevention of type 2 diabetes amongst South Asians with central obesity and prediabetes: study protocol for a randomised controlled trial.

BACKGROUND: People from South Asia are at increased risk of type 2 diabetes (T2D). There is an urgent need to develop approaches for the prevention of T2D in South Asians that are cost-effective, generalisable and scalable across settings. HYPOTHESIS: Compared to usual care, the risk of T2D can be reduced amongst South Asians with central obesity or raised HbA1c, through a 12-month lifestyle modification programme delivered by community health workers. DESIGN: Cluster randomised clinical trial (1:1 allocation to intervention or usual care), carried out in India, Pakistan, Sri Lanka and the UK, with 30 sites per country (120 sites total). Target recruitment 3600 (30 participants per site) with annual follow-up for 3 years. ENTRY CRITERIA: South Asian, men or women, age 40-70 years with (i) central obesity (waist circumference ≥ 100 cm in India and Pakistan; ≥90 cm in Sri Lanka) and/or (ii) prediabetes (HbA1c 6.0-6.4% inclusive). EXCLUSION CRITERIA: known type 1 or 2 diabetes, normal or underweight (body mass index < 22 kg/m2); pregnant or planning pregnancy; unstable residence or planning to leave the area; and serious illness. ENDPOINTS: The primary endpoint is new-onset T2D at 3 years, defined as (i) HbA1c ≥ 6.5% or (ii) physician diagnosis and on treatment for T2D. Secondary endpoints at 1 and 3 years are the following: (i) physical measures: waist circumference, weight and blood pressure; (ii) lifestyle measures: smoking status, alcohol intake, physical activity and dietary intake; (iii) biochemical measures: fasting glucose, insulin and lipids (total and HDL cholesterol, triglycerides); and (iv) treatment compliance. INTERVENTION: Lifestyle intervention (60 sites) or usual care (60 sites). Lifestyle intervention was delivered by a trained community health worker over 12 months (5 one-one sessions, 4 group sessions, 13 telephone sessions) with the goal of the participants achieving a 7% reduction in body mass index and a 10-cm reduction in waist circumference through (i) improved diet and (ii) increased physical activity. Usual care comprised a single 30-min session of lifestyle modification advice from the community health worker. RESULTS: We screened 33,212 people for inclusion into the study. We identified 10,930 people who met study entry criteria, amongst whom 3682 agreed to take part in the intervention. Study participants are 49.2% female and aged 52.8 (SD 8.2) years. Clinical characteristics are well balanced between intervention and usual care sites. More than 90% of follow-up visits are scheduled to be complete in December 2020. Based on the follow-up to end 2019, the observed incidence of T2D in the study population is in line with expectations (6.1% per annum). CONCLUSION: The iHealth-T2D study will advance understanding of strategies for the prevention of diabetes amongst South Asians, use approaches for screening and intervention that are adapted for low-resource settings. Our study will thus inform the implementation of strategies for improving the health and well-being of this major global ethnic group. IRB APPROVAL: 16/WM/0171 TRIAL REGISTRATION: EudraCT 2016-001350-18 . Registered on 14 April 2016. ClinicalTrials.gov NCT02949739 . Registered on 31 October 2016, First posted on 31/10/2016.

Effects of a lifestyle intervention programme after 1 year of follow-up among South Asians at high risk of type 2 diabetes: a cluster randomised controlled trial.

INTRODUCTION: South Asians are at high risk of type 2 diabetes (T2D). We assessed whether intensive family-based lifestyle intervention leads to significant weight loss, improved glycaemia and blood pressure in adults at elevated risk for T2D. METHODS: This cluster randomised controlled trial (iHealth-T2D) was conducted at 120 locations across India, Pakistan, Sri Lanka and the UK. We included 3684 South Asian men and women, aged 40-70 years, without T2D but with raised haemoglobin A1c (HbA1c) and/or waist circumference. Participants were randomly allocated either to the family-based lifestyle intervention or control group by location clusters. Participants in the intervention received 9 visits and 13 telephone contacts by community health workers over 1-year period, and the control group received usual care. Reductions in weight (aim >7% reduction), waist circumference (aim ≥5 cm reduction), blood pressure and HbA1C at 12 months of follow-up were assessed. Our linear mixed-effects regression analysis was based on intention-to-treat principle and adjusted for age, sex and baseline values. RESULTS: There were 1846 participants in the control and 1838 in the intervention group. Between baseline and 12 months, mean weight of participants in the intervention group reduced by 1.8 kg compared with 0.4 kg in the control group (adjusted mean difference -1.10 kg (95% CI -1.70 to -1.06), p<0.001). The adjusted mean difference for waist circumference was -1.9 cm (95% CI -2.5; to 1.3), p<0.001). No overall difference was observed for blood pressure or HbA1c. People who attended multiple intervention sessions had a dose-dependent effect on waist circumference, blood pressure and HbA1c, but not on weight. CONCLUSION: An intensive family-based lifestyle intervention adopting low-resource strategies led to effective reduction in weight and waist circumference at 12 months, which has potential long-term benefits for preventing T2D. A higher number of attended sessions increased the effect on waist circumference, blood pressure and HbA1c. TRIAL REGISTRATION NUMBER: EudraCT: 2016-001350-18; ClinicalTrials.gov: NCT02949739.

