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Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes.
Bull, CJ, Hazelwood, E, Legge, DN, Corbin, LJ, Richardson, TG, Lee, M, Yarmolinsky, J, Smith-Byrne, K, Hughes, DA, Johansson, M, et al
EBioMedicine. 2024;:104977
Abstract
BACKGROUND Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. METHODS Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. FINDINGS Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value <0.05). Mendelian randomization analyses indicated a causal relationship between predicted circulating furin and glycoprotein Nmb on breast cancer risk (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67-0.99, P-value = 0.03; and OR = 0.88, 95% CI = 0.78-0.99, P-value = 0.04 respectively), though these results were not supported in sensitivity analyses examining violations of MR assumptions. INTERPRETATION Intentional weight loss among individuals with recently diagnosed diabetes may modify levels of cancer-related proteins in serum. Further evaluation of the proteins identified in this analysis could reveal molecular pathways that mediate the effect of adiposity and type 2 diabetes on cancer risk. FUNDING The main sources of funding for this work were Diabetes UK, Cancer Research UK, World Cancer Research Fund, and Wellcome.
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5-year follow-up of the randomised Diabetes Remission Clinical Trial (DiRECT) of continued support for weight loss maintenance in the UK: an extension study.
Lean, ME, Leslie, WS, Barnes, AC, Brosnahan, N, Thom, G, McCombie, L, Kelly, T, Irvine, K, Peters, C, Zhyzhneuskaya, S, et al
The lancet. Diabetes & endocrinology. 2024;(4):233-246
Abstract
BACKGROUND In DiRECT, a randomised controlled effectiveness trial, weight management intervention after 2 years resulted in mean weight loss of 7·6 kg, with 36% of participants in remission of type 2 diabetes. Of 36 in the intervention group who maintained over 10 kg weight loss at 2 years, 29 (81%) were in remission. Continued low-intensity dietary support was then offered up to 5 years from baseline to intervention participants, aiming to maintain weight loss and gain clinical benefits. This extension study was designed to provide observed outcomes at 5 years. METHODS The DiRECT trial took place in primary care practices in the UK. Participants were individuals aged 20-65 years who had less than 6 years' duration of type 2 diabetes, a BMI greater than 27 kg/m2, and were not on insulin. The intervention consisted of withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal per day formula diet for 12-20 weeks), stepped food reintroduction (2-8 weeks), and then structured support for weight-loss maintenance. After sharing the 2-year results with all participants, UK National Health Service data were collected annually until year 5 from remaining intervention participants who received low-intensity dietary support, intervention withdrawals, and the original randomly allocated groups. The primary outcome was remission of type 2 diabetes; having established in the DiRECT trial that sustained weight loss was the dominant driver of remission, this was assumed for the Extension study. The trial is registered with the ISRCTN registry, number 03267836. FINDINGS Between July 25, 2014, and Aug 5, 2016, 149 participants were randomly assigned to the intervention group and 149 were assigned to the control group in the original DiRECT study. After 2 years, all intervention participants still in the trial (101 [68%] of 149) were approached to receive low-intensity support for a further 3 years. 95 (94%) of 101 were able to continue and consented and were allocated to the DiRECT extension group. 54 participants were allocated to the non-extension group, where intervention was withdrawn. At 5 years, DiRECT extension participants (n=85) lost an average of 6·1 kg, with 11 (13%) of 85 in remission. Compared with the non-extension group, DiRECT extension participants had more visits with HbA1c <48 mmol/mol (<6·5%; 36% vs 17%, p=0·0004), without glucose-lowering medication (62% vs 30%, p<0·0001), and in remission (34% vs 12%, p<0·0001). Original control participants (n=149) had mean weight loss 4·6 kg (n=82), and 5 (5%) of 93 were in remission. Compared with control participants, original intervention participants had more visits with weight more than 5% below baseline (61% vs 29%, p<0·0001), HbA1c below 48 mmol/mol (29% vs 15%, p=0·0002), without antidiabetic medication (51% vs 16%, p<0·0001), and in remission (27% vs 4%, p<0·0001). Of those in remission at year 2, 26% remained in remission at 5 years. Serious adverse events in the original intervention group (4·8 events per 100 patient-years) were under half those in the control group (10·2 per 100 patient-years, p=0·0080). INTERPRETATION The extended DiRECT intervention was associated with greater aggregated and absolute weight loss, and suggested improved health status over 5 years. FUNDING Diabetes UK.
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Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies.
Taylor, R, Zhang, C, George, D, Kotecha, S, Abdelghaffar, M, Forster, T, Santos Rodrigues, PD, Reisinger, AC, White, D, Hamilton, F, et al
EBioMedicine. 2024;:104981
Abstract
BACKGROUND Mechanistic studies have established a biological role of sterol metabolism in infection and immunity with clinical data linking deranged cholesterol metabolism during sepsis with poorer outcomes. In this systematic review we assess the relationship between biomarkers of cholesterol homeostasis and mortality in critical illness. METHODS We identified articles by searching a total of seven electronic databases from inception to October 2023. Prospective observational cohort studies included those subjects who had systemic cholesterol (Total Cholesterol (TC), HDL-C or LDL-C) levels assessed on the first day of ICU admission and short-term mortality recorded. Meta-analysis and meta-regression were used to evaluate overall mean differences in serum cholesterol levels between survivors and non-survivors. Study quality was assessed using the Newcastle-Ottawa Scale. FINDINGS From 6469 studies identified by searches, 24 studies with 2542 participants were included in meta-analysis. Non-survivors had distinctly lower HDL-C at ICU admission -7.06 mg/dL (95% CI -9.21 to -4.91, p < 0.0001) in comparison with survivors. Corresponding differences were also seen less robustly for TC -21.86 mg/dL (95% CI -31.23 to -12.49, p < 0.0001) and LDL-C -8.79 mg/dL (95% CI, -13.74 to -3.83, p = 0.0005). INTERPRETATION Systemic cholesterol levels (TC, HDL-C and LDL-C) on admission to critical care are inversely related to mortality. This finding is consistent with the notion that inflammatory and metabolic setpoints are coupled, such that the maladaptive-setpoint changes of cholesterol in critical illness are related to underlying inflammatory processes. We highlight the potential of HDL-biomarkers as early predictors of severity of illness and emphasise that future research should consider the metabolic and functional heterogeneity of HDLs. FUNDING EU-ERDF-Welsh Government Ser Cymru programme, BBSRC, and EU-FP7 ClouDx-i project (PG).
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Very low calorie diets and total diet replacement in type 2 diabetes: where are we now?
Taylor, R
Drug and therapeutics bulletin. 2024;(3):39-42
Abstract
Management of type 2 diabetes has now been simplified by the understanding that the condition is caused by excess fat in the liver together with suppression of beta cell function by the associated excess liver export of fat. These factors can be reversed by substantial weight loss leading to remission in the early years after diagnosis, or at least major decrease in cardiovascular risks and improvement in glucose control for all. Weight loss by any means is successful, but it is most easily achieved by rapid action using a low or very low calorie diet of around 800 kcal/day followed by sustained modest restraint of dietary habits. Oral hypoglycaemic agents and one antihypertensive drug can be withdrawn on day 1 of the weight loss diet, raising the importance of appropriate deprescribing.
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The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT).
Corbin, LJ, Hughes, DA, Bull, CJ, Vincent, EE, Smith, ML, McConnachie, A, Messow, CM, Welsh, P, Taylor, R, Lean, MEJ, et al
Diabetologia. 2024;(1):74-87
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AIMS/HYPOTHESIS High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes. METHODS We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted 1H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels. RESULTS Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission. CONCLUSIONS/INTERPRETATION We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes. DATA AVAILABILITY The data used for analysis are available on a research data repository ( https://researchdata.gla.ac.uk/ ) with access given to researchers subject to appropriate data sharing agreements. Metabolite data preparation, data pre-processing, statistical analyses and figure generation were performed in R Studio v.1.0.143 using R v.4.0.2. The R code for this study has been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct .
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A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease.
Payne, T, Appleby, M, Buckley, E, van Gelder, LMA, Mullish, BH, Sassani, M, Dunning, MJ, Hernandez, D, Scholz, SW, McNeill, A, et al
Movement disorders : official journal of the Movement Disorder Society. 2023;(8):1493-1502
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BACKGROUND Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD. OBJECTIVES To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement. METHODS The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (31 P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment. RESULTS UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain 31 P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups. CONCLUSIONS High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Prediction of Cardiometabolic Health Through Changes in Plasma Proteins With Intentional Weight Loss in the DiRECT and DIADEM-I Randomized Clinical Trials of Type 2 Diabetes Remission.
Sattar, N, Taheri, S, Astling, DP, Chadwick, J, Hinterberg, MA, Holmes, MV, Troth, EV, Welsh, P, Zaghloul, H, Chagoury, O, et al
Diabetes care. 2023;(11):1949-1957
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OBJECTIVE To determine the extent to which changes in plasma proteins, previously predictive of cardiometabolic outcomes, predict changes in two diabetes remission trials. RESEARCH DESIGN AND METHODS We applied SomaSignal predictive tests (each derived from ∼5,000 plasma protein measurements using aptamer-based proteomics assay) to baseline and 1-year samples of trial intervention (Diabetes Remission Clinical Trial [DiRECT], n = 118, and Diabetes Intervention Accentuating Diet and Enhancing Metabolism [DIADEM-I], n = 66) and control (DiRECT, n = 144, DIADEM-I, n = 76) group participants. RESULTS Mean (SD) weight loss in DiRECT (U.K.) and DIADEM-I (Qatar) was 10.2 (7.4) kg and 12.1 (9.5) kg, respectively, vs. 1.0 (3.7) kg and 4.0 (5.4) kg in control groups. Cardiometabolic SomaSignal test results showed significant improvement (Bonferroni-adjusted P < 0.05) in DiRECT and DIADEM-I (expressed as relative difference, intervention minus control) as follows, respectively: liver fat (-26.4%, -37.3%), glucose tolerance (-36.6%, -37.4%), body fat percentage (-8.6%, -8.7%), resting energy rate (-8.0%, -5.1%), visceral fat (-34.3%, -26.1%), and cardiorespiratory fitness (9.5%, 10.3%). Cardiovascular risk (measured with SomaSignal tests) also improved in intervention groups relative to control, but this was significant only in DiRECT (DiRECT, -44.2%, and DIADEM-I, -9.2%). However, weight loss >10 kg predicted significant reductions in cardiovascular risk, -19.1% (95% CI -33.4 to -4.91) in DiRECT and -33.4% (95% CI -57.3, -9.6) in DIADEM-I. DIADEM-I also demonstrated rapid emergence of metabolic improvements at 3 months. CONCLUSIONS Intentional weight loss in recent-onset type 2 diabetes rapidly induces changes in protein-based risk models consistent with widespread cardiometabolic improvements, including cardiorespiratory fitness. Protein changes with greater (>10 kg) weight loss also predicted lower cardiovascular risk, providing a positive outlook for relevant ongoing trials.
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Understanding the pathways between prenatal and postnatal factors and overweight outcomes in early childhood: a pooled analysis of seven cohorts.
Zheng, M, Hesketh, KD, Vuillermin, P, Dodd, J, Wen, LM, Baur, LA, Taylor, R, Byrne, R, Mihrshahi, S, Burgner, D, et al
International journal of obesity (2005). 2023;(7):574-582
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BACKGROUND/OBJECTIVES Childhood overweight and obesity are influenced by a range of prenatal and postnatal factors. Few studies have explored the integrative pathways linking these factors and childhood overweight. This study aimed to elucidate the integrative pathways through which maternal pre-pregnancy body mass index (BMI), infant birth weight, breastfeeding duration, and rapid weight gain (RWG) during infancy are associated with overweight outcomes in early childhood from ages 3 to 5 years. SUBJECTS/METHODS Pooled data from seven Australian and New Zealand cohorts were used (n = 3572). Generalized structural equation modelling was used to examine direct and indirect associations of maternal pre-pregnancy BMI, infant birth weight, breastfeeding duration, and RWG during infancy with child overweight outcomes (BMI z-score and overweight status). RESULTS Maternal pre-pregnancy BMI was directly associated with infant birth weight (β 0.01, 95%CI 0.01, 0.02), breastfeeding duration ≥6 months (OR 0.92, 95%CI 0.90, 0.93), child BMI z-score (β 0.03, 95%CI 0.03, 0.04) and overweight status (OR 1.07, 95%CI 1.06, 1.09) at ages 3-5 years. The association between maternal pre-pregnancy BMI and child overweight outcomes was partially mediated by infant birth weight, but not RWG. RWG in infancy exhibited the strongest direct association with child overweight outcomes (BMI z-score: β 0.72, 95%CI 0.65, 0.79; overweight status: OR 4.49, 95%CI 3.61, 5.59). Infant birth weight was implicated in the indirect pathways of maternal pre-pregnancy BMI with RWG in infancy, breastfeeding duration, and child overweight outcomes. The associations between breastfeeding duration (≥6 months) and lower child overweight outcomes were fully mediated by RWG in infancy. CONCLUSIONS Maternal pre-pregnancy BMI, infant birth weight, breastfeeding duration and RWG in infancy act in concert to influence early childhood overweight. Future overweight prevention interventions should target RWG in infancy, which showed the strongest association with childhood overweight; and maternal pre-pregnancy BMI, which was implicated in several pathways leading to childhood overweight.
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.
Tobias, DK, Merino, J, Ahmad, A, Aiken, C, Benham, JL, Bodhini, D, Clark, AL, Colclough, K, Corcoy, R, Cromer, SJ, et al
Nature medicine. 2023;(10):2438-2457
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Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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Evaluation of a Type 2 diabetes risk reduction online program for women with recent gestational diabetes: a randomised trial.
Taylor, R, Rollo, ME, Baldwin, JN, Hutchesson, M, Aguiar, EJ, Wynne, K, Young, A, Callister, R, Collins, CE
The international journal of behavioral nutrition and physical activity. 2022;(1):35
Abstract
BACKGROUND To evaluate the preliminary efficacy, feasibility and acceptability of the 3-month Body Balance Beyond (BBB) online program among Australian women with overweight/obesity and recent gestational diabetes mellitus. METHODS Women were randomised into either: 1) High Personalisation (HP) (access to 'BBB' website, video coaching sessions, text message support); 2) Medium Personalisation (MP) (website and text message support); or 3) Low Personalisation (LP) (website only). Generalised linear mixed models were used to evaluate preliminary efficacy, weight, diet quality, physical activity levels, self-efficacy and quality of life (QoL) at baseline and 3-months. Feasibility was assessed by recruitment and retention metrics and acceptability determined via online process evaluation survey at 3-months. RESULTS Eighty three women were randomised, with 76 completing the study. Self-efficacy scores showed significant improvements in confidence to resist eating in a variety of situations from baseline to 3-months in HP compared to MP and LP groups (P=.03). The difference in mean QoL scores favoured the HP compared to MP and LP groups (P=.03). Half of the women (HP n=17[81%], MP n=12[75%], LP n=9[56%]) lost weight at 3-months. No significant group-by-time effect were reported for other outcomes. Two-thirds of women in the HP group were satisfied with the program overall and 86% would recommend it to others, compared with 25% and 44% in the MP group, and 14% and 36% in the LP group, respectively. CONCLUSIONS Video coaching sessions were associated with improvements in QoL scores and self-efficacy, however further refinement of the BBB website and text messages support could improve program acceptability. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000162112 , registered 5 February 2019.