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

doi:10.1007/s00125-023-06019-x

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 journal › Article (Academic Journal) › peer-review

9 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 language	English
Pages (from-to)	74-87
Number of pages	14
Journal	Diabetologia
Volume	67
Issue number	1
Early online date	25 Oct 2023
DOIs	https://doi.org/10.1007/s00125-023-06019-x
Publication status	Published - 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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ICEP

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00125-023-06019-xLicence: CC BY

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Persistent link

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research

Poster Prize
Corbin, L. J. (Recipient), 15 Mar 2023
Prize: Prizes, Medals, Awards and Grants

Media press release 'Type 2 diabetes remission diet impacts on metabolic health'
Corbin, L. J. (Speaker)
26 Oct 2023
Activity: Other activity types › Media coverage or participation

Cite this

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

abstract = "Aims/hypothesisHigh-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.MethodsWe 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.ResultsDecreases 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/interpretationWe 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.",

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

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{\textquoteright}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{\textquoteright}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 {\textquoteleft}Reversal of Type 2 diabetes Upon Normalisation of Energy intake in non-obese people{\textquoteright} (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: {\textcopyright} 2023, The Author(s).",

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T1 - The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT)

AU - Corbin, Laura J

AU - Hughes, David A

AU - Bull, Caroline J

AU - Vincent, Emma E

AU - Smith, Madeleine L

AU - McConnachie, Alex

AU - Messow, Claudia-Martina

AU - Welsh, Paul

AU - Taylor, Roy

AU - Lean, Mike E.J.

AU - Sattar, Naveed

AU - Timpson, Nicholas John

N1 - 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).

PY - 2024/1/1

Y1 - 2024/1/1

N2 - Aims/hypothesisHigh-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.MethodsWe 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.ResultsDecreases 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/interpretationWe 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.

AB - Aims/hypothesisHigh-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.MethodsWe 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.ResultsDecreases 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/interpretationWe 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.

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DO - 10.1007/s00125-023-06019-x

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VL - 67

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JO - Diabetologia

JF - Diabetologia

IS - 1

ER -

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

Abstract

Bibliographical note

Research Groups and Themes

UN SDGs

Access to Document

Handle.net

Fingerprint

Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

Prizes

Poster Prize

Activities

Media press release 'Type 2 diabetes remission diet impacts on metabolic health'

Cite this