Genetic evidence for distinct biological mechanisms that link adiposity to type 2 diabetes: towards precision medicine.

We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We employed MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites and Magnetic Resonance Imaging-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size, enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat.

The value of neck adipose tissue as a predictor for metabolic risk in health and type 2 diabetes.

Upper-body adiposity is adversely associated with metabolic health whereas the opposite is observed for the lower-body. The neck is a unique upper-body fat depot in adult humans, housing thermogenic brown adipose tissue (BAT), which is increasingly recognised to influence whole-body metabolic health. Loss of BAT, concurrent with replacement by white adipose tissue (WAT), may contribute to metabolic disease, and specific accumulation of neck fat is seen in certain conditions accompanied by adverse metabolic consequences. Yet, few studies have investigated the relationships between neck fat mass (NFM) and cardiometabolic risk, and the influence of sex and metabolic status. Typically, neck circumference (NC) is used as a proxy for neck fat, without considering other determinants of NC, including variability in neck lean mass. In this study we develop and validate novel methods to quantify NFM using dual x-ray absorptiometry (DEXA) imaging, and subsequently investigate the associations of NFM with metabolic biomarkers across approximately 7000 subjects from the Oxford BioBank. NFM correlated with systemic insulin resistance (Homeostatic Model Assessment for Insulin Resistance; HOMA-IR), low-grade inflammation (plasma high-sensitivity C-Reactive Protein; hsCRP), and metabolic markers of adipose tissue function (plasma triglycerides and non-esterified fatty acids; NEFA). NFM was higher in men than women, higher in type 2 diabetes mellitus compared with non-diabetes, after adjustment for total body fat, and also associated with overall cardiovascular disease risk (calculated QRISK3 score). This study describes the development of methods for accurate determination of NFM at scale and suggests a specific relationship between NFM and adverse metabolic health.

Precision MRI phenotyping of muscle volume and quality at a population scale.

Introduction: Magnetic resonance imaging (MRI) enables direct measurements of muscle volume and quality, allowing for an in-depth understanding of their associations with anthropometric traits, and health conditions. However, it is unclear which muscle volume measurements: total muscle volume, regional measurements, measurements of muscle quality: intermuscular adipose tissue (IMAT) or proton density fat fraction (PDFF), are most informative and associate with relevant health conditions such as dynapenia and frailty. Methods: We have measured image-derived phenotypes (IDPs) including total and regional muscle volumes and measures of muscle quality, derived from the neck-to-knee Dixon images in 44,520 UK Biobank participants. We further segmented paraspinal muscle from 2D quantitative MRI to quantify muscle PDFF and iron concentration. We defined dynapenia based on grip strength below sex-specific cut-off points and frailty based on five criteria (weight loss, exhaustion, grip strength, low physical activity and slow walking pace). We used logistic regression to investigate the association between muscle volume and quality measurements and dynapenia and frailty. Results: Muscle volumes were significantly higher in male compared with female participants, even after correcting for height while, IMAT (corrected for muscle volume) and paraspinal muscle PDFF were significantly higher in female compared with male participants. From the overall cohort, 7.6% (N = 3,261) were identified with dynapenia, and 1.1% (N = 455) with frailty. Dynapenia and frailty were positively associated with age and negatively associated with physical activity levels. Additionally, reduced muscle volume and quality measurements were associated with both dynapenia and frailty. In dynapenia, muscle volume IDPs were most informative, particularly total muscle exhibiting odds ratios (OR) of 0.392, while for frailty, muscle quality was found to be most informative, in particular thigh IMAT volume indexed to height squared (OR = 1.396), both with p-values below the Bonferroni-corrected threshold (p<8.8×10-5). Conclusion: Our fully automated method enables the quantification of muscle volumes and quality suitable for large population-based studies. For dynapenia, muscle volumes particularly those including greater body coverage such as total muscle are the most informative, whilst, for frailty, markers of muscle quality were the most informative IDPs. These results suggest that different measurements may have varying diagnostic values for different health conditions.

Liver shape analysis using statistical parametric maps at population scale.

BACKGROUND: Morphometric image analysis enables the quantification of differences in the shape and size of organs between individuals. METHODS: Here we have applied morphometric methods to the study of the liver by constructing surface meshes from liver segmentations from abdominal MRI images in 33,434 participants in the UK Biobank. Based on these three dimensional mesh vertices, we evaluated local shape variations and modelled their association with anthropometric, phenotypic and clinical conditions, including liver disease and type-2 diabetes. RESULTS: We found that age, body mass index, hepatic fat and iron content, as well as, health traits were significantly associated with regional liver shape and size. Interaction models in groups with specific clinical conditions showed that the presence of type-2 diabetes accelerates age-related changes in the liver, while presence of liver fat further increased shape variations in both type-2 diabetes and liver disease. CONCLUSIONS: The results suggest that this novel approach may greatly benefit studies aiming at better categorisation of pathologies associated with acute and chronic clinical conditions.

