Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes

Medientyp: E-Artikel

Titel: Impact of weight loss on cancer-related proteins in serum : results from a cluster randomised controlled trial of individuals with type 2 diabetes

Beteiligte: Bull, Caroline J. [Verfasser:in]; Hazelwood, Emma [Verfasser:in]; Legge, Danny N. [Verfasser:in]; Corbin, Laura J. [Verfasser:in]; Richardson, Tom G. [Verfasser:in]; Lee, Matthew [Verfasser:in]; Yarmolinsky, James [Verfasser:in]; Smith-Byrne, Karl [Verfasser:in]; Hughes, David A. [Verfasser:in]; Johansson, Mattias [Verfasser:in]; Peters, Ulrike [Verfasser:in]; Berndt, Sonja I. [Verfasser:in]; Brenner, Hermann [Verfasser:in]; Burnett-Hartman, Andrea [Verfasser:in]; Cheng, Iona [Verfasser:in]; Kweon, Sun-Seog [Verfasser:in]; Le Marchand, Loic [Verfasser:in]; Li, Li [Verfasser:in]; Newcomb, Polly A. [Verfasser:in]; Pearlman, Rachel [Verfasser:in]; McConnachie, Alex [Verfasser:in]; Welsh, Paul [Verfasser:in]; Taylor, Roy [Verfasser:in]; Lean, Mike E. J. [Verfasser:in]; Sattar, Naveed [Verfasser:in]; Murphy, Neil [Verfasser:in]; Gunter, Marc J. [Verfasser:in]; Timpson, Nicholas J. [Verfasser:in]; Vincent, Emma E. [Verfasser:in]

Erschienen: February 2024

Sprache: Englisch

DOI: 10.1016/j.ebiom.2024.104977

Identifikator:

Schlagwörter: Cancer ; Diabetes ; DiRECT ; Mendelian randomization ; Obesity ; Weight loss

Entstehung:

Anmerkungen: Online verfügbar: 29. Januar 2024

Beschreibung: 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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