Effects of Sustained Hyperglycemia on Skeletal Muscle Lipids in Healthy Subjects

Christopher E. Shannon, Aurora Merovci, Marcel Fourcaudot, Devjit Tripathy, Muhammad Abdul-Ghani, Hu Wang, Xianlin Han, Luke Norton, Ralph A. DeFronzo

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Context: Sustained increases in plasma glucose promote skeletal muscle insulin resistance independent from obesity and dyslipidemia (ie, glucotoxicity). Skeletal muscle lipids are key molecular determinants of insulin action, yet their involvement in the development of glucotoxicity is unclear. Objective: To explore the impact of mild physiologic hyperglycemia on skeletal muscle lipids. Design: Single group pretest-posttest. Participants: Healthy males and females with normal glucose tolerance. Interventions: 72-hour glucose infusion raising plasma glucose by ∼50 mg/dL. Main Outcome Measures: Skeletal muscle lipids, insulin sensitivity, lipid oxidation. Results: Despite impairing insulin-mediated glucose disposal and suppressing fasting lipid oxidation, hyperglycemia did not alter either the content or composition of skeletal muscle triglycerides, diacylglycerides, or phospholipids. Skeletal muscle ceramides decreased after glucose infusion, likely in response to a reduction in free fatty acid concentrations. Conclusions: Our results demonstrate that the major lipid pools in skeletal muscle are unperturbed by sustained increases in glucose availability and suggest that glucotoxicity and lipotoxicity drive insulin resistance through distinct mechanistic pathways.

Original languageEnglish (US)
Pages (from-to)E3177-E3185
JournalJournal of Clinical Endocrinology and Metabolism
Issue number8
StatePublished - Aug 1 2022


  • glucotoxicity
  • insulin resistance
  • lipidomics
  • lipotoxicity
  • skeletal muscle

ASJC Scopus subject areas

  • Biochemistry, medical
  • Endocrinology
  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism


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