The roles of DGAT1 and DGAT2 in human myotubes are dependent on donor patho-physiological background.

The roles of DGAT1 and DGAT2 in lipid metabolism and insulin responsiveness of human skeletal muscle were studied using cryosections and myotubes prepared from muscle biopsies from control, athlete, and impaired glucose regulation (IGR) cohorts of men. The previously observed increases in intramuscular triacylglycerol (IMTG) in athletes and IGR were shown to be related to an increase in lipid droplet (LD) area in type I fibers in athletes but, conversely, in type II fibers in IGR subjects. Specific inhibition of both diacylglycerol acyltransferase (DGAT) 1 and 2 decreased fatty acid (FA) uptake by myotubes, whereas only DGAT2 inhibition also decreased fatty acid oxidation. Fatty acid uptake in myotubes was negatively correlated with the lactate thresholds of the respective donors. DGAT2 inhibition lowered acetate uptake and oxidation in myotubes from all cohorts whereas DGAT1 inhibition had no effect. A positive correlation between acetate oxidation in myotubes and resting metabolic rate (RMR) from fatty acid oxidation in vivo was observed. Myotubes from athletes and IGR had higher rates of de novo lipogenesis from acetate that were normalized by DGAT2 inhibition. Moreover, DGAT2 inhibition in myotubes also resulted in increased insulin-induced Akt phosphorylation. The differential effects of DGAT1 and DGAT2 inhibition suggest that the specialized role of DGAT2 in esterifying nascent diacylglycerols and de novo synthesized FA is associated with synthesis of a pool of triacylglycerol, which upon hydrolysis results in effectors that promote mitochondrial fatty acid oxidation but decrease insulin signaling in skeletal muscle cells.

Liver, visceral and subcutaneous fat in men and women of South Asian and white European descent: a systematic review and meta-analysis of new and published data.

AIMS/HYPOTHESIS: South Asians have a two- to fivefold higher risk of developing type 2 diabetes than those of white European descent. Greater central adiposity and storage of fat in deeper or ectopic depots are potential contributing mechanisms. We collated existing and new data on the amount of subcutaneous (SAT), visceral (VAT) and liver fat in adults of South Asian and white European descent to provide a robust assessment of potential ethnic differences in these factors. METHODS: We performed a systematic review of the Embase and PubMed databases from inception to August 2021. Unpublished imaging data were also included. The weighted standardised mean difference (SMD) for each adiposity measure was estimated using random-effects models. The quality of the studies was assessed using the ROBINS-E tool for risk of bias and overall certainty of the evidence was assessed using the GRADE approach. The study was pre-registered with the OSF Registries ( https://osf.io/w5bf9 ). RESULTS: We summarised imaging data on SAT, VAT and liver fat from eight published and three previously unpublished datasets, including a total of 1156 South Asian and 2891 white European men, and 697 South Asian and 2271 white European women. Despite South Asian men having a mean BMI approximately 0.5-0.7 kg/m2 lower than white European men (depending on the comparison), nine studies showed 0.34 SMD (95% CI 0.12, 0.55; I2=83%) more SAT and seven studies showed 0.56 SMD (95% CI 0.14, 0.98; I2=93%) more liver fat, but nine studies had similar VAT (-0.03 SMD; 95% CI -0.24, 0.19; I2=85%) compared with their white European counterparts. South Asian women had an approximately 0.9 kg/m2 lower BMI but 0.31 SMD (95% CI 0.14, 0.48; I2=53%) more liver fat than their white European counterparts in five studies. Subcutaneous fat levels (0.03 SMD; 95% CI -0.17, 0.23; I2=72%) and VAT levels (0.04 SMD; 95% CI -0.16, 0.24; I2=71%) did not differ significantly between ethnic groups in eight studies of women. CONCLUSIONS/INTERPRETATION: South Asian men and women appear to store more ectopic fat in the liver compared with their white European counterparts with similar BMI levels. Given the emerging understanding of the importance of liver fat in diabetes pathogenesis, these findings help explain the greater diabetes risks in South Asians. FUNDING: There was no primary direct funding for undertaking the systematic review and meta-analysis.

Association Between Device-Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of 94 739 UK Biobank Participants.

