| 1. |
- Alenaini, Wareed, et al.
(författare)
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Ethnic Differences in Body Fat Deposition and Liver Fat Content in Two UK‐Based Cohorts
- 2020
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Ingår i: Obesity. - : John Wiley & Sons. - 1930-7381 .- 1930-739X. ; 28:11, s. 2142-2152
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveDifferences in the content and distribution of body fat and ectopic lipids may be responsible for ethnic variations in metabolic disease susceptibility. The aim of this study was to examine the ethnic distribution of body fat in two separate UK‐based populations.MethodsAnthropometry and body composition were assessed in two separate UK cohorts: the Hammersmith cohort and the UK Biobank, both comprising individuals of South Asian descent (SA), individuals of Afro‐Caribbean descent (AC), and individuals of European descent (EUR). Regional adipose tissue stores and liver fat were measured by magnetic resonance techniques.ResultsThe Hammersmith cohort (n = 747) had a mean (SD) age of 41.1 (14.5) years (EUR: 374 men, 240 women; SA: 68 men, 22 women; AC: 14 men, 29 women), and the UK Biobank (n = 9,533) had a mean (SD) age of 55.5 (7.5) years (EUR: 4,483 men, 4,873 women; SA: 80 men, 43 women, AC: 31 men, 25 women). Following adjustment for age and BMI, no significant differences in visceral adipose tissue or liver fat were observed between SA and EUR individuals in the either cohort.ConclusionsOur data, consistent across two independent UK‐based cohorts, present a limited number of ethnic differences in the distribution of body fat depots associated with metabolic disease. These results suggest that the ethnic variation in susceptibility to features of the metabolic syndrome may not arise from differences in body fat.
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| 2. |
- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Atabaki-Pasdar, Naeimeh, et al.
(författare)
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Inferring causal pathways between metabolic processes and liver fat accumulation: an IMI DIRECT study
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) often co-occur. Defining causal pathways underlying this relationship may help optimize the prevention and treatment of both diseases. Thus, we assessed the strength and magnitude of the putative causal pathways linking dysglycemia and fatty liver, using a combination of causal inference methods.Measures of glycemia, insulin dynamics, magnetic resonance imaging (MRI)-derived abdominal and liver fat content, serological biomarkers, lifestyle, and anthropometry were obtained in participants from the IMI DIRECT cohorts (n=795 with new onset T2D and 2234 individuals free from diabetes). UK Biobank (n=3641) was used for modelling and replication purposes. Bayesian networks were employed to infer causal pathways, with causal validation using two-sample Mendelian randomization.Bayesian networks fitted to IMI DIRECT data identified higher basal insulin secretion rate (BasalISR) and MRI-derived excess visceral fat (VAT) accumulation as the features of dysmetabolism most likely to cause liver fat accumulation; the unconditional probability of fatty liver (>5%) increased significantly when conditioning on high levels of BasalISR and VAT (by 23%, 32% respectively; 40% for both). Analyses in UK Biobank yielded comparable results. MR confirmed most causal pathways predicted by the Bayesian networks.Here, BasalISR had the highest causal effect on fatty liver predisposition, providing mechanistic evidence underpinning the established association of NAFLD and T2D. BasalISR may represent a pragmatic biomarker for NAFLD prediction in clinical practice.Competing Interest StatementHR is an employee and shareholder of Sanofi. MIM: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MIM has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MIM is an employee of Genentech, and a holder of Roche stock. AM is a consultant for Lilly and has received research grants from several diabetes drug companies. PWF has received research grants from numerous diabetes drug companies and fess as consultant from Novo Nordisk, Lilly, and Zoe Global Ltd. He is currently the Scientific Director in Patient Care at the Novo Nordisk Foundation. Other