Behavioral Circadian Timing System Disruptors and Incident Type 2 Diabetes in a Nonshift Working Multiethnic Population.

OBJECTIVE: This study aimed to describe distributions of behavioral circadian disruptors in a free-living setting among a nonshift working multiethnic population, estimate the associated risk of type 2 diabetes (T2D), and determine whether disruptors account for ethnic differences in T2D. METHODS: Participants from six ethnic groups were included (Amsterdam, the Netherlands; n = 1,347-3,077 per group). Multinomial logistic regression was used to estimate ethnic differences in disruptors, such as skipping breakfast, eating erratically, and sleep duration. Associations between disruptors and incident T2D and the interaction by ethnicity were studied by Cox regression. RESULTS: Ethnic minority populations skipped breakfast more often, timed meals differently, had longer periods of fasting, ate more erratically, and had more short/long sleep durations than the Dutch. Night snacking from 4 am to 6 am (HR: 5.82; 95% CI: 1.42-23.91) and both short (HR: 1.48; 95% CI: 1.03-2.12) and long sleep (HR: 3.09; 95% CI: 1.54-6.22), but no other disruptors, were associated with T2D. The higher T2D risk among ethnic minority populations compared with Dutch did not decrease after adjustment for last snack or length of sleep. CONCLUSIONS: Although prevalence of circadian disruptors was higher among ethnic minority populations and some disruptors were associated with T2D, disruptors did not account for ethnic differences in T2D risk.

Contributions of amino acid, acylcarnitine and sphingolipid profiles to type 2 diabetes risk among South-Asian Surinamese and Dutch adults.

INTRODUCTION: People of South Asian origin are at high risk of type 2 diabetes (T2D), but the underpinning mechanisms are not fully understood. We determined ethnic differences in acylcarnitine, amino acid and sphingolipid concentrations and determined the associations with T2D. RESEARCH DESIGN AND METHODS: Associations between these metabolites and incident T2D among Dutch and South-Asian Surinamese were determined in participants from the Healthy Life in an Urban Setting (HELIUS) study (Amsterdam, the Netherlands) using Prentice-weighted Cox regression. The HELIUS study includes 95 incident T2D cases and a representative subcohort of 700 people from a cohort of 5977 participants with a mean follow-up of 4 years. RESULTS: Concentrations of acylcarnitines were comparable between both ethnic groups. Amino acid and lactosylceramide concentrations were higher among South-Asian Surinamese than Dutch (eg, isoleucine 65.7 (SD 16.3) vs 60.7 (SD 15.6) µmol/L). Ceramide concentrations were lower among South-Asian Surinamese than Dutch (eg, Cer d18:1 8.48 (SD 2.04) vs 9.08 (SD 2.29) µmol/L). Metabolic dysregulation preceded T2D without evidence for a multiplicative interaction by ethnicity. Most amino acids and (dihydro)ceramides were associated with increased risk (eg, Cer d18:1 HR 2.38, 95% CI 1.81 to 3.12) while acylcarnitines, glycine, glutamine and lactosylceramides were associated with decreased risk for T2D (eg, LacCer d18:2 HR 0.56, 95% CI 0.42 to 0.77). CONCLUSIONS: Overall, these data suggest that the disturbances underlying amino acid and sphingolipid metabolism may be predictive of T2D risk in populations of both South Asian and European background. These observations may be used as starting point to unravel the underlying metabolic disturbances.

The high risk for type 2 diabetes among ethnic minority populations is not explained by low-grade inflammation.

