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Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and

G Kroder1, B Bossenmaier, M Kellerer

  • 1IV Abteilung Medizinische Klinik und Poliklinik, Eberhard-Karls Universität, Tubingen, Germany.

The Journal of Clinical Investigation
|March 15, 1996
PubMed

Insights

High glucose and TNF-alpha inhibit insulin receptor signaling via different pathways. TNF-alpha uses phosphotyrosine phosphatase activation, while high glucose utilizes protein kinase C activation, impacting downstream signaling differently.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Endocrinology

Background:

  • Insulin receptor (IR) signaling is crucial for glucose homeostasis.
  • Both high glucose (hyperglycemia) and tumor necrosis factor-alpha (TNF-α) can inhibit IR signaling.
  • The distinct mechanisms and downstream consequences of these inhibitions require detailed characterization.

Purpose of the Study:

  • To elucidate the mechanism of TNF-α-induced IR inhibition.
  • To compare the downstream signal transduction effects of TNF-α- and hyperglycemia-induced IR inhibition.
  • To differentiate the molecular pathways affected by each inhibitory factor.

Main Methods:

  • Utilized NIH3T3 cells overexpressing the human insulin receptor.
  • Administered TNF-α and high glucose (25 mM) to assess IR autophosphorylation inhibition.
  • Employed specific inhibitors for phosphotyrosine phosphatase (PTPase), protein kinase C (PKC), phosphatidylinositol-3 kinase (PI3K), and troglitazone (CS045).
  • Analyzed tyrosine phosphorylation of key downstream substrates including insulin receptor substrate-1 (IRS-1), Shc, and focal adhesion kinase (FAK).

Main Results:

  • Both TNF-α and high glucose rapidly inhibited IR autophosphorylation (>50% within 5-10 min).
  • TNF-α inhibition was prevented by PTPase inhibitors but unaffected by PKC inhibitors or wortmannin.
  • High glucose-induced inhibition was prevented by PKC inhibitors and CS045 but unaffected by PTPase inhibitors.
  • Both agents similarly inhibited IRS-1 and Shc tyrosine phosphorylation.
  • Hyperglycemia blocked insulin-induced dephosphorylation of FAK125, while TNF-α did not.

Conclusions:

  • TNF-α inhibits insulin receptor signaling via PTPase activation.
  • High glucose inhibits insulin receptor signaling through PKC activation.
  • Hyperglycemia causes broader inhibition of IR downstream signaling, affecting both phosphorylation and dephosphorylation events, unlike TNF-α.

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