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

Abstract

Use of high throughput metabolomics technologies in a variety of study designs has demonstrated a strong and consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be recovered with weight loss and diabetes remission has not been investigated. We aimed to characterise the metabolomic consequences of a weight loss intervention in diabetes, within an existing randomised controlled trial, the Diabetes Remission Clinical Trial (DiRECT), to provide insight into how weight loss-induced metabolic changes could lead to improved health. 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. The change in metabolomic pattern with mean 8.8kg weight loss thus reverses many features associated with the development of type 2 diabetes. Furthermore, metabolomic profiling also appears to capture variation in response to treatment seen across patients.

Competing Interest Statement

RT has received lecture honoraria from Eli Lilly, Nestle Health and Janssen. All other authors declare no competing interests.

Clinical Trial

ISRCTN03267836

Funding Statement

The DiRECT study was funded as a Strategic Research Initiative by Diabetes UK (award number 13/0004691). 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-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). D.A.H. & L.J.C. are supported by N.J.T.s Wellcome Investigator Award (202802/Z/16/Z). E.E.V. 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 program (IIG_2019_2009). C.J.B is supported by E.E.V.s World Cancer Research Fund grant (IIG_2019_2009). M.L.S is supported by the Wellcome Trust through a PhD studentship [218495/Z/19/Z]. RT is the CI of the study "Reversal of Type 2 diabetes Upon Normalisation of Energy intake in non-obese people" (ReTUNE) funded by Diabetes UK (17/0005645).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

West of Scotland REC 3 of NHS Health Research Authority gave ethical approval for this work in January 2014, with approvals by the National Health Service (NHS) health board areas in Scotland and clinical commissioning groups in Tyneside.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

The terms of participant consent in DiRECT do not allow making the study data freely available in its raw form. The data used for analysis will be placed on a research data repository (https://researchdata.gla.ac.uk/) with access given to researchers subject to appropriate data sharing agreements. The R code for this study have been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct.

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