Our aim was to identify whether low-grade inflammation, reflected by C-reactive protein (CRP), explains the higher risk for incident type 2 diabetes (T2D) among ethnic minorities. We included 837 Dutch, 712 South-Asian Surinamese, 797 African Surinamese, 804 Ghanaian, 817 Turkish and 778 Moroccan origin participants of the HELIUS study (Amsterdam, the Netherlands). We used multiple linear regression to assess ethnic differences in CRP levels. We determined the association of CRP with T2D and the modifying effect of ethnicity by cox regression, and compared hazard ratios for the association between ethnicity and T2D before and after adjustment for CRP. CRP levels were higher in ethnic minority groups than in Dutch origin participants. CRP was associated with a higher T2D incidence, similarly across ethnic groups (overall HR per SD 1.38 [95% CI 1.14; 1.68]). However, the association was attenuated and no longer statistically significant after adjustment for adiposity measures (HR 1.11 [95% CI 0.90; 1.37]). CRP accounted for a very small part of the ethnic differences in T2D, but only in models unadjusted for adiposity. Low-grade inflammation does not substantially contribute to the higher risk of T2D among ethnic minority populations compared to the Dutch.

Contribution of type 2 diabetes to all-cause mortality, cardiovascular disease incidence and cancer incidence in white Europeans and South Asians: findings from the UK Biobank population-based cohort study.

Objective: To investigate whether the health implications of having type 2 diabetes (T2D) were different in South Asian compared with white European participants. Research design and methods: Prospective data from UK Biobank were used, and 457 935 participants of white European and 7102 of South Asian background were included. Cox proportional regression was performed to investigate the association between T2D and health outcome by ethnicity. Results: Over a mean of 7.0 years (IQR 6.3-7.6) of follow-up, 12 974 participants had died, and 30 347 and 27 159 developed cardiovascular disease (CVD) and cancer, respectively. South Asians had a higher risk for CVD mortality (HR: 1.42, 95% CI 1.07 to 1.89) and incidence (HR: 1.78, 95% CI 1.63 to 1.94), but a decreased risk for cancer mortality (HR: 0.59, 95% CI 0.41 to 0.85) and incidence (HR: 0.80, 95% CI 0.70 to 0.92) compared with white Europeans. Compared with individuals without T2D, both white Europeans and South Asians with T2D had a higher risk for all-cause mortality (1.59 (1.48 to 1.71) vs 2.83 (1.76 to 4.53)), CVD mortality (2.04 (1.82 to 2.28) vs 4.40 (2.37 to 8.16)) and CVD incidence (1.37 (1.31 to 1.44) vs 1.60 (1.31 to 1.95)), respectively. However, the magnitude of the risk was higher for South Asians than white Europeans. Conclusions: Although T2D was associated with a higher risk for all-cause mortality and CVD incidence and mortality, in both white Europeans and South Asians, the risk experienced by South Asians with T2D was higher than their white European counterparts.

The Association of Acylcarnitines and Amino Acids With Age in Dutch and South-Asian Surinamese Living in Amsterdam.

Context: Type 2 diabetes and cardiovascular disease occur more frequently and at a younger age in South-Asians than Europeans. This may be related to differences in regulation of the fatty acid metabolism during aging. We compared age-related acylcarnitine and amino acid concentrations in Dutch and South-Asian Surinamese study participants. Methods: We measured types of acylcarnitine and amino acid concentrations in plasma (by tandem mass spectrometry) in a random subsample of 350 Dutch and 350 South-Asian Surinamese origin participants of the Healthy Life in an Urban Setting study (Amsterdam, Netherlands). We derived principal components (PCs) from the metabolites. Linear regression was used to assess differences in PCs and individual metabolite concentrations, and their age trends between the groups by sex. We adjusted for body mass index and intake of fat and total energy. Results: Mean age was 44.8 (SD, 13.3) years. Amino acid concentrations were higher among South-Asian Surinamese women compared with Dutch women; acylcarnitine and amino acid levels were higher among South-Asian Surinamese men than Dutch men. Metabolite levels increased similarly with age in both ethnic groups. Results remained similar after adjustment. Conclusion: Ethnic differences in metabolite concentrations suggest that fatty acid and amino acid metabolism are more dysregulated among South-Asian Surinamese compared with Dutch from a young age. During adulthood, metabolites increase similarly in both ethnic groups.