FIGURE 21-1

Insulin and glucose uptake by tissues in physiological conditions.

Insulin promotes insulin-mediated glucose uptake (IMGU) in adipose tissues, skeletal and cardiac muscles by activating GLUT-4 transporters. Simultaneously, insulin activates GLUT-2 transporters in the liver, which decrease the endogenous glucose production. The global effect is a decrease in blood glucose level (insulin is a hypoglycemic hormone). As a consequence, noninsulin-mediated glucose uptake (NIMGU) by GLUT-1 transporters decreases. (Adapted with permission from Lena D, Kalfon P, Preiser JC, Ichai C. Glycemic control in the intensive care unit and during the postoperative period. Anesthesiology. February 2011;114(2):438-444.)

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Toxicity Associated with High Glucose Conscentrations

In stress conditions, an overall massive glucose overload happens in NIMGU?] tissues under the influence of proinflammatory mediators, counterregulatory hormones, and hypoxia.

A wide range of tissues, including hepatocytes, endothelial cells, neurons, nephrons, and immune cells may be susceptible to enhanced glucose toxicity as a result of acute illness. In these tissues, several deleterious effects have been associated with these high glucose concentrations in cells.1,9 Damages to mitochondrial proteins occur and the formation of reactive oxygen species (ROS) is increased as a consequence of the shift from glycolysis toward accessory metabolic pathways (pentose phosphate, hexosamines, polyols).10 

Other effects of excess glucose concentrations include the exacerbation of inflammatory pathways, decreased complement activity, modifications in the innate immune system, impairment in endothelial and hepatic mitochondrial functions, abolishment of the ischemic preconditioning, and protein glycosylation. Acute complications attributed to stress hyperglycemia include renal failure, increased susceptibility to infections, polyneuropathy, and impaired microcirculation.1

 

 

 

 

 

 

 

 

 

Glucose disposal by insulin-sensitive tissues is regulated initially by an increase in glucose transport and enzyme phosphorylation leading to the activation of glycogen synthase, phosphofructokinase, and pyruvate dehydrogenase (see Figure 7–5).

Glucagon receptor-mediated cellular effects. Glucagon binds to G protein–coupled receptor (GPCR) on target cells leading to activation of adenylate cyclase, elevation in cAMP and increased protein kinase A activity resulting in phosphorylation of enzymes responsible for control of glucose metabolism. The ultimate result is an increase in hepatic glucose production through increased gluconeogenesis and glycogenolysis. cAMP, cyclic 3′,5′-adenosine monophosphate; GDP, guanosine 5′-diphosphate; G-6-Pase, glucose-6-phosphatase; GTP, guanosine 5′-triphophate; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1, peroxisome proliferator-activated receptor-coactivator-1; PKA, protein kinase A.

The majority of insulin-stimulated glucose taken up is stored as glycogen. Hormonally induced changes in intracellular fructose 2,6-bisphosphate concentrations play a key role in muscle glycolytic flux and both glycolytic and gluconeogenic flux in the liver.

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Oxidation of one gram of carbohydrate yields approximately 4 kcal of energyl. Energy obtained from metabolism (e.g. oxidation of glucose) is usually stored temporarily within cells in the form of ATP. Organisms capable of aerobic respiration metabolize glucose and oxygen to release energy with carbon dioxide and water as byproducts.

Numerous studies suggest, however, that both sugars and starches produce an unpredictable range of glycemic and insulinemic responses. While some studies support a more rapid absorption of sugars relative to starches[3] other studies reveal that many complex carbohydrates such as bread, rice, and potatoes have glycemic indices similar to or higher than simple carbohydrates such as sucrose.[4] Sucrose, for example, has a glycemic index lower than expected because the sucrose molecule is half fructose, which has little effect on blood glucose.[5] The value of classifying carbohydrates as simple or complex is questionable. The glycemic index is a better predictor of a carbohydrate's effect on blood glucose.[6]

Carbohydrates are a superior short-term fuel for organisms because they are simpler to metabolize than fats or those amino acids (components of proteins) that can be used for fuel. In animals, the most important carbohydrate is glucose. The concentration of glucose in the blood is used as the main control for the central metabolic hormone,insulin. Starch, and cellulose in a few organisms (e.g., some animals (such as termites[7]) and some microorganisms (such as protists and bacteria)), both being glucose polymers, are disassembled during digestion and absorbed as glucose. Some simple carbohydrates have their own enzymatic oxidation pathways, as do only a few of the more complex carbohydrates. The disaccharide lactose, for instance, requires the enzyme lactase to be broken into its monosaccharides components; many animals lack this enzyme in adulthood.

Carbohydrates are typically stored as long polymers of glucose molecules with glycosidic bonds for structural support (e.g. chitin, cellulose) or for energy storage (e.g.glycogen, starch). However, the strong affinity of most carbohydrates for water makes storage of large quantities of carbohydrates inefficient due to the large molecular weight of the solvated water-carbohydrate complex. In most organisms, excess carbohydrates are regularly catabolised to form acetyl-CoA, which is a feed stock for the fatty acid synthesis pathway; fatty acids, triglycerides, and other lipids are commonly used for long-term energy storage. The hydrophobic character of lipids