학술논문
Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetesResearch in context
Document Type
article
Author
Caroline J. Bull; Emma Hazelwood; Danny N. Legge; Laura J. Corbin; Tom G. Richardson; Matthew Lee; James Yarmolinsky; Karl Smith-Byrne; David A. Hughes; Mattias Johansson; Ulrike Peters; Sonja I. Berndt; Hermann Brenner; Andrea Burnett-Hartman; Iona Cheng; Sun-Seog Kweon; Loic Le Marchand; Li Li; Polly A. Newcomb; Rachel Pearlman; Alex McConnachie; Paul Welsh; Roy Taylor; Mike E.J. Lean; Naveed Sattar; Neil Murphy; Marc J. Gunter; Nicholas J. Timpson; Emma E. Vincent
Source
EBioMedicine, Vol 100, Iss , Pp 104977- (2024)
Subject
Language
English
ISSN
2352-3964
Abstract
Summary: 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