BACKGROUND: Studies of objectively measured physical activity (PA) have investigated acute cardiovascular outcomes but not heart failure (HF), an emerging chronic condition. This study aimed to investigate the dose-response relationship between device-measured PA and HF by intensity of PA. METHODS: This was a prospective cohort study of 94 739 UK Biobank participants who had device-measured PA in 2013 to 2015 and were free from myocardial infarction and HF. PA was measured with a wrist-worn accelerometer, and time spent on light-, moderate-, and vigorous-intensity PA was extracted. Incident HF was ascertained from linked hospital and death records. Cox proportional hazard models with cubic penalized splines were used to study the associations, which were adjusted for sociodemographic and lifestyle factors. Competing risk was handled with cause-specific hazard ratios. RESULTS: The overall incidence of HF was 98.5 per 10 000 person-years over a median 6.1 years of follow-up. Compared with participants who undertook no moderate- to vigorous-intensity PA, those who performed 150 to 300 min/wk of moderate-intensity PA (hazard ratio, 0.37 [95% CI, 0.34-0.41]) and 75 to 150 min/wk of vigorous-intensity PA (hazard ratio, 0.34 [95% CI, 0.25-0.46]) were at lower HF risk. The association between vigorous-intensity PA and HF was reverse-J shaped with a potentially lower risk reduction above 150 min/wk. CONCLUSIONS: Device-measured PA, especially moderate-intensity PA, was associated with a lower risk of HF. Current vigorous-intensity PA recommendations should be encouraged but not increased. In contrast, increasing moderate-intensity PA may be beneficial even among those meeting current recommendations.

Social connection and mortality in UK Biobank: a prospective cohort analysis.

BACKGROUND: Components of social connection are associated with mortality, but research examining their independent and combined effects in the same dataset is lacking. This study aimed to examine the independent and combined associations between functional and structural components of social connection and mortality. METHODS: Analysis of 458,146 participants with full data from the UK Biobank cohort linked to mortality registers. Social connection was assessed using two functional (frequency of ability to confide in someone close and often feeling lonely) and three structural (frequency of friends/family visits, weekly group activities, and living alone) component measures. Cox proportional hazard models were used to examine the associations with all-cause and cardiovascular disease (CVD) mortality. RESULTS: Over a median of 12.6 years (IQR 11.9-13.3) follow-up, 33,135 (7.2%) participants died, including 5112 (1.1%) CVD deaths. All social connection measures were independently associated with both outcomes. Friends/family visit frequencies < monthly were associated with a higher risk of mortality indicating a threshold effect. There were interactions between living alone and friends/family visits and between living alone and weekly group activity. For example, compared with daily friends/family visits-not living alone, there was higher all-cause mortality for daily visits-living alone (HR 1.19 [95% CI 1.12-1.26]), for never having visits-not living alone (1.33 [1.22-1.46]), and for never having visits-living alone (1.77 [1.61-1.95]). Never having friends/family visits whilst living alone potentially counteracted benefits from other components as mortality risks were highest for those reporting both never having visits and living alone regardless of weekly group activity or functional components. When all measures were combined into overall functional and structural components, there was an interaction between components: compared with participants defined as not isolated by both components, those considered isolated by both components had higher CVD mortality (HR 1.63 [1.51-1.76]) than each component alone (functional isolation 1.17 [1.06-1.29]; structural isolation 1.27 [1.18-1.36]). CONCLUSIONS: This work suggests (1) a potential threshold effect for friends/family visits, (2) that those who live alone with additional concurrent markers of structural isolation may represent a high-risk population, (3) that beneficial associations for some types of social connection might not be felt when other types of social connection are absent, and (4) considering both functional and structural components of social connection may help to identify the most isolated in society.

Dose-response relationship between device-measured physical activity and incident type 2 diabetes: findings from the UK Biobank prospective cohort study.

BACKGROUND: Most studies investigating the association between physical activity (PA) and the risk of type 2 diabetes are derived from self-reported questionnaires, with limited evidence using device-based measurements. Therefore, this study aimed to investigate the dose-response relationship between device-measured PA and incident type 2 diabetes. METHODS: This prospective cohort study included 40,431 participants of the UK Biobank. Wrist-worn accelerometers were used to estimate total, light, moderate, vigorous and moderate-to-vigorous PA. The associations between PA and incident type 2 diabetes were analysed using Cox-proportional hazard models. The mediating role of body mass index (BMI) was tested under a causal counterfactual framework. RESULTS: The median follow-up period was 6.3 years (IQR: 5.7-6.8), with 591 participants developing type 2 diabetes. Compared to those achieving < 150 min/week of moderate PA, people achieving 150-300, 300-600 and > 600 min/week were at 49% (95% CI 62-32%), 62% (95% CI 71-50%) and 71% (95% CI 80-59%) lower risk of type 2 diabetes, respectively. For vigorous PA, compared to those achieving < 25 min/week, individuals achieving 25-50, 50-75 and > 75 min/week were at 38% (95% CI 48-33%), 48% (95% CI 64-23%) and 64% (95% CI 78-42%) lower type 2 diabetes risk, respectively. Twelve per cent and 20% of the associations between vigorous and moderate PA and type 2 diabetes were mediated by lower BMI, respectively. CONCLUSIONS: PA has clear dose-response relationship with a lower risk of type 2 diabetes. Our findings support the current aerobic PA recommendations but suggest that additional PA beyond the recommendations is associated with even greater risk reduction. TRIAL REGISTRATION: The UK Biobank study was approved by the North West Multi-Centre Research Ethics Committee (Ref 11/NW/0382 on June 17, 2011).

