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Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85

The Two Sides of a Coin

¹ Research Service, Denver VA Medical Center, Denver, Colorado
² Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Address correspondence and reprint requests to Dr. Boris Draznin, Research Service (151), Denver VA Medical Center, 1055 Clermont St., Denver, CO 80220. E-mail: boris.draznin{at}med.va.gov

Abbreviations: I B, inhibitor of B; IKKß inhibitor of B kinase ß; IRS, insulin receptor substrate; JNK, c-Jun NH₂-terminal kinase; mTOR, molecular target of rapamycin; PI, phosphatidylinositol; PKC, protein kinase C; TNF, tumor necrosis factor

Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible for insulin resistance in the majority of patients lies at the postreceptor level of insulin signaling. Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. However, the nature of the triggering event(s) remains largely enigmatic. Two separate, but likely, complementary mechanisms have recently emerged as a potential explanation. First, it became apparent that serine phosphorylation of IRS proteins can reduce their ability to attract PI 3-kinase, thereby minimizing its activation. A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. Additionally, mitochondrial dysfunction has been suggested to trigger activation of several serine kinases, leading to a serine phosphorylation of IRS-1. Second, a distinct mechanism involving increased expression of p85 has also been found to play an important role in the pathogenesis of insulin resistance. Conceivably, a combination of both increased expression of p85 and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance.

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