authors declare non competing interests.Funding StatementThe work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115317 (DIRECT) resources of which are composed of financial contribution from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. NAP is supported in part by Henning och Johan Throne-Holsts Foundation, Hans Werthen Foundation, an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. HPM is supported by an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. AGJ is supported by an NIHR Clinician Scientist award (17/0005624). RK is funded by the Novo Nordisk Foundation (NNF18OC0031650) as part of a postdoctoral fellowship, an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. AK, PM, HF, JF and GNG are supported by an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. TJM is funded by an NIHR clinical senior lecturer fellowship. S.Bru acknowledges support from the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). ATH is a Wellcome Trust Senior Investigator and is also supported by the NIHR Exeter Clinical Research Facility. JMS acknowledges support from Science for Life Laboratory (Plasma Profiling Facility), Knut and Alice Wallenberg Foundation (Human Protein Atlas) and Erling-Persson Foundation (KTH Centre for Precision Medicine). MIM is supported by the following grants; Wellcome (090532, 098381, 106130, 203141, 212259); NIH (U01-DK105535). PWF is supported by an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approval for the study protocol was obtained from each of the regional research ethics review boards separately (Lund, Sweden: 20130312105459927, Copenhagen, Denmark: H-1-2012-166 and H-1-2012-100, Amsterdam, Netherlands: NL40099.029.12, Newcastle, Dundee and Exeter, UK: 12/NE/0132), and all participants provided written informed consent at enrolment. The research conformed to the ethical principles for medical research involving human participants outlined in the Declaration of Helsinki.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAuthors agree to make data and materials supporting the results or analyses presented in their paper available upon reasonable request
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| 4. |
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| 5. |
- Bizzotto, Roberto, et al.
(författare)
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Processes Underlying Glycemic Deterioration in Type 2 Diabetes : An IMI DIRECT Study
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44:2, s. 511-518
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
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| 6. |
- Borga, Magnus, 1965-, et al.
(författare)
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Advanced body composition assessment: From body mass index to body composition profiling
- 2018
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Ingår i: Journal of Investigative Medicine. - : BMJ Publishing Group Ltd. - 1081-5589 .- 1708-8267. ; 66:5, s. 887-895
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Forskningsöversikt (refereegranskat)abstract
- This paper gives a brief overview of common non-invasive techniques for body composition analysis and a more in-depth review of a body composition assessment method based on fat-referenced quantitative magnetic resonance imaging (MRI). Earlier published studies of this method are summarized, and a previously un-published validation study, based on 4.753 subjects from the UK Biobank imaging cohort, comparing the quantitative MRI method with dual-energy x-ray absorptiometry (DXA) is presented. For whole-body measurements of adipose tissue (AT) or fat and lean tissue (LT), DXA and quantitative MRI show excellent agreement with linear correlation of 0.99 and 0.97, and coefficient of variation (CV) of 4.5 % and 4.6 % for fat (computed from AT) and lean tissue respectively, but the agreement was found significantly lower for visceral adipose tissue, with a CV of more than 20 %. The additional ability of MRI to also measure muscle volumes, muscle AT infiltration and ectopic fat in combination with rapid scanning protocols and efficient image analysis tools make quantitative MRI a powerful tool for advanced body composition assessment.
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| 7. |
- Borga, Magnus, et al.