The effect of home-based resistance exercise training in people with type 2 diabetes: A randomized controlled trial.

AIMS: To evaluate the effects of pragmatic home-based resistance exercise training on glycated haemoglobin (HbA1c) as well as muscle strength and body composition in people with type 2 diabetes. MATERIALS AND METHODS: People with type 2 diabetes were randomized (1:1) to usual care or usual care plus home-based resistance exercise for 32 weeks. The changes in HbA1c, body composition, physical function, quality of life, continuous glucose monitoring and liver fat were compared by randomized group using linear regression. RESULTS: This study recruited 120 participants (female: n = 46 [38%], age 60.2 (9.4) years, BMI 31.1 (5.4) kg.m-2 ), 64 to intervention and 56 to usual care. Intention to treat analysis revealed no effect on HbA1c (difference in difference: -0.4 mmol/mol, 95% confidence interval [CI]: -3.26, 2.47; p = 0.78) but the intervention increased the number of push-ups (3.6 push-ups, 95% CI: 0.8, 6.4), arm lean mass (116 g, 95% CI: 6, 227) and leg lean mass (438 g, 95% CI 65, 810) and decreased liver fat (-1.27%, 95% CI -2.17, -0.38), with no differences in other outcomes. Per-protocol analysis revealed similar results. CONCLUSIONS: Home-based resistance exercise is unlikely to lower HbA1c in people with type 2 diabetes but may be of benefit for maintaining muscle mass and function and reducing liver fat.

Recommendations from Diabetes UK's 2022 diabetes and physical activity workshop.

AIMS: To describe the process and outputs of a workshop convened to identify key priorities for future research in the area of diabetes and physical activity and provide recommendations to researchers and research funders on how best to address them. METHODS: A 1-day research workshop was conducted, bringing together researchers, people living with diabetes, healthcare professionals, and members of staff from Diabetes UK to identify and prioritise recommendations for future research into physical activity and diabetes. RESULTS: Workshop attendees prioritised four key themes for further research: (i) better understanding of the physiology of exercise in all groups of people: in particular, what patient metabolic characteristics influence or predict the physiological response to physical activity, and the potential role of physical activity in beta cell preservation; (ii) designing physical activity interventions for maximum impact; (iii) promoting sustained physical activity across the life course; (iv) designing physical activity studies for groups with multiple long-term conditions. CONCLUSIONS: This paper outlines recommendations to address the current gaps in knowledge related to diabetes and physical activity and calls on the research community to develop applications in these areas and funders to consider how to stimulate research in these areas.

Association between walking pace and incident type 2 diabetes by adiposity level: A prospective cohort study from the UK Biobank.

AIMS: To investigate the combined association of adiposity and walking pace with incident type 2 diabetes. METHODS: We undertook a prospective cohort study in 194 304 White-European participants (mean age 56.5 years, 55.9% women). Participants' walking pace was self-reported as brisk, average or slow. Adiposity measures included body mass index (BMI), waist circumference (WC) and body fat percentage (BF%). Associations were investigated using Cox proportional hazard models, with a 2-year landmark analysis. A four-way decomposition analysis was used for mediation and additive interaction. RESULTS: The median (interquartile range) follow-up was 5.4 (4.8-6.3) years. During the follow-up period, 4564 participants developed type 2 diabetes. Compared to brisk-walking participants with normal BMI, those with obesity who walked briskly were at an approximately 10- to 12-fold higher risk of type 2 diabetes (hazard ratio [HR] 9.64, 95% confidence interval [CI] 7.24-12.84, in women; HR 11.91, 95% CI 8.80-16.12, in men), whereas those with obesity and walked slowly had an approximately 12- to 15-fold higher risk (HR 12.68, 95% CI 9.62-16.71, in women; HR 15.41, 95% CI 11.27-21.06, in men). There was evidence of an additive interaction between WC and BF% and walking pace among women, explaining 17.8% and 47.9% excess risk respectively. Obesity mediated the association in women and men, accounting for 60.1% and 44.9%, respectively. CONCLUSIONS: Slow walking pace is a risk factor for type 2 diabetes independent of adiposity. Promoting brisk walking as well as weight management might be an effective type 2 diabetes prevention strategy given their synergistic effects.

