Insulin resistance does not impair mechanical overload-stimulated glucose uptake, but does alter the metabolic fate of glucose in mouse muscle

Luke A. Weyrauch, Shawna L. McMillin, Carol A. Witczak

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Skeletal muscle glucose uptake and glucose metabolism are impaired in insulin resistance. Mechanical overload stimulates glucose uptake into insulin-resistant muscle; yet the mechanisms underlying this beneficial effect remain poorly understood. This study examined whether a differential partitioning of glucose metabolism is part of the mechanosensitive mechanism underlying overloadstimulated glucose uptake in insulin-resistant muscle. Mice were fed a high-fat diet to induce insulin resistance. Plantaris muscle overload was induced by unilateral synergist ablation. After 5 days, muscles were excised for the following measurements: (1) [3H]-2-deoxyglucose uptake; (2) glycogen; 3) [5-3H]glucose flux through glycolysis; (4) lactate secretion; (5) metabolites; and (6) immunoblots. Overload increased glucose uptake ~80% in both insulin-sensitive and insulin-resistant muscles. Overload increased glycogen content ~20% and this was enhanced to ~40% in the insulin-resistant muscle. Overload did not alter glycolytic flux, but did increase muscle lactate secretion 40–50%. In both insulin-sensitive and insulinresistant muscles, overload increased 6-phosphogluconate levels ~150% and decreased NADP:NADPH ~60%, indicating pentose phosphate pathway activation. Overload increased protein O-GlcNAcylation ~45% and this was enhanced to ~55% in the insulin-resistant muscle, indicating hexosamine pathway activation. In conclusion, insulin resistance does not impair mechanical overload-stimulated glucose uptake but does alter the metabolic fate of glucose in muscle.

Original languageEnglish (US)
Article number4715
Pages (from-to)1-15
Number of pages15
JournalInternational journal of molecular sciences
Volume21
Issue number13
DOIs
StatePublished - Jul 2020

Bibliographical note

Funding Information:
This research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant number R00AR056298 (C.A.W.), and the National Institute of Diabetes and Digestive and Kidney Diseases R01DK103562 (C.A.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, or the National Institutes of Health. The APC was funded by C.A.W. Acknowledgments: We would like to thank Kristen Turner, Erin Stanley and Parker Evans for their participation in data acquisition.

Funding Information:
Funding: This research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant number R00AR056298 (C.A.W.), and the National Institute of Diabetes and Digestive and Kidney Diseases R01DK103562 (C.A.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, or the National Institutes of Health. The APC was funded by C.A.W.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Exercise
  • Glucose transporter
  • Glycogen
  • Glycolysis
  • Hexosamine pathway
  • Lactate
  • Pentose phosphate pathway

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