A group of investigators is studying the mechanisms of signal transduction involved in the pathogenesis of type 2 diabetes mellitus. Their research focuses on the intracellular signaling cascade that begins when insulin binds to the insulin receptor. In a series of experiments, they demonstrate that pre-treatment with tumor necrosis factor alpha (TNF-α) results in decreased insulin-mediated glucose uptake. This effect of TNF-α is most likely mediated through upregulation of which of the following processes?

Question

A group of investigators is studying the mechanisms of signal transduction involved in the pathogenesis of type 2 diabetes mellitus.  Their research focuses on the intracellular signaling cascade that begins when insulin binds to the insulin receptor.  In a series of experiments, they demonstrate that pre-treatment with tumor necrosis factor alpha (TNF-α) results in decreased insulin-mediated glucose uptake.  This effect of TNF-α is most likely mediated through upregulation of which of the following processes?

Quizplus · Accepted Answer

11ec160b_3ab6_4e66_9249_b9cd29b315c4_MD0001_00 The insulin receptor (IR) is a tetrameric structure consisting of 2 alpha and 2 beta subunits. The alpha subunits are extracellular and provide the binding site for insulin. The beta subunits are intracellular and contain tyrosine kinase domains that are activated when insulin attaches to the alpha subunits. A series of downstream signaling is then triggered, starting with the autophosphorylation of IR, phosphorylation of IR substrates 1 and 2 (IRS-1/2), and ultimately, translocation of glucose transporter-4 (GLUT-4) to the cell membrane. Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine that induces insulin resistance through the activation of serine kinases, which then phosphorylate serine residues on the beta subunits of IR and IRS-1. This inhibits tyrosine phosphorylation of IRS-1 by IR and subsequently hinders downstream signaling, resulting in resistance to the normal actions of insulin. Phosphorylation of threonine residues has similar effects. Catecholamines, glucocorticoids, and glucagon can also induce insulin resistance by this same mechanism. (Choice A) Cyclic AMP (cAMP) is inactivated via hydrolysis by phosphodiesterase. Phosphodiesterase can thereby dampen the effects of various hormones (eg, glucagon) that use cAMP as a second messenger. cAMP is also involved in insulin release by pancreatic beta cells, but it does not participate in IR downstream signaling. (Choice B) Some hormones (eg, angiotensin II, gonadotropin-releasing hormone) act on transmembrane receptors coupled with a G_q-protein that activates phospholipase C, which then cleaves phosphatidylinositol biphosphate into two important secondary messengers: inositol triphosphate and diacylglycerol (DAG). Inositol triphosphate mediates its action by increasing intracellular calcium influx, and DAG activates protein kinase C. (Choice C) Hydroxyproline, a major component of bone and skin collagen, is formed by the hydroxylation of proline, which requires vitamin C. Insulin plays no role in the hydroxylation of proline. (Choice E) Peroxisome proliferator-activated receptor-gamma (PPAR-γ) alters gene transcription by binding to the promoter region of target genes. Activation of PPAR-γ results in improved insulin sensitivity. Educational objective: Phosphorylation of serine and threonine residues of insulin receptor and insulin receptor substrate by serine kinase leads to insulin resistance. This type of phosphorylation can be induced by TNF-α, catecholamines, glucocorticoids, and glucagon. __________ References: Insulin resistance induced by tumor necrosis factor-alpha in myocytes and brown adipocytes. (http://www.ncbi.nlm.nih.gov/pubmed/17940160)

A Group of Investigators Is Studying the Mechanisms of Signal