Involvement of phosphoinositide 3-kinase in insulin stimulation of MAP-kinase and phosphorylation of protein kinase-B in human skeletal muscle: implications for glucose metabolism

Diabetologia. 1997 Oct;40(10):1172-7. doi: 10.1007/s001250050803.

Abstract

Isolated skeletal muscle from healthy individuals was used to evaluate the role of phosphoinositide 3-kinase (PI 3-kinase) in insulin signalling pathways regulating mitogen activated protein kinase (MAP-kinase) and protein kinase-B and to investigate whether MAP-kinase was involved in signalling pathways regulating glucose metabolism. Insulin stimulated glycogen synthase activity (approximately 1.7 fold), increased 3-o-methylglucose transport into human skeletal muscle strips (approximately 2 fold) and stimulated phosphorylation of the p42 ERK-2 isoform of MAP-kinase. This phosphorylation of p42 ERK2 was not blocked by the PI 3-kinase inhibitors LY294002 and wortmannin although it was blocked by the MAP-kinase kinase (MEK) inhibitor PD 98059. However, PD98059 (up to 20 micromol/l) did not block insulin activation of glycogen synthase or stimulation of 3-o-methylglucose transport. Wortmannin and LY294002 did block insulin stimulation of protein kinase-B (PKB) phosphorylation and stimulation of 3-o-methylglucose transport was inhibited by wortmannin (IC50 approximately 100 nmol/l). These results indicate that MAP-kinase is activated by insulin in human skeletal muscle by a PI 3-kinase independent pathway. Furthermore this activation is not necessary for insulin stimulation of glucose transport or activation of glycogen synthase in this tissue.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-O-Methylglucose / antagonists & inhibitors
  • 3-O-Methylglucose / metabolism*
  • Adult
  • Androstadienes / pharmacology
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Flavonoids / pharmacology
  • Glycogen Synthase / antagonists & inhibitors
  • Glycogen Synthase / metabolism*
  • Humans
  • Insulin / pharmacology*
  • Male
  • Mitogen-Activated Protein Kinase 1 / analysis
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Morpholines / pharmacology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / enzymology*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • Flavonoids
  • Insulin
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • 3-O-Methylglucose
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Glycogen Synthase
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Wortmannin