Associations of grip strength and walking pace with mortality in stroke survivors: A prospective study from UK Biobank.

INTRODUCTION: Although stroke is an emerging cause of disability and mortality globally, associations between physical capability markers and mortality in stroke survivors are elusive. This study investigated the individual and combined associations of walking pace and grip strength with all-cause and stroke mortality in stroke survivors. METHODS: Individual and combined associations of walking pace and grip strength with stroke deaths and all-cause mortality were investigated using Cox proportional-hazard models adjusted for sociodemographic, lifestyle, and health-related variables. RESULTS: Seven thousand four hundred eighty-six stroke survivors from the UK Biobank study (aged 40-70 years; 42.4% women) were included in this prospective study. Over a median follow-up of 12.6 (IQR: 11.9-13.3) years, 1490 (19.9%) participants died, of whom 222 (3.0%) died from stroke. After adjusting for confounding factors, and compared to individuals in the average/brisk walking pace category, those who reported a slow walking pace had 2.00 (95% CI: 1.50-2.68) and 1.99 (95% CI: 1.78-2.23) times higher risk of stroke mortality and all-cause mortality, respectively. Similar associations were identified for participants with low grip strength compared with those with normal levels. For combined associations, those with both slow walking pace and low grip strength showed the highest risk of stroke mortality (hazard ratio: 2.86 [95% CI: 1.93-4.22]). Similar results were found for all-cause mortality. CONCLUSIONS: Low grip strength and slow walking pace were associated with a higher risk of stroke and all-cause mortality in stroke survivors. If these associations are causal, improving physical capability among stroke survivors might potentially prolong survival.

Effects of increasing light versus moderate-to-vigorous physical activity on cardiometabolic health in Chinese adults with obesity.

Increasing daily physical activity (PA) is a practical way to decrease the risk of cardiometabolic diseases, while the studies on exercise intensity remain limited. The purpose of the present study was to compare the effects of increasing light PA (LPA) or moderate-to-vigorous PA (MVPA) for 12 weeks on cardiometabolic markers in Chinese adults with obesity. Fifty-three adults were randomly assigned to the 1) control group, 2) LPA group, and 3) MVPA group in free-living settings. The intervention effects on body composition, cardiorespiratory fitness, and cardiometabolic biomarkers were analysed using a generalized estimated equation model adjusted for baseline values and potential confounders. Compared with the control group, the MVPA group showed improvements in body composition, lipids, C-peptide, monocyte chemoattractant protein-1 (MCP-1), interleukin-8, leptin, and E-selectin. A favourable change in triglycerides and E-selectin were observed in the LPA group when compared to the control group. Lastly, improvements in waist circumference, C-reactive protein, and MCP-1 were observed in the MVPA group when compared to those in the LPA group. Although increasing both LPA and MVPA improved certain cardiometabolic biomarkers, the latter may have more benefits. These findings imply that MVPA may reduce cardiometabolic disease risk more effectively than LPA, especially in Chinese adults with obesity.

Derivation and Validation of a 10-Year Risk Score for Symptomatic Abdominal Aortic Aneurysm: Cohort Study of Nearly 500 000 Individuals.

BACKGROUND: Abdominal aortic aneurysm (AAA) can occur in patients who are ineligible for routine ultrasound screening. A simple AAA risk score was derived and compared with current guidelines used for ultrasound screening of AAA. METHODS: United Kingdom Biobank participants without previous AAA were split into a derivation cohort (n=401 820, 54.6% women, mean age 56.4 years, 95.5% White race) and validation cohort (n=83 816). Incident AAA was defined as first hospital inpatient diagnosis of AAA, death from AAA, or an AAA-related surgical procedure. A multivariable Cox model was developed in the derivation cohort into an AAA risk score that did not require blood biomarkers. To illustrate the sensitivity and specificity of the risk score for AAA, a theoretical threshold to refer patients for ultrasound at 0.25% 10-year risk was modeled. Discrimination of the risk score was compared with a model of US Preventive Services Task Force (USPSTF) AAA screening guidelines. RESULTS: In the derivation cohort, there were 1570 (0.40%) cases of AAA over a median 11.3 years of follow-up. Components of the AAA risk score were age (stratified by smoking status), weight (stratified by smoking status), antihypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and diabetes. In the validation cohort, over 10 years of follow-up, the C-index for the model of the USPSTF guidelines was 0.705 (95% CI, 0.678-0.733). The C-index of the risk score as a continuous variable was 0.856 (95% CI, 0.837-0.878). In the validation cohort, the USPSTF model yielded sensitivity 63.9% and specificity 71.3%. At the 0.25% 10-year risk threshold, the risk score yielded sensitivity 82.1% and specificity 70.7% while also improving the net reclassification index compared with the USPSTF model +0.176 (95% CI, 0.120-0.232). A combined model, whereby risk scoring was combined with the USPSTF model, also improved prediction compared with USPSTF alone (net reclassification index +0.101 [95% CI, 0.055-0.147]). CONCLUSIONS: In an asymptomatic general population, a risk score based on patient age, height, weight, and medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. Further development and validation of risk scores to detect asymptomatic AAA are needed.

