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Inositol hexakisphosphate kinase 1 is implicated in the insulin response to protein ingestion in older adults
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  • Published: 18 February 2026

Inositol hexakisphosphate kinase 1 is implicated in the insulin response to protein ingestion in older adults

  • Richie D. Barclay1,
  • Diana E. Motei1,
  • Oana Ancu1,
  • Christopher J. Tyler1,
  • Neale A. Tillin1,
  • Volker Behrends4,
  • Nicholas A. Burd2,3,
  • Nicholas M. Hurren1 &
  • …
  • Richard W.A. Mackenzie  ORCID: orcid.org/0000-0001-6799-62181,5,6,7 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Ageing
  • Endocrine system and metabolic diseases
  • Endocrinology
  • Metabolism
  • Molecular biology

Abstract

Age-related muscle mass is driven by a reduction in insulin sensitivity partly mediated by reduced amino acid and anabolic signalling kinetics. Insulin activates Akt-mTORC1 signalling in skeletal muscle, with inositol hexakisphosphate kinase 1 (IP6K1) shown to inhibit this signalling pathway in pre-diabetic humans. We aimed to compare muscle and plasma IP6K1 in young vs older adults and the possible role of IP6K1 in the anabolic response to protein and protein plus resistance exercise (RE). Nine young (24.9 ± 0.4 years) and nine older (66.2 ± 0.5 years), moderately active adults received primed continuous infusions of L-[ring-2H5]phenylalanine in basal and postprandial state. Blood and muscle biopsy samples were collected prior to and following ingestion of 25 g whey protein with or without knee extension exercise to examine skeletal muscle protein signalling and whole-body phenylalanine kinetics. Young adults had greater plasma IP6K1 at all time points. Older adults had reduced muscle IP6K1 at 120 min post-exercise. Muscle IP6K1 decreased 240 min postprandially in young adults compared with basal and there was no effect of exercise in either group. Older adults presented with reduced plasma and muscle IP6K1 in both postprandially and post-RE states, as well as reduced phenylalanine rate of disappearance for the same comparisons. IP6K1 may be involved in the reduction in amino acid metabolism, and the insulin-mediated response to protein and RE.

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Data availability

All datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Abbreviations

IP6K1:

Inositol hexakisphosphate kinase 1

mTOR:

Mechanistic target of rapamycin

mTORC1:

MTOR complex 1

mTORC2:

MTOR complex 2

Akt:

Protein kinase B

PI3K:

Phosphoinositide 3-kinases

IGF-1:

Insulin-like growth factor 1

IGFR:

IGF receptor

IRS-1:

Insulin receptor substrate 1

Rheb, p70s6k :

Ribosomal protein S6 kinase beta-1

4E-BP1:

Eukaryotic translation initiation factor 4E-binding protein 1

MPS:

Muscle protein synthesis

MPB:

Muscle protein breakdown

PA:

Phosphatidic acid

PtdIns3P:

Phosphatidylinositol 3-phosphate

LAT1:

L-type amino acid transporter 1

NPB:

Net protein balance

PDK1:

Phosphoinositide-dependent kinase 1

IGFBP:

Insulin-like growth factor-binding protein

PH:

Pleckstrin homology

BMI:

Body mass index

HOMAIR :

Homeostasis model assessment of insulin resistance

RE:

Resistance exercise

1RM:

One-repetition maximum

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Author information

Authors and Affiliations

  1. School of Life and Health Sciences, University of Roehampton, London, UK

    Richie D. Barclay, Diana E. Motei, Oana Ancu, Christopher J. Tyler, Neale A. Tillin, Nicholas M. Hurren & Richard W.A. Mackenzie

  2. Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Nicholas A. Burd

  3. Department of Health and Kinesiology, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Nicholas A. Burd

  4. School of Biomedical Science, University of West London, London, UK

    Volker Behrends

  5. Centre for Health & Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, UK

    Richard W.A. Mackenzie

  6. Institute of Cardio-Metabolic Medicine, Coventry University, University Hospital Coventry & Warwick NHS Trust, Coventry, CV1 5FB, UK

    Richard W.A. Mackenzie

  7. London Institute for Human Performance and Longevity, 1 Blythe Road, London, W14 0HG , UK

    Richard W.A. Mackenzie

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Contributions

RDB, NAB, CJT, NAT and RWM contributed to the conception and the design of the experiment. RDB, DEM, OA, VB, NMH and RWM contributed to collection, analysis, and interpretation of data. RDB, CJT, NAT, VB, NAB, NMH and RWM contributed to drafting or revising intellectual content of the manuscript. RB and RWAM had primary responsibility for final content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Richard W.A. Mackenzie.

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The authors declare no competing interests.

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Barclay, R.D., Motei, D.E., Ancu, O. et al. Inositol hexakisphosphate kinase 1 is implicated in the insulin response to protein ingestion in older adults. Sci Rep (2026). https://doi.org/10.1038/s41598-026-35711-2

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  • Received: 12 February 2025

  • Accepted: 07 January 2026

  • Published: 18 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-35711-2

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Keywords

  • IP6K1
  • Metabolism
  • Resistance exercise
  • Amino acids
  • Ageing
  • Insulin resistance
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