Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes

Alice-Mihaela Mezincescu; Amelia Elizabeth Rudd; Lesley Cheyne; Graham Horgan; Sam Philip; Donnie Cameron; Luc  van Loon; Phil  Whitefield; Rachael  Gribbin; May Khei Hu; Mirela Delibegovic; Barbara Fielding; Gerald Lobley; Frank Thies; David E Newby; Stuart  Gray; Anke Henning; Dana Dawson

doi:10.1038/s41467-024-47843-y

Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes

Alice-Mihaela Mezincescu, Amelia Elizabeth Rudd, Lesley Cheyne, Graham Horgan, Sam Philip, Donnie Cameron, Luc van Loon, Phil Whitefield, Rachael Gribbin, May Khei Hu, Mirela Delibegovic, Barbara Fielding, Gerald Lobley, Frank Thies, David E Newby, Stuart Gray, Anke Henning, Dana Dawson^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Downloads (Pure)

Abstract

Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called "athlete's paradox". In a parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY).

Original language	English
Article number	3690
Pages (from-to)	3690
Number of pages	14
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-47843-y https://doi.org/10.6084/m9.figshare.24219934
Publication status	Accepted/In press - 5 Apr 2024

Bibliographical note

Contributions
D.D., A.H., S.G., S.P. and M.D. conceived the study and together with L.v.L., G.L., F.T. obtained the grant funding. AM executed the patient screening, recruitment, intervention planning, carried out all study investigations under respective specialist supervision (A.H./D.C./D.D. for magnetic resonance spectroscopy, F.T./G.L./D.D. for stable isotope investigation, S.G. for exercise intervention, S.P. for clinical supervision/management of diabetes as required, M.D. for all molecular laboratory analyses, A.M. analysed all data and performed statistical analysis under the supervision of G.H. L.v.L. provided expert advice in athletic physiology. Lipidomic analyses were carried out in P.W. laboratory. Blood/skeletal muscle enrichment analyses were carried out in B.F./F.T.-G.L. laboratories respectively, with practical input from R.G. A.R. and L.C. contributed as overall help to deliver study assessments in a technical role. M.K.H. analysed the food diaries. D.E.N. contributed to manuscript writing. D.D. and M.D. were the PhD supervisors for A.M. whose PhD thesis was based on this work. All authors contributed their respective specialist sections in drafting the manuscript.

Data Availability Statement

The source data and lipidomic source data generated in this study have been deposited in the Figshare Database (https://doi.org/10.6084/m9.figshare.24219934). Participant level data for the study is also available in the Figshare Database. The Lipidomics Minimal Reporting Checklist is included in the Supplemental Material. The trial protocol can be made available upon request by contacting the Corresponding Author. Requests for data should be made and these requests will be fulfilled by the corresponding author ([email protected]), providing the data will be used within the scope of the originally provided informed consent. The corresponding author aims to respond to data requests within three months. The data will be made available for a year following publication of the manuscript.

Keywords

Humans
Male
Athletes
Lipid Metabolism
Diabetes Mellitus, Type 2/metabolism
Insulin Resistance
Adult
Middle Aged
Endurance Training
Muscle, Skeletal/metabolism
Triglycerides/metabolism

UN SDGs

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

Access to Document

10.1038/s41467-024-47843-yLicence: CC BY
10.6084/m9.figshare.24219934Licence: CC BY

Mezincescu_etal_Comparison_intramyocellular_lipid_VOR
https://creativecommons.org/licenses/by/4.0/
Final published version, 1.29 MBLicence: CC BY

Cite this

Mezincescu, A.-M., Rudd, A. E., Cheyne, L., Horgan, G., Philip, S., Cameron, D., van Loon, L., Whitefield, P., Gribbin, R., Hu, M. K., Delibegovic, M., Fielding, B., Lobley, G., Thies, F., Newby, D. E., Gray, S., Henning, A., & Dawson, D. (Accepted/In press). Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes. Nature Communications, 15(1), 3690. Article 3690. https://doi.org/10.1038/s41467-024-47843-y, https://doi.org/10.6084/m9.figshare.24219934

Mezincescu, A-M, Rudd, AE, Cheyne, L, Horgan, G , Philip, S, Cameron, D, van Loon, L, Whitefield, P, Gribbin, R, Hu, MK, Delibegovic, M, Fielding, B, Lobley, G, Thies, F, Newby, DE, Gray, S, Henning, A & Dawson, D 2024, 'Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes', Nature Communications, vol. 15, no. 1, 3690, pp. 3690. https://doi.org/10.1038/s41467-024-47843-y, https://doi.org/10.6084/m9.figshare.24219934