Ethnic differences in cardiovascular risk: examining differential exposure and susceptibility to risk factors.

BACKGROUND: Ethnic differences in cardiovascular disease (CVD) risk have been known for decades, but a systematic exploration of how exposure and susceptibility to risk factors may contribute is lacking. This study aimed to investigate the potential impact of differential exposure and susceptibility between South Asian, Black, and White individuals. METHODS: This is a population-based prospective cohort study of UK Biobank participants with a median follow-up of 11.3 years. The association between ethnic group and CVD risk was studied. Additional risk factors were then adjusted to examine mediations. Moderation analysis was conducted to identify whether risk factors had a stronger association in the ethnic minority groups. Population attributable fractions were also calculated to quantify the relative contributions of risk factors for each ethnic group. RESULTS: When adjusted for only age and sex, there was a higher risk of CVD among South Asian (n=8815; HR [95% CI] 1.69 [1.59-1.79]) and Black (n=7526; HR [95% CI] 1.12 [1.03-1.22]) compared with White participants (n=434,809). The excess risk of Black participants was completely attenuated following adjustment for deprivation. Compared with White participants, the associations of BMI, triglycerides, and HbA1c with CVD were stronger in South Asians. Adiposity was attributable to the highest proportion of CVD regardless of ethnicity. Smoking had the second largest contribution to CVD among White and Black participants, and HbA1c among South Asian participants. CONCLUSIONS: Adiposity is an important risk factor for CVD regardless of ethnicity. Ethnic inequalities in CVD incidence may be best tackled by targeting interventions according to ethnic differences in risk profiles.

High prevalence and significant ethnic differences in actionable HbA1C after gestational diabetes mellitus in women living in Norway.

BACKGROUND: The type 2 diabetes risk after gestational diabetes mellitus (GDM) is twice as high in South Asian compared to European women. Current guidelines differ regarding which test to use as a screening-tool post-GDM. We aimed to identify ethnic differences in the prevalence rates and early predictors for actionable HbA1c (defined as prediabetes and diabetes) short time after GDM. METHODS: This cross-sectional study, enrolling South Asian and Nordic women 1-3 years after a diagnosis of GDM, was undertaken at three hospitals in Norway. We performed a clinical and laboratory evaluation including an oral glucose tolerance test (OGTT). Medical records were used to retrieve data during pregnancy. Prediabetes was classified with HbA1c alone or combined with OGTT glucose measurements according to the WHO, WHO-IEC, and ADA criteria (fasting plasma glucose (FPG) 6.1-6.9 mmol/L, FPG 6.1-6.9 mmol/L and/or HbA1c 42-47 mmol/mol (6.0-6.4%), and FPG 5.6-6.9 mmol/L and/or HbA1c 39-47 mmol/mol (5.7-6.4%)). Ethnic differences in prevalence and predictors of glucose deterioration were assed by χ2 (Pearson) tests and logistic regression models. RESULTS: We included 163 South Asian and 108 Nordic women. Actionable HbA1c levels were highly prevalent and more so among South Asian than Nordic women (WHO-IEC-HbA1c: 25.8% vs. 6.5% (p ≤ 0.001), ADA-HbA1c: 58.3% vs. 22.2% (p ≤ 0.001)). Although adding OGTT-data gave higher combined prevalence rates of prediabetes and diabetes (WHO: 65.6% vs. 47.2% (p ≤ 0.05), WHO-IEC: 70.6% vs. 47.2% (p ≤ 0.001), ADA: 87.8% vs. 65.7% (p ≤ 0.001)), the excess risk in the South Asian women was best captured by the HbA1c. Important predictors for glucose deterioration after GDM were: South Asian ethnicity, GDM before the index pregnancy, use of glucose-lowering drugs in pregnancy, higher age, and higher in-pregnancy fasting glucose levels. CONCLUSIONS: In women with GDM 1-3 year previously, we found high prevalence and significant ethnic differences in actionable ADA-HbA1c levels, with South Asian ethnicity, GDM before the index pregnancy, and the use of glucose-lowering drugs in pregnancy as the most important risk factors. This study reinforces the importance of annual screening-preferably with HbA1c measurements-to facilitate early intervention after GDM.