(författare)
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Validation of a Fast Method for Quantification of Intra-abdominal and Subcutaneous Adipose Tissue for Large Scale Human Studies
- 2015
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Ingår i: NMR in Biomedicine. - : John Wiley & Sons. - 1099-1492 .- 0952-3480. ; 28:12, s. 1747-1753
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Tidskriftsartikel (refereegranskat)abstract
- Central obesity is the hallmark of a number of non-inheritable disorders. The advent of imaging techniques such as magnetic resonance imaging (MRI) has allowed for a fast and accurate assessment of body fat content and distribution. However, image analysis continues to be one of the major obstacles for the use of MRI in large scale studies. In this study we assess the validity of the recently proposed fat-muscle-quantitation-system (AMRATM Profiler) for the quantification of intra-abdominal adipose tissue (IAAT) and abdominal subcutaneous adipose tissue (ASAT) from abdominal MR images. Abdominal MR images were acquired from 23 volunteers with a broad range of BMIs and analysed using SliceOmatic, the current gold-standard, and the AMRATM Profiler based on a non-rigid image registration of a library of segmented atlases. The results show that there was a highly significant correlation between the fat volumes generated by both analysis methods, (Pearson correlation r = 0.97 p<0.001), with the AMRATM Profiler analysis being significantly faster (~3 mins) than the conventional SliceOmatic approach (~40 mins). There was also excellent agreement between the methods for the quantification of IAAT (AMRA 4.73 ± 1.99 vs SliceOmatic 4.73 ± 1.75 litres, p=0.97). For the AMRATM Profiler analysis, the intra-observer coefficient of variation was 1.6 % for IAAT and 1.1 % for ASAT, the inter-observer coefficient of variation was 1.4 % for IAAT and 1.2 % for ASAT, the intra-observer correlation was 0.998 for IAAT and 0.999 for ASAT, and the inter-observer correlation was 0.999 for both IAAT and ASAT. These results indicate that precise and accurate measures of body fat content and distribution can be obtained in a fast and reliable form by the AMRATM Profiler, opening up the possibility of large-scale human phenotypic studies.
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| 8. |
- Chung, Yuen-Li, et al.
(författare)
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Creatine supplements in patients with idiopathic inflammatory myopathies who are clinically weak after conventional pharmacologic treatment: Six-month, double-blind, randomized, placebo-controlled trial
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 57:4, s. 694-702
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To test the hypothesis that oral creatine supplements with exercise are more effective than exercise alone in improving muscle function in patients with established dermatomyositis or polymyositis receiving chronic medical therapies who are clinically weak yet stable. Methods. In a 6-month, 2-center, double-blind, randomized controlled trial, patients were randomized to receive oral creatine supplements (8 days, 20 gm/day then 3 gm/day) or placebo. All patients followed a home exercise program. The primary outcome was aggregate functional performance time (AFPT), reflecting the ability to undertake high-intensity exercise. Secondary outcomes included a Functional index measuring endurance and muscle bioenergetics on P-31 magnetic resonance spectroscopy (P-31 MRS). Patients were receiving stable immunosuppressive treatment and/or corticosteroids. Results. A total of 37 patients with polymyositis or dermatomyositis were randomized (19 to creatine, 18 to placebo); 29 completed 6 months. Intent-to-treat analyses demonstrated that AFPT improved significantly at 6 months with creatine (median decrease 13%, range -32-8%) compared with placebo (median decrease 3%, range -13-16%; P = 0.029 by Mann-Whitney U test). A completer analysis also showed significant benefits from creatine (P = 0.014). The functional index improved significantly with both creatine and placebo (P < 0.05 by paired Wilcoxon's rank sum test), with a significant benefit between groups in the completer analysis only. Phosphocreatine/beta-nucleoside triphosphate ratios using MRS increased significantly in the creatine group (P < 0.05) but not in the control group. No clinically relevant adverse events were associated with creatine. Conclusion. Oral creatine supplements combined with home exercises improve functional performance without significant adverse effects in patients with polymyositis or dermatomyositis. They appear safe, effective, and inexpensive.
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| 9. |
- Dahlqvist Leinhard, Olof, 1978-, et al.
(författare)
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Body Composition Profiling using MRI - Normative Data for Subjects with Cardiovascular Disease Extracted from the UK Biobank Imaging Cohort
- 2016
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- PURPOSETo describe the distribution of MRI-derived body composition measurements in subjects with cardiovascular disease (CVD) compared to subjects without any history of CVD.METHOD AND MATERIALS1864 males and 2036 females with an age range from 45 to 78 years from the UK Biobank imaging study were included in the study. Visceral adipose tissue volume normalized with height2 (VATi), total abdominal adipose tissue volume normalized with height2 (ATATi), total lean thigh muscle volume normalized with body weight (muscle ratio) and liver proton density fat fraction (PDFF) were measured with a 2-point Dixon imaging protocol covering neck to knee and a 10-point Dixon single slice protocol positioned within the liver using a 1.5T MR-scanner (Siemens, Germany). The MR-images were analyzed using AMRA® Profiler research (AMRA, Sweden). 213 subjects with history of cardiovascular events (angina, heart attack, or stroke) (event group) were age and gender matched to subjects with high blood pressure (HBP group), and subjects without CVD (controls).Kruskal-Wallis and Mann-Whitney U tests were used to test the observed differences for each measurement and group without correction for multiple comparisons.RESULTSVATi in the event group was 1.73 (1.13 - 2.32) l/m2 (median, 25%-75% percentile) compared to 1.68 (1.19 - 2.23) in the HBP group, and 1.30 (0.82-1.87) in the controls. ATATi in the event group was 4.31 (2.90-5.39) l/m2 compared to 4.05 (3.07-5.12) in the HBP group, and 3.48 (2.48-4.61) in the controls. Muscle ratio in the event group was 0.13 (0.12 - 0.15) l/kg as well as in the HBP group, compared to 0.14 (0.12 - 0.15) in the controls. Liver PDFF in the event group was 2.88 (1.77 - 7.72) % compared to 3.44 (2.04-6.18) in the HBP group, and 2.50 (1.58 - 5.15) in the controls. Kruskal-Wallis test showed significant differences for all variables and group comparisons (p<0.007). The post hoc test showed significant differences comparing the controls to both the event group and the HBP group. These were more significant for VATi and ATATi (p<10-4) than for muscle ratio and PDFF (p<0.03). No significant differences were detected between the event group and the HBP group.CONCLUSIONCardiovascular disease is strongly associated with high VATi, liver fat, and ATATi, and with low muscle ratio.CLINICAL RELEVANCE/APPLICATIONThe metabolic syndrome component in CVD can be effectively described using MRI-based body composition profiling.
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| 10. |
- Dahlqvist Leinhard, Olof, 1978-, et al.
(författare)
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Body Composition Profiling using MRI - Normative Data for Subjects with Diabetes Extracted from the UK Biobank Imaging Cohort
- 2016
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- PURPOSETo describe the distribution of MRI derived body composition measurements in subjects with diabetes mellitus (DM) compared to subjects without diabetes.METHOD AND MATERIALS3900 subjects (1864 males and 2036 females) from the UK Biobank imaging study were included in the study. The age range was 45 to 78 years. Visceral adipose tissue volume normalized with height2 (VATi), total abdominal adipose tissue volume normalized with height2 (ATATi), total lean thigh muscle volume normalized with body weight (muscle ratio) and liver proton density fat fraction (PDFF) were measured with a 6 minutes 2-point Dixon imaging protocol covering neck to knee and a 10-point Dixon single axial slice protocol positioned within the liver using a 1.5T MR-scanner (Siemens, Germany). The MR-images were analyzed using AMRA® Profiler research (AMRA, Sweden). 194 subjects with clinically diagnosed DM (DM group) were age and gender matched to subjects without DM (control group). For each variable and group, the median, 25%-percentile and 75%-percentile was calculated. Mann-Whitney U test was used to test the observed differences.RESULTSVATi in the DM group was 2.13 (1.43-2.62) l/m2 (median, 25% - 75% percentile) compared to 1.32 (0.86 - 1.79) l/m2 in the control group. ATATi in the DM group was 4.94 (3.86-6.19) l/m2 compared to 3.40 (2.56 - 4.70) l/m2 in the control group. Muscle ratio in the DM group was 0.13 (0.11 - 0.14) l/kg compared to 0.14 (0.12 - 0.15) l/kg in the control group. Liver PDFF in the DM group was 7.23 (2.68 - 13.26) % compared to 2.49 (1.53 - 4.73) % in the control group. Mann-Whitney U test detected significant differences between the DM group and the control group for all variables (p<10-5).CONCLUSIONDM is strongly associated with high visceral fat, liver fat, and total abdominal fat, and low muscle ratio.CLINICAL RELEVANCE/APPLICATIONBody composition profiling shows high potential to provide direct biomarkers to improve characterization and early diagnosis of DM.
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