@article{32def9dd91e54a398c0d7bbdc7cc4c91,

title = "Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes",

abstract = "Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called {"}athlete's paradox{"}. In a parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY).",

keywords = "Humans, Male, Athletes, Lipid Metabolism, Diabetes Mellitus, Type 2/metabolism, Insulin Resistance, Adult, Middle Aged, Endurance Training, Muscle, Skeletal/metabolism, Triglycerides/metabolism",

author = "Alice-Mihaela Mezincescu and Rudd, {Amelia Elizabeth} and Lesley Cheyne and Graham Horgan and Sam Philip and Donnie Cameron and {van Loon}, Luc and Phil Whitefield and Rachael Gribbin and Hu, {May Khei} and Mirela Delibegovic and Barbara Fielding and Gerald Lobley and Frank Thies and Newby, {David E} and Stuart Gray and Anke Henning and Dana Dawson",

note = "Contributions D.D., A.H., S.G., S.P. and M.D. conceived the study and together with L.v.L., G.L., F.T. obtained the grant funding. AM executed the patient screening, recruitment, intervention planning, carried out all study investigations under respective specialist supervision (A.H./D.C./D.D. for magnetic resonance spectroscopy, F.T./G.L./D.D. for stable isotope investigation, S.G. for exercise intervention, S.P. for clinical supervision/management of diabetes as required, M.D. for all molecular laboratory analyses, A.M. analysed all data and performed statistical analysis under the supervision of G.H. L.v.L. provided expert advice in athletic physiology. Lipidomic analyses were carried out in P.W. laboratory. Blood/skeletal muscle enrichment analyses were carried out in B.F./F.T.-G.L. laboratories respectively, with practical input from R.G. A.R. and L.C. contributed as overall help to deliver study assessments in a technical role. M.K.H. analysed the food diaries. D.E.N. contributed to manuscript writing. D.D. and M.D. were the PhD supervisors for A.M. whose PhD thesis was based on this work. All authors contributed their respective specialist sections in drafting the manuscript.",

year = "2024",

month = apr,

day = "5",

doi = "10.1038/s41467-024-47843-y",

language = "English",

volume = "15",

pages = "3690",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes

AU - Mezincescu, Alice-Mihaela

AU - Rudd, Amelia Elizabeth

AU - Cheyne, Lesley

AU - Horgan, Graham

AU - Philip, Sam

AU - Cameron, Donnie

AU - van Loon, Luc

AU - Whitefield, Phil

AU - Gribbin, Rachael

AU - Hu, May Khei

AU - Delibegovic, Mirela

AU - Fielding, Barbara

AU - Lobley, Gerald

AU - Thies, Frank

AU - Newby, David E

AU - Gray, Stuart

AU - Henning, Anke

AU - Dawson, Dana

N1 - Contributions D.D., A.H., S.G., S.P. and M.D. conceived the study and together with L.v.L., G.L., F.T. obtained the grant funding. AM executed the patient screening, recruitment, intervention planning, carried out all study investigations under respective specialist supervision (A.H./D.C./D.D. for magnetic resonance spectroscopy, F.T./G.L./D.D. for stable isotope investigation, S.G. for exercise intervention, S.P. for clinical supervision/management of diabetes as required, M.D. for all molecular laboratory analyses, A.M. analysed all data and performed statistical analysis under the supervision of G.H. L.v.L. provided expert advice in athletic physiology. Lipidomic analyses were carried out in P.W. laboratory. Blood/skeletal muscle enrichment analyses were carried out in B.F./F.T.-G.L. laboratories respectively, with practical input from R.G. A.R. and L.C. contributed as overall help to deliver study assessments in a technical role. M.K.H. analysed the food diaries. D.E.N. contributed to manuscript writing. D.D. and M.D. were the PhD supervisors for A.M. whose PhD thesis was based on this work. All authors contributed their respective specialist sections in drafting the manuscript.

PY - 2024/4/5

Y1 - 2024/4/5

N2 - Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called "athlete's paradox". In a parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY).

AB - Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called "athlete's paradox". In a parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY).

KW - Humans

KW - Male

KW - Athletes

KW - Lipid Metabolism

KW - Diabetes Mellitus, Type 2/metabolism

KW - Insulin Resistance

KW - Adult

KW - Middle Aged

KW - Endurance Training

KW - Muscle, Skeletal/metabolism

KW - Triglycerides/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85193313580&partnerID=8YFLogxK

UR - https://abdn.elsevierpure.com/en/publications/32def9dd-91e5-4a39-8c0d-7bbdc7cc4c91

U2 - 10.1038/s41467-024-47843-y

DO - 10.1038/s41467-024-47843-y

M3 - Article

C2 - 38750012

SN - 2041-1723

VL - 15

SP - 3690

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3690

ER -

Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes

Abstract

Bibliographical note

Data Availability Statement

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this