Device-measured physical activity and incident affective disorders.

BACKGROUND: Studies on physical activity (PA) and mental health are largely limited to self-reported PA. This study aims to use prospective cohort data to investigate the association between device-measured PA and affective disorders. METHODS: A total of 37,327 participants from UK Biobank who had not had any prior affective disorder diagnoses were included in this prospective cohort study. Wrist-worn accelerometers were used to measure total, light (LPA), moderate (MPA), and vigorous (VPA) PA. Associations between PA domains and affective disorders were analysed using penalised splines in Cox proportional hazard models. Analyses were adjusted for other intensity-specific PA and sociodemographic and lifestyle factors. Sensitivity analyses were conducted adjusting for body mass index and longstanding illnesses as well as excluding events in the first 2 years of follow-up. Preventable fractions for the population were estimated for MPA and VPA. RESULTS: Over a median follow-up of 6.8 years, 1262 (3.4%) individuals were diagnosed with affective disorders. Replacing 30 min of sedentary behaviour in a week with MPA (HR 0.95, 95% CI 0.94-0.97) or VPA (HR 0.91, 95% CI 0.85-0.98) was associated with lower risk of affective behaviours, up to 500 and 120 min of MPA and VPA. Assuming causality, 5.14% and 18.88% of affective disorders could have been prevented if MPA ≥150 min/week and VPA ≥75 min/week were achieved, respectively, across the study population. CONCLUSIONS: Device-measured MPA and VPA were associated with lower risk of affective disorders. The potential mental health benefits of MPA continue to accrue above the current World Health Organization recommendation.

The association between a lifestyle score, socioeconomic status, and COVID-19 outcomes within the UK Biobank cohort.

BACKGROUND: Infection with SARS-CoV-2 virus (COVID-19) impacts disadvantaged groups most. Lifestyle factors are also associated with adverse COVID-19 outcomes. To inform COVID-19 policy and interventions, we explored effect modification of socioeconomic-status (SES) on associations between lifestyle and COVID-19 outcomes. METHODS: Using data from UK-Biobank, a large prospective cohort of 502,536 participants aged 37-73 years recruited between 2006 and 2010, we assigned participants a lifestyle score comprising nine factors. Poisson regression models with penalised splines were used to analyse associations between lifestyle score, deprivation (Townsend), and COVID-19 mortality and severe COVID-19. Associations between each exposure and outcome were examined independently before participants were dichotomised by deprivation to examine exposures jointly. Models were adjusted for sociodemographic/health factors. RESULTS: Of 343,850 participants (mean age > 60 years) with complete data, 707 (0.21%) died from COVID-19 and 2506 (0.76%) had severe COVID-19. There was evidence of a nonlinear association between lifestyle score and COVID-19 mortality but limited evidence for nonlinearity between lifestyle score and severe COVID-19 and between deprivation and COVID-19 outcomes. Compared with low deprivation, participants in the high deprivation group had higher risk of COVID-19 outcomes across the lifestyle score. There was evidence for an additive interaction between lifestyle score and deprivation. Compared with participants with the healthiest lifestyle score in the low deprivation group, COVID-19 mortality risk ratios (95% CIs) for those with less healthy scores in low versus high deprivation groups were 5.09 (1.39-25.20) and 9.60 (4.70-21.44), respectively. Equivalent figures for severe COVID-19 were 5.17 (2.46-12.01) and 6.02 (4.72-7.71). Alternative SES measures produced similar results. CONCLUSIONS: Unhealthy lifestyles are associated with higher risk of adverse COVID-19, but risks are highest in the most disadvantaged, suggesting an additive influence between SES and lifestyle. COVID-19 policy and interventions should consider both lifestyle and SES. The greatest public health benefit from lifestyle focussed COVID-19 policy and interventions is likely to be seen when greatest support for healthy living is provided to the most disadvantaged groups.

Are people with metabolically healthy obesity really healthy? A prospective cohort study of 381,363 UK Biobank participants.