Kidney shape statistical analysis: associations with disease and anthropometric factors.

BACKGROUND: Organ measurements derived from magnetic resonance imaging (MRI) have the potential to enhance our understanding of the precise phenotypic variations underlying many clinical conditions. METHODS: We applied morphometric methods to study the kidneys by constructing surface meshes from kidney segmentations from abdominal MRI data in 38,868 participants in the UK Biobank. Using mesh-based analysis techniques based on statistical parametric maps (SPMs), we were able to detect variations in specific regions of the kidney and associate those with anthropometric traits as well as disease states including chronic kidney disease (CKD), type-2 diabetes (T2D), and hypertension. Statistical shape analysis (SSA) based on principal component analysis was also used within the disease population and the principal component scores were used to assess the risk of disease events. RESULTS: We show that CKD, T2D and hypertension were associated with kidney shape. Age was associated with kidney shape consistently across disease groups. Body mass index (BMI) and waist-to-hip ratio (WHR) were also associated with kidney shape for the participants with T2D. Using SSA, we were able to capture kidney shape variations, relative to size, angle, straightness, width, length, and thickness of the kidneys, within disease populations. We identified significant associations between both left and right kidney length and width and incidence of CKD (hazard ratio (HR): 0.74, 95% CI: 0.61-0.90, p < 0.05, in the left kidney; HR: 0.76, 95% CI: 0.63-0.92, p < 0.05, in the right kidney) and hypertension (HR: 1.16, 95% CI: 1.03-1.29, p < 0.05, in the left kidney; HR: 0.87, 95% CI: 0.79-0.96, p < 0.05, in the right kidney). CONCLUSIONS: The results suggest that shape-based analysis of the kidneys can augment studies aiming at the better categorisation of pathologies associated with chronic kidney conditions.

Abdominal imaging associates body composition with COVID-19 severity.

The main drivers of COVID-19 disease severity and the impact of COVID-19 on long-term health after recovery are yet to be fully understood. Medical imaging studies investigating COVID-19 to date have mostly been limited to small datasets and post-hoc analyses of severe cases. The UK Biobank recruited recovered SARS-CoV-2 positive individuals (n = 967) and matched controls (n = 913) who were extensively imaged prior to the pandemic and underwent follow-up scanning. In this study, we investigated longitudinal changes in body composition, as well as the associations of pre-pandemic image-derived phenotypes with COVID-19 severity. Our longitudinal analysis, in a population of mostly mild cases, associated a decrease in lung volume with SARS-CoV-2 positivity. We also observed that increased visceral adipose tissue and liver fat, and reduced muscle volume, prior to COVID-19, were associated with COVID-19 disease severity. Finally, we trained a machine classifier with demographic, anthropometric and imaging traits, and showed that visceral fat, liver fat and muscle volume have prognostic value for COVID-19 disease severity beyond the standard demographic and anthropometric measurements. This combination of image-derived phenotypes from abdominal MRI scans and ensemble learning to predict risk may have future clinical utility in identifying populations at-risk for a severe COVID-19 outcome.

Artifact-free fat-water separation in Dixon MRI using deep learning.

Chemical-shift encoded MRI (CSE-MRI) is a widely used technique for the study of body composition and metabolic disorders, where derived fat and water signals enable the quantification of adipose tissue and muscle. The UK Biobank is acquiring whole-body Dixon MRI (a specific implementation of CSE-MRI) for over 100,000 participants. Current processing methods associated with large whole-body volumes are time intensive and prone to artifacts during fat-water separation performed by the scanner, making quantitative analysis challenging. The most common artifacts are fat-water swaps, where the labels are inverted at the voxel level. It is common for researchers to discard swapped data (generally around 10%), which is wasteful and may lead to unintended biases. Given the large number of whole-body Dixon MRI acquisitions in the UK Biobank, thousands of swaps are expected to be present in the fat and water volumes from image reconstruction performed on the scanner. If they go undetected, errors will propagate into processes such as organ segmentation, and dilute the results in population-based analyses. There is a clear need for a robust method to accurately separate fat and water volumes in big data collections like the UK Biobank. We formulate fat-water separation as a style transfer problem, where swap-free fat and water volumes are predicted from the acquired Dixon MRI data using a conditional generative adversarial network, and introduce a new loss function for the generator model. Our method is able to predict highly accurate fat and water volumes free from artifacts in the UK Biobank. We show that our model separates fat and water volumes using either single input (in-phase only) or dual input (in-phase and opposed-phase) data, with the latter producing superior results. Our proposed method enables faster and more accurate downstream analysis of body composition from Dixon MRI in population studies by eliminating the need for visual inspection or discarding data due to fat-water swaps. Supplementary Information: The online version contains supplementary material available at 10.1186/s40537-022-00677-1.

