The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT)

Laura J Corbin*, David A Hughes, Caroline J Bull, Emma E Vincent, Madeleine L Smith, Alex McConnachie, Claudia-Martina Messow, Paul Welsh, Roy Taylor, Mike E.J. Lean, Naveed Sattar, Nicholas John Timpson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)74-87
Number of pages14
JournalDiabetologia
Volume67
Issue number1
Early online date25 Oct 2023
DOIs
Publication statusPublished - 1 Jan 2024

Bibliographical note

Funding Information:
The DiRECT study was funded as a Strategic Research Initiative by Diabetes UK (award no. 13/0004691). The formula diet was donated by Cambridge Weight Plan. Neither organisation had any input into the study design, data analysis or interpretation. Metabolomics analysis was funded by Wellcome Trust (award number 202802/Z/16/Z). NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the principal investigator 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-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011/1), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). DAH and LJC are supported by NJT’s Wellcome Investigator Award (202802/Z/16/Z). EEV is supported by a Diabetes UK RD Lawrence Fellowship (17/0005587), by Cancer Research UK (C18281/A29019) and by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). CJB is supported by EEV’s World Cancer Research Fund grant (IIG_2019_2009). MLS is supported by the Wellcome Trust through a PhD studentship (218495/Z/19/Z). RT is the chief investigator of the study ‘Reversal of Type 2 diabetes Upon Normalisation of Energy intake in non-obese people’ (ReTUNE) funded by Diabetes UK (17/0005645). NS acknowledges funding support from the British Heart Foundation Research Excellence Award (RE/18/6/34217). This research was funded in whole, or in part, by the Wellcome Trust (202802/Z/16/Z).

Publisher Copyright:
© 2023, The Author(s).

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