AIMS/HYPOTHESIS: People with obesity and a normal metabolic profile are sometimes referred to as having 'metabolically healthy obesity' (MHO). However, whether this group of individuals are actually 'healthy' is uncertain. This study aims to examine the associations of MHO with a wide range of obesity-related outcomes. METHODS: This is a population-based prospective cohort study of 381,363 UK Biobank participants with a median follow-up of 11.2 years. MHO was defined as having a BMI ≥ 30 kg/m2 and at least four of the six metabolically healthy criteria. Outcomes included incident diabetes and incident and fatal atherosclerotic CVD (ASCVD), heart failure (HF) and respiratory diseases. RESULTS: Compared with people who were not obese at baseline, those with MHO had higher incident HF (HR 1.60; 95% CI 1.45, 1.75) and respiratory disease (HR 1.20; 95% CI 1.16, 1.25) rates, but not higher ASCVD. The associations of MHO were generally weaker for fatal outcomes and only significant for all-cause (HR 1.12; 95% CI 1.04, 1.21) and HF mortality rates (HR 1.44; 95% CI 1.09, 1.89). However, when compared with people who were metabolically healthy without obesity, participants with MHO had higher rates of incident diabetes (HR 4.32; 95% CI 3.83, 4.89), ASCVD (HR 1.18; 95% CI 1.10, 1.27), HF (HR 1.76; 95% CI 1.61, 1.92), respiratory diseases (HR 1.28; 95% CI 1.24, 1.33) and all-cause mortality (HR 1.22; 95% CI 1.14, 1.31). The results with a 5 year landmark analysis were similar. CONCLUSIONS/INTERPRETATION: Weight management should be recommended to all people with obesity, irrespective of their metabolic status, to lower risk of diabetes, ASCVD, HF and respiratory diseases. The term 'MHO' should be avoided as it is misleading and different strategies for risk stratification should be explored.

Dose-response association between device-measured physical activity and incident dementia: a prospective study from UK Biobank.

BACKGROUND: Previous cohort studies have investigated the relationship between self-reported physical activity (PA) and dementia. Evidence from objective device-measured PA data is lacking. This study aimed to explore the association of device-measured PA with the risk of dementia incidence and common subtypes (Alzheimer's disease [AD] and vascular dementia) using the UK Biobank study. METHODS: 84,854 participants (55.8% women), invited to participate in the device-measured PA between 2013 and 2015, were included in this prospective cohort study. Wrist accelerometers were used to measure light, moderate, vigorous, moderate-to-vigorous PA (MVPA) and total PA intensity and duration (MET/min/week). Incident dementia (fatal and non-fatal) was extracted from hospital episodes records for incidence and death register for mortality. Incidence follow-up was carried out until the end of March 2021in England and Scotland and the end of March 2018 in Wales. Mortality data were available until February 2021. Nonlinear associations were first investigated using penalised cubic splines fitted in the Cox proportional hazard models. In addition, using MVPA, five categories were created. Associations of these categories with the outcomes were investigated using Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors. RESULTS: After a median follow-up of 6.3 years, 678 individuals were diagnosed with dementia. Evidence of nonlinearity was observed for all PA modes and all-cause dementia. For categories of MVPA, there was a significant trend towards a low risk of overall dementia when higher levels of MVPA were achieved (HRtrend 0.66 [95% CI 0.62 to 0.70]. The lowest risk was identified in individuals who performed more than 1200 MET/min/week, those who had 84% (95% CI 0.12 to 0.21) lower risk of incident dementia compared to those who performed < 300 MET/min/week. CONCLUSIONS: Participants with higher PA levels had a lower risk of incident dementia than those less active, independently of sociodemographic, lifestyle factors and comorbidity. Considering that the majority of previous studies have reported this association using self-reported data, our findings highlight the strong inverse association between PA objectively measured and incident dementia.

Developing a realist informed framework for cultural adaptation of lifestyle interventions for the prevention of type 2 diabetes in South Asian populations in Europe.

AIMS: Selected lifestyle interventions proven effective for White-European populations have been culturally adapted for South Asian populations living in Europe, who are at higher risk of type 2 diabetes. However, a limited theoretical basis underpins how cultural adaptations are believed to augment intervention effectiveness. We undertook a realist review to synthesise existing literature on culturally adapted type 2 diabetes prevention interventions, to develop a framework that shows 'how' cultural adaptation works, for 'whom' and in 'what contexts'. METHODS: We followed the stepped methodological approach of realist review. Our work concluded a European-wide project (EuroDHYAN), and core studies were identified from the preceding EuroDHYAN reviews. Data were extracted, coded into themes and synthesised to create 'Context-Mechanism-Outcome' configurations and to generate a refined explanatory framework. RESULTS: We identified eight core intervention papers. From this evidence, and supporting literature, we examined the 'Team' domain of cultural adaptation and identified a mechanism of shared cultural identity which we theorised as contributing to strong team-participant relationships. We also identified four key contexts which influenced intervention outcomes: 'research setting' and 'heterogeneous populations' (intrinsic to the intervention) and 'broader environment' and 'socio-cultural stress' (extrinsic barriers). CONCLUSIONS: This work instigates research into the mechanisms of cultural adaptation which, if pursued, will allow a more nuanced understanding of how to apply adaptations, and for whom. In practice we recommend greater consideration of heterogeneous and intersecting population characteristics; how intervention design can safeguard sustainability; and how the four key contexts identified influence how, and whether, these interventions work.

