Abstract
Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (n = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by “priming” a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.
Original language | English |
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Journal | Cell Metabolism |
Volume | 36 |
Issue number | 12 |
Pages (from-to) | 2542-2559 |
ISSN | 1550-4131 |
DOIs | |
Publication status | Published - 2024 |
Bibliographical note
Funding Information:We thank Betina Bolmgreen, Nikoline R. Andersen, Jesper B. Birk, and Irene B. Nielsen (Department of Nutrition, Exercise, and Sports) for their skilled technical help in the laboratory. We would like to thank Professor Bente Kiens for scientific discussion, Kasper E. Villumsen and Kim A. Sj\u00F8berg for assistance during the experimental trials, and Le Lene S. Stevner for support on data regulation and protection. This work was funded by a Pfizer, Inc. grant (to D.E.J., J.F.P.W., and C.P.) and a grant from the National Health and Medical Research Council (NHMRC; GNT2011083 to S.J.H., D.E.J., and J.F.P.W.). E.J.N. was supported by an Australian Government Research Training Program Scholarship, the University of Sydney Val Street Scholarship, EMBO (ALTF 1071-2021), and was supported by the Schmidt Science Fellows, in partnership with the Rhodes Trust. S.J.H. is supported by an NHMRC Investigator Grant (2026905). D.E.J. is an Australian Research Council (ARC) Laureate Fellow. J.F.P.W. was supported by The Novo Nordisk Foundation (no. NN0070370, NNF082659, and NNF0079480) and The University of Sydney University of Copenhagen Partnership Collaboration Awards (to J.F.P.W. and D.E.J.). J.D.O. and M.R.L. were supported by a research grant from the Danish Diabetes and Endocrinology Academy, which is funded by the Novo Nordisk Foundation, grant no. NNF17SA0031406; Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research 19K20007 (to K.K.); and the European Foundation for the Study of Diabetes JDS Fellowship Program (to K.K.). B.L.P. is supported by an NHMRC Investigator Grant (2009642). E.J.N. was supported by core funding from the British Heart Foundation (RG/18/13/33946); NIHR Cambridge Biomedical Research Centre (BRC-1215-20014 and NIHR203312); Cambridge BHF Centre of Research Excellence (RE/18/1/34212); BHF Chair Award (CH/12/2/29428); Health Data Research UK, which is funded by the UK Medical Research Council; the Engineering and Physical Sciences Research Council; the Economic and Social Research Council; the Department of Health and Social Care (England); the Chief Scientist Office of the Scottish Government Health and Social Care Directorates; the Health and Social Care Research and Development Division (Welsh Government); the Public Health Agency (Northern Ireland); the British Heart Foundation; and Wellcome. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHMRC, ARC, the NIHR, or the Department of Health and Social Care. The authors acknowledge the facilities and support of the Sydney Mass Spectrometry Facility (SydneyMS), University of Sydney.
Funding Information:
We thank Betina Bolmgreen, Nikoline R. Andersen, Jesper B. Birk, and Irene B. Nielsen (Department of Nutrition, Exercise, and Sports) for their skilled technical help in the laboratory. We would like to thank Professor Bente Kiens for scientific discussion, Kasper E. Villumsen and Kim A. Sj\u00F8berg for assistance during the experimental trials, and Le Lene S. Stevner for support on data regulation and protection. This work was funded by a Pfizer, Inc. grant (to D.E.J., J.F.P.W., and C.P.) and a grant from the National Health and Medical Research Council (NHMRC; GNT2011083 to S.J.H., D.E.J., and J.F.P.W.). E.J.N. was supported by an Australian Government Research Training Program Scholarship , the University of Sydney Val Street Scholarship , and the Schmidt Science Fellows, in partnership with the Rhodes Trust . S.J.H. is supported by an NHMRC Investigator Grant ( 2026905 ). D.E.J. is an Australian Research Council (ARC) Laureate Fellow supported by The Novo Nordisk Foundation (no. NN0070370 , NNF082659 , and NNF0079480 to J.F.P.W.) and The University of Sydney University of Copenhagen Partnership Collaboration Awards (to J.F.P.W. and D.E.J.). J.D.O. and M.R.L. were supported by a research grant from the Danish Diabetes and Endocrinology Academy , which is funded by the Novo Nordisk Foundation , grant no. NNF17SA0031406 ; Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research 19K20007 (to K.K.); and the European Foundation for the Study of Diabetes JDS Fellowship Program (to K.K.). B.L.P. is supported by an NHMRC Investigator Grant ( 2009642 ). E.J.N. was supported by core funding from EMBO ( ALTF 1071-2021 ); the British Heart Foundation ( RG/18/13/33946 ); NIHR Cambridge Biomedical Research Centre ( BRC-1215-20014 and NIHR203312 ); Cambridge BHF Centre of Research Excellence ( RE/18/1/34212 ); BHF Chair Award ( CH/12/2/29428 ); Health Data Research UK , which is funded by the UK Medical Research Council ; the Engineering and Physical Sciences Research Council ; the Economic and Social Research Council ; the Department of Health and Social Care (England) ; the Chief Scientist Office of the Scottish Government Health and Social Care Directorates ; the Health and Social Care Research and Development Division (Welsh Government) ; the Public Health Agency (Northern Ireland) ; the British Heart Foundation ; and Wellcome. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHMRC, ARC, the NIHR, or the Department of Health and Social Care. The authors acknowledge the facilities and support of the Sydney Mass Spectrometry Facility (SydneyMS), University of Sydney .
Publisher Copyright:
© 2024 The Author(s)
Keywords
- cell signaling
- exercise
- insulin
- insulin resistance
- MINDY1
- phosphoproteomics
- proteomics
- skeletal muscle