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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 #68: Regulation of Glucose Metabolism in Liver Part 4 of 11

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Gluconeogenic pathways: Gluconeogenesis is the synthesis of glucose from three carbon precursors such as alanine, pyruvate, lactate, and glycerol and is essentially a reversal of glycolysis. Under normal conditions, 90% of gluconeogenesis occurs in liver, and the rest occurs mainly in the renal cortex. Other sites of gluconeogenesis, such as the small intestine have been suggested but remain controversial.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #67: Regulation of Glucose Metabolism in Liver Part 3 of 11

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Regulation of glycogenolysis: Glycogen metabolism is regulated by reciprocal changes in the activities of glycogen synthase and glycogen phosphorylase. Net glucose production from glycogen occurs when phosphorylase activity is higher than synthase activity. Activation of glycogen phosphorylase is the culmination of a “glycogenolytic cascade” that is initiated by the binding of glucagon or beta-adrenergic agonists to their receptors in liver cells.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #66: Regulation of Glucose Metabolism in Liver Part 2 of 11

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Hepatic glucose production: Typical lean humans spend more than half of their lives in the post-absorptive state, with less than 5 g of glucose circulating in their blood to support life. Many tissues rely on glucose as their primary fuel source. Notable examples are brain, which has limited access to fatty acids, and erythrocytes which do not possess mitochondria and, therefore, rely on glycolysis to meet energy requirements. Even during rest the body uses roughly 8 g of glucose per hour, and during exercise this rate can increase more than twofold. The body would deplete circulating glucose in less than 30 min, resulting in severe hypoglycemia, loss of neurologic function and death, if not for a constant endogenous supply of glucose.

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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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