Comparison of risk factors between people with type 2 diabetes and matched controls in Nairobi, Kenya.

OBJECTIVE: To identify risk factors associated with type 2 diabetes (T2D) in Nairobi, Kenya. METHODS: A case-control study comparing 70 (53% women) recently diagnosed T2D cases with age-, sex- and socioeconomic status-matched normoglycemic controls (1:1). Objectively measured data were obtained on anthropometrics, handgrip strength and physical activity (by accelerometer). Self-reported data were collected on demographic characteristics and lifestyle factors. Logistic regression models, adjusted for covariates, were used to analyse the data. RESULTS: Each standard deviation (SD) increase in height was associated with lower odds for T2D (adjusted odds ratio (AOR) = 0.34 (95% confidence intervals [CIs] 0.17, 0.66), P = 0.0031). Fat-free mass was inversely associated with T2D (AOR = 0.42 (95% CI 0.24, 0.75), P = 0.0032, per SD increase). Grip strength was associated with a lower risk of T2D (AOR = 0.20 (95% CI 0.08, 0.45), P < 0.001, per SD increase). BMI was not associated with T2D, but higher waist-to-hip ratio was associated higher odds of T2D (AOR = 2.28 (95% CI 1.38, 3.79), P = 0.0014, per SD increase). Physical activity was not associated with T2D. Cases reported higher intakes of fruits and vegetables and a lower intake of sugar than controls. CONCLUSIONS: Central obesity, rather than BMI, may have more utility for T2D risk stratification in Kenya, and interventions that increase muscle mass and strength, as well as support weight loss, may be useful for T2D prevention in this and other SSA populations. However, more evidence is needed to determine whether low muscle mass, strength and height are causally related to T2D risk and/or are indicators of adverse early-life environment.

Contributions of changes in physical activity, sedentary time, diet and body weight to changes in cardiometabolic risk.

BACKGROUND: Increased physical activity (PA), reduced time spent sedentary (SED), healthier diet and reduced body weight may all have a positive impact on cardiometabolic risk. The relative importance of change in each of these variables on cardiometabolic risk, however, is unclear. We therefore sought to investigate the relative contributions of changes in PA, SED, diet and body weight on cardiometabolic risk. METHODS: This is a secondary analysis of data collected from the EuroFIT randomised controlled trial, which was a 12-week group-based lifestyle intervention for overweight middle-aged men delivered by coaches in football club stadia aiming to improve PA, SED, diet, and body weight. PA and SED were assessed by accelerometry, diet using the Dietary Instrument for Nutrition Education (DINE). An overall cardiometabolic risk score was derived from combining z-scores for glucose, HbA1c, insulin, lipids and blood pressure. In total, 707 men (from the overall cohort of 1113) with complete data for these variables at baseline and 12-month follow-up were included in the multivariable linear regression analyses. RESULTS: In multivariable analyses, change in number of steps (explaining 5.1% of R2) and dietary factors (less alcohol, fatty and sugary food, and more fruit and vegetables) (together explaining 4.5% of R2), but not changes in standing time or SED, were significantly associated with change in body weight. Changes in number of steps (R2 = 1.7%), fatty food score (R2 = 2.4%), and sugary food score (R2 = 0.4%) were significantly associated with change in cardiometabolic risk score in univariable models. However, in multivariable models which included changes in weight as well as changes in steps and dietary variables, change in weight explained a substantially larger proportion of the change in cardiometabolic risk score, explaining 14.1% of R2 (out of an overall model R2 of 19.0%). When baseline (as well as change) values were also included in the model, 38.8% of R2 for change in cardiometabolic risk score was explained overall, with 14.1% of R2 still explained by change in weight. CONCLUSION: Change in body weight, together with baseline cardiometabolic risk explained most of the change in cardiometabolic risk. Thus, the benefits of increasing physical activity and improving diet on cardiometabolic risk appear to act largely via an effect on changes in body weight. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN-81935608. Registered 06052015. https://www.isrctn.com/ISRCTN81935608?q=&filters=recruitmentCountry:Portugal&sort=&offset=7&totalResults=92&page=1&pageSize=10&searchType=basic-search.