Improving the accuracy of fatty liver index to reflect liver fat content with predictive regression modelling.

BACKGROUND: The fatty liver index (FLI) is frequently used as a non-invasive clinical marker for research, prognostic and diagnostic purposes. It is also used to stratify individuals with hepatic steatosis such as non-alcoholic fatty liver disease (NAFLD), and to detect the presence of type 2 diabetes or cardiovascular disease. The FLI is calculated using a combination of anthropometric and blood biochemical variables; however, it reportedly excludes 8.5-16.7% of individuals with NAFLD. Moreover, the FLI cannot quantitatively predict liver fat, which might otherwise render an improved diagnosis and assessment of fatty liver, particularly in longitudinal studies. We propose FLI+ using predictive regression modelling, an improved index reflecting liver fat content that integrates 12 routinely-measured variables, including the original FLI. METHODS AND FINDINGS: We evaluated FLI+ on a dataset from the UK Biobank containing 28,796 individual estimates of proton density fat fraction derived from magnetic resonance imaging across normal to severe levels and interpolated to align with the original FLI range. The results obtained for FLI+ outperform the original FLI by delivering a lower mean absolute error by approximately 47%, a lower standard deviation by approximately 20%, and an increased adjusted R2 statistic by approximately 49%, reflecting a more accurate representation of liver fat content. CONCLUSIONS: Our proposed model predicting FLI+ has the potential to improve diagnosis and provide a more accurate stratification than FLI between absent, mild, moderate and severe levels of hepatic steatosis.

Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and hemolysis.

The spleen plays a key role in iron homeostasis. It is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this role, spleen iron concentration has not been measured in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank by using magnetic resonance imaging and provide a reference range for spleen iron in an unselected population. Through genome-wide association study, we identify associations between spleen iron and regulatory variation at two hereditary spherocytosis genes, ANK1 and SPTA1. Spherocytosis-causing coding mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while these common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes that have been observed clinically. Our genetic study also identifies a signal that co-localizes with a splicing quantitative trait locus for MS4A7, and we show this gene is abundantly expressed in the spleen and in macrophages. The combination of deep learning and efficient image processing enables non-invasive measurement of spleen iron and, in turn, characterization of genetic factors related to the lytic phase of the erythrocyte life cycle and iron reuptake in the spleen.

Precision MRI phenotyping enables detection of small changes in body composition for longitudinal cohorts.

Longitudinal studies provide unique insights into the impact of environmental factors and lifespan issues on health and disease. Here we investigate changes in body composition in 3088 free-living participants, part of the UK Biobank in-depth imaging study. All participants underwent neck-to-knee MRI scans at the first imaging visit and after approximately two years (second imaging visit). Image-derived phenotypes for each participant were extracted using a fully-automated image processing pipeline, including volumes of several tissues and organs: liver, pancreas, spleen, kidneys, total skeletal muscle, iliopsoas muscle, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue, as well as fat and iron content in liver, pancreas and spleen. Overall, no significant changes were observed in BMI, body weight, or waist circumference over the scanning interval, despite some large individual changes. A significant decrease in grip strength was observed, coupled to small, but statistically significant, decrease in all skeletal muscle measurements. Significant increases in VAT and intermuscular fat in the thighs were also detected in the absence of changes in BMI, waist circumference and ectopic-fat deposition. Adjusting for disease status at the first imaging visit did not have an additional impact on the changes observed. In summary, we show that even after a relatively short period of time significant changes in body composition can take place, probably reflecting the obesogenic environment currently inhabited by most of the general population in the United Kingdom.

Genetic architecture of 11 organ traits derived from abdominal MRI using deep learning.

Cardiometabolic diseases are an increasing global health burden. While socioeconomic, environmental, behavioural, and genetic risk factors have been identified, a better understanding of the underlying mechanisms is required to develop more effective interventions. Magnetic resonance imaging (MRI) has been used to assess organ health, but biobank-scale studies are still in their infancy. Using over 38,000 abdominal MRI scans in the UK Biobank, we used deep learning to quantify volume, fat, and iron in seven organs and tissues, and demonstrate that imaging-derived phenotypes reflect health status. We show that these traits have a substantial heritable component (8-44%) and identify 93 independent genome-wide significant associations, including four associations with liver traits that have not previously been reported. Our work demonstrates the tractability of deep learning to systematically quantify health parameters from high-throughput MRI across a range of organs and tissues, and use the largest-ever study of its kind to generate new insights into the genetic architecture of these traits.

Genetic Evidence for Different Adiposity Phenotypes and Their Opposing Influences on Ectopic Fat and Risk of Cardiometabolic Disease.

To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants: one with "adverse" metabolic effects (UFA) and the other with, paradoxically, "favorable" metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, and higher fat in subcutaneous and visceral adipose tissue, liver, and pancreas for UFA and a favorable metabolic profile, lower risk of disease, higher CRP and higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for a risk-increasing effect of UFA and protective effect of FA for type 2 diabetes, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting, and treating cardiometabolic diseases.

Large-scale analysis of iliopsoas muscle volumes in the UK Biobank.

Psoas muscle measurements are frequently used as markers of sarcopenia and predictors of health. Manually measured cross-sectional areas are most commonly used, but there is a lack of consistency regarding the position of the measurement and manual annotations are not practical for large population studies. We have developed a fully automated method to measure iliopsoas muscle volume (comprised of the psoas and iliacus muscles) using a convolutional neural network. Magnetic resonance images were obtained from the UK Biobank for 5000 participants, balanced for age, gender and BMI. Ninety manual annotations were available for model training and validation. The model showed excellent performance against out-of-sample data (average dice score coefficient of 0.9046 ± 0.0058 for six-fold cross-validation). Iliopsoas muscle volumes were successfully measured in all 5000 participants. Iliopsoas volume was greater in male compared with female subjects. There was a small but significant asymmetry between left and right iliopsoas muscle volumes. We also found that iliopsoas volume was significantly related to height, BMI and age, and that there was an acceleration in muscle volume decrease in men with age. Our method provides a robust technique for measuring iliopsoas muscle volume that can be applied to large cohorts.

Snacking on whole almonds for 6 weeks improves endothelial function and lowers LDL cholesterol but does not affect liver fat and other cardiometabolic risk factors in healthy adults: the ATTIS study, a randomized controlled trial.

BACKGROUND: There is convincing evidence that daily whole almond consumption lowers blood LDL cholesterol concentrations, but effects on other cardiometabolic risk factors such as endothelial function and liver fat are still to be determined. OBJECTIVES: We aimed to investigate whether isoenergetic substitution of whole almonds for control snacks with the macronutrient profile of average snack intakes, had any impact on markers of cardiometabolic health in adults aged 30-70 y at above-average risk of cardiovascular disease (CVD). METHODS: The study was a 6-wk randomized controlled, parallel-arm trial. Following a 2-wk run-in period consuming control snacks (mini-muffins), participants consumed either whole roasted almonds (n = 51) or control snacks (n = 56), providing 20% of daily estimated energy requirements. Endothelial function (flow-mediated dilation), liver fat (MRI/magnetic resonance spectroscopy), and secondary outcomes as markers of cardiometabolic disease risk were assessed at baseline and end point. RESULTS: Almonds, compared with control, increased endothelium-dependent vasodilation (mean difference 4.1%-units of measurement; 95% CI: 2.2, 5.9), but there were no differences in liver fat between groups. Plasma LDL cholesterol concentrations decreased in the almond group relative to control (mean difference -0.25 mmol/L; 95% CI: -0.45, -0.04), but there were no group differences in triglycerides, HDL cholesterol, glucose, insulin, insulin resistance, leptin, adiponectin, resistin, liver function enzymes, fetuin-A, body composition, pancreatic fat, intramyocellular lipids, fecal SCFAs, blood pressure, or 24-h heart rate variability. However, the long-phase heart rate variability parameter, very-low-frequency power, was increased during nighttime following the almond treatment compared with control (mean difference 337 ms2; 95% CI: 12, 661), indicating greater parasympathetic regulation. CONCLUSIONS: Whole almonds consumed as snacks markedly improve endothelial function, in addition to lowering LDL cholesterol, in adults with above-average risk of CVD.This trial was registered at clinicaltrials.gov as NCT02907684.