Differential regulation of intracellular glucose metabolism by glucose and insulin in human muscle

L. J. Mandarino, A. Consoli, A. Jain, D. E. Kelley

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Insulin and glucose stimulate glucose uptake in human muscle by different mechanisms. Insulin has well-known effects on glucose transport, glycogen synthesis, and glucose oxidation, but the effects of hyperglycemia on the intracellular routing of glucose are less well characterized. We used euglycemic and hyperglycemic clamps with leg balance measurements to determine how hyperglycemia affects skeletal muscle glucose storage, glycolysis, and glucose oxidation in normal human subjects. Glycogen synthase (GS) and pyruvate dehydrogenase complex (PDHC) activities were determined using muscle biopsies. During basal insulin replacement, hyperglycemia (11.6 ± 0.31 mM) increased leg muscle glucose uptake (0.522 ± 0.129 vs. 0.261 ± 0.071 μmol · min-1 · 100 ml leg tissue-1, P < 0.05), storage (0.159 ± 0.082 vs. -0.061 ± 0.055, P < 0.05), and oxidation (0.409 ± 0.080 vs. 0.243 ± 0.085, P < 0.05) compared with euglycemia (6.63 ± 0.33 mM). The increase in basal glucose oxidation due to hyperglycemia was associated with increased muscle PDHC activity (0.499 ± 0.087 vs. 0.276 ± 0.049, P < 0.05). However, the increase in leg glucose storage was not accompanied by an increase in muscle GS activity. During hyperinsulinemia, hyperglycemia (11.9 ± 0.49 mM) also caused an additional increase in leg glucose uptake over euglycemia (6.14 ± 0.42 mM) alone (5.75 ± 1.25 vs. 3.75 ± 0.58 μmol · min-1 · 100 ml leg-1, P < 0.05). In this case the major intracellular effect of hyperglycemia was to increase glucose storage (5.03 ± 1.16 vs. 2.39 ± 0.37, P < 0.05). At hyperinsulinemia, hyperglycemia had no effect on muscle GS or PDHC activity. We conclude that at basal insulin levels, hyperglycemia increases muscle glucose storage and glycolysis by increasing substrate availability and that glucose oxidation is preferentially increased by covalent activation of PDHC. During hyperinsulinemia, additional increases in substrate availability further activate GS allosterically and preferentially stimulate glycogen synthesis.

Original languageEnglish (US)
Pages (from-to)E898-E905
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number6 28-6
StatePublished - 1993
Externally publishedYes


  • glucose oxidation
  • glycogen synthase
  • glycogen synthesis
  • hyperglycemia
  • pyruvate dehydrogenase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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