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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 #75: Insulin actions in vivo: glucose metabolism Part 1 of 9

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Glucose is widespread in living organisms and, with protein and fat, completes the triad of the major metabolic fuels. To a much lesser extent than in plants, glucose also constitutes a building block for structural and enzymatic components of cells as well as the extracellular matrix. As a metabolic substrate, glucose is present in organisms essentially in its simple, monomeric form (alpha-D-glucopyranose) and as a branched polymer of alpha-glucose, namely glycogen. Disaccharides of glucose (lactose, maltose, and sucrose) are quantitatively less important. Glucose is present in plasma water at a concentration that — in a healthy adult who has fasted overnight — ranges between 3.6 and 5.5 mmol L−1 (65 – 99 mg dL−1 ).

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #74: Regulation of Glucose Metabolism in Liver Part 10 of 11

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Glycolysis: Glucose-6-phosphate not used for direct glycogen synthesis can be metabolized in the glycolytic pathway. About half of the glucose taken up by liver during duodenal glucose absorption will undergo glycolysis to pyruvate. The resulting pyruvate can be used for lipogenesis and amino acid synthesis, lactate production, or cycled back to glucose-6-phosphate for indirect glycogen synthesis.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #73: Regulation of Glucose Metabolism in Liver Part 9 of 11

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Glucose phosphorylation as a therapeutic target for diabetes: Early experiments using genetic overexpression of glucokinase in liver of rodent models showed promise for the protection against hyperglycemia during diabetes, spawning the development of glucokinase activators. These drugs interact with allosteric sites of glucokinase, thus promoting a conformation that exposes the catalytic domain and potentiates the activity of the enzyme.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #72: Regulation of Glucose Metabolism in Liver Part 8 of 11

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Linking molecular and metabolic regulation of hepatic glucose metabolism: Cross-talk between metabolism and molecular biology is an emerging mechanism of metabolic regulation and is particularly relevant to the control glucose metabolism in liver. Some transcription factors and nuclear receptors are activated in response to metabolites. During fasting lipid metabolites are released that activate PPARα and induce the gene expression of oxidative metabolism.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #71: Regulation of Glucose Metabolism in Liver Part 7 of 11

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Allosteric regulation of hexose flux is another example where the regulation of gluconeogenesis occurs by interaction with glycolytic regulation. The conversion of F-1-P to F-1,6-P2 is irreversibly catalyzed by the gluconeogenic enzyme fructose-1,6- bisphosphatase, and the opposite glycolytic reaction is irreversibly catalyzed by phosphofructokinase.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #70: Regulation of Glucose Metabolism in Liver Part 6 of 11

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Acute regulation of gluconeogenesis: Prior to discovery of the transcriptional mechanisms described earlier, the control of hepatic glucose metabolism was examined in great detail on the basis of substrate, allosteric, and posttranslational modification. These factors alter gluconeogenic flux rapidly (seconds to minutes) and are a critical first response to increased glucose demand.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #69: Regulation of Glucose Metabolism in Liver Part 5 of 11

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Transcriptional regulation of gluconeogenesis: The gradual shift from the fed-to-fasted state is followed closely by hormonal regulation of genes encoding PEPCK, fructose-1,6-bisphosphatase, and the glucose-6-phosphatase catalytic subunit. The transcriptional regulation of these genes remains a developing research area and its many emerging nuances cannot be completely covered here.

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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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