Bull, C. J. et al. (2024) Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes. EBioMedicine, 100, 104977. (doi: 10.1016/j.ebiom.2024.104977) (PMID:38290287) (PMCID:PMC10844806)
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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.
| Item Type: | Articles |
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| Additional Information: | The DiRECT study was funded as a Strategic Research Initiative by Diabetes UK (award number 13/0004691). The formula diet was donated by Cambridge Weight Plan. Neither organisation had any input into the study design, data analysis or interpretation. The Olink analysis was funded by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). C.J.B. is supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). E.E.V. is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). D.N.L. is supported by Diabetes UK (17/0005587). NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011), the MRC Integrative Epidemiology Unit (MC_UU_12013/3) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). EH is supported by a Cancer Research UK Population Research Committee Studentship (C18281/A30905), is supported by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019), and is part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00032/03) and the University of Bristol. DAH and LJC aresupported by NJT’s WT grant (202802/Z/16/Z). SIB is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. This research was funded in part, by the Wellcome Trust [202802/Z/16/Z]. JY is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C68933/A28534). DAH and LJC are supported by NJT’s WT grant (202802/Z/16/Z). |
| Keywords: | Obesity, Diabetes, Cancer, DiRECT, Weight loss, Mendelian randomization |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | McConnachie, Professor Alex and Lean, Professor Michael and Sattar, Professor Naveed and Welsh, Professor Paul |
| Creator Roles: | Sattar, N.Conceptualization, Resources, Funding acquisition, Writing – review and editing Lean, M.Resources, Funding acquisition, Writing – review and editing McConnachie, A.Writing – review and editing Welsh, P.Writing – review and editing |
| Authors: | Bull, C. J., Hazelwood, E., Legge, D. N., Corbin, L. J., Richardson, T. G., Lee, M., Yarmolinsky, J., Smith-Byrne, K., Hughes, D. A., Johansson, M., Peters, U., Berndt, S. I., Brenner, H., Burnett-Hartman, A., Cheng, I., Kweon, S.-S., Le Marchand, L., Li, L., Newcomb, P. A., Pearlman, R., McConnachie, A., Welsh, P., Taylor, R., Lean, M. E.J., Sattar, N., Murphy, N., Gunter, M. J., Timpson, N. J., and Vincent, E. E. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| Journal Name: | EBioMedicine |
| Publisher: | Elsevier |
| ISSN: | 2352-3964 |
| ISSN (Online): | 2352-3964 |
| Published Online: | 29 January 2024 |
| Copyright Holders: | Copyright: © 2024 The Author(s) |
| First Published: | First published in EBioMedicine 100: 104977 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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