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Clinical Gems

Our clinical gems come from the top selling medical books, and text books because knowledge is everything when it comes to diabetes.

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #63: Mechanisms of Insulin Signal Transduction Part 7 of 8

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Insulin resistance in humans: abnormalities in insulin signaling and in the glucose transport effector system Although the key elements of the insulin signaling network have been defined by studies employing molecular and cell biology techniques, a number of studies have focused on translating this knowledge to human studies in a clinical research setting. Insulin resistance in peripheral tissues characterizes obesity and T2DM, and is involved in the pathogenesis of diabetes.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #62: Mechanisms of Insulin Signal Transduction Part 6 of 8

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The glucose transport effector system, GLUT4 vesicle translocation and trafficking: Glucose transport proteins are the key functional units of the glucose transport effector system. Multiple glucose transporter genes have been identified that encode a family of homologous proteins exhibiting different functional properties and marked differences in tissue-specific expression.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #61: Mechanisms of Insulin Signal Transduction Part 5 of 8

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PI-3 kinase-independent pathways for stimulation of glucose transport: The CAP/Cbl/TC10 pathway. Substantial evidence confirms the presence of PI-3 kinase independent pathways for stimulation of glucose transport. It had long been clear that other growth factor receptors (i.e., the platelet-derived growth factor (PDGF) receptor, cytokine receptors such as IL-4, and certain integrins) activate PI-3 kinase to the same extent as the insulin receptor with generation of PI(3,4,5)P3, yet still do not stimulate glucose transport.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #60: Mechanisms of Insulin Signal Transduction Part 4 of 8

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PI-3 kinase pathways: regulation of metabolism and gene expression: Signal transduction for insulin’s metabolic effects also diverges from insulin receptor substrate proteins and proceeds via the PI-3 kinase pathway. The first committed step involves type 1A PI-3 kinase, a heterodimer consisting of a p85 regulatory subunit and a p110 catalytic subunit. In quiescent cells, the regulatory subunit maintains a state of low activity for the catalytic subunit.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #59: Mechanisms of insulin signal transduction Part 3 of 8

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Insulin receptor substrate molecules -- receptor substrate/docking protein: Following insulin binding and receptor autophosphorylation, the next committed step in signal transduction is tyrosine phosphorylation of intracellular proteins. To accomplish this, autophosphorylation of the beta subunit mediates noncovalent but stable interactions between the receptor and intracellular substrate proteins, and this positions these molecules for tyrosine phosphorylation by the activated insulin receptor kinase.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #58: Mechanisms of insulin signal transduction Part 2 of 8

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Insulin receptors, ligand binding: The insulin action sequence is initiated with specific binding to high-affinity receptors on the plasma membrane of target cells. The insulin receptor is a large transmembrane glycoprotein consisting of two alpha- and two beta- subunits that form a heterotetramer, as depicted in Figure 12.1. The insulin receptor is synthesized from a single gene as a polypeptide pro receptor comprised of alpha- and beta- subunit sequences in tandem.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #56: Incretin Physiology in Health and Disease Part 6 of 6

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Potential mechanisms of incretin dysfunction in type 2 diabetes: Various potential explanations have been expounded in order to explain the reduced incretin effect in type 2 diabetes. One obvious factor to examine was the secretion of GIP and GLP-1. Regarding GIP, a number of studies have compared postprandial plasma concentrations between patients with and without diabetes. These studies have revealed increased, normal, or reduced GIP levels in patients with diabetes. Considering all studies together, there does not appear to be a general defect in GIP secretion. If anything, a slight increase in postprandial GIP levels might occur in patients with early type 2 diabetes, but clearly the differences in GIP levels would not sufficiently explain any alterations in insulin of glucose concentrations.

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