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. Author manuscript; available in PMC: 2010 Dec 1.

Published in final edited form as: Physiol Rev. 2007 Apr;87(2):507–520. doi: 10.1152/physrev.00024.2006

Fatty acid metabolites (LCCoA, DAG), which may accumulate within myotubules and hepatocytes due to increased fatty acid delivery and/ or decreased mitochondrial oxidation, trigger a serine/threonine kinase cascade (possibly involving nPKC, IKKβ and/ or JNK-1). This ultimately induces serine/ threonine phosphorylation of critical IRS-1 sites (at least in muscle), thereby inhibiting IRS-1/2 tyrosine phosphorylation and activation of PI 3-kinase, resulting in i) reduced insulin–stimulated glucose transport in muscle; and ii) reduced glycogen synthesis and increased gluconeogenesis in liver. GLUT4, glucose transporter 4; LCCoA, long chain acylcoenzymeA; DAG, diacylglycerol; IRS, insulin receptor substrate; PI3-kinase, phosphoinositol 3-kinase; nPKCs, novel protein kinase Cs; JNK-1, Jun kinase-1; IKK β; IκB kinase-β.

Fatty acid metabolites (LCCoA, DAG), which may accumulate within myotubules and hepatocytes due to increased fatty acid delivery and/ or decreased mitochondrial oxidation, trigger a serine/threonine kinase cascade (possibly involving nPKC, IKKβ and/ or JNK-1). This ultimately induces serine/ threonine phosphorylation of critical IRS-1 sites (at least in muscle), thereby inhibiting IRS-1/2 tyrosine phosphorylation and activation of PI 3-kinase, resulting in i) reduced insulin–stimulated glucose transport in muscle; and ii) reduced glycogen synthesis and increased gluconeogenesis in liver. GLUT4, glucose transporter 4; LCCoA, long chain acylcoenzymeA; DAG, diacylglycerol; IRS, insulin receptor substrate; PI3-kinase, phosphoinositol 3-kinase; nPKCs, novel protein kinase Cs; JNK-1, Jun kinase-1; IKK β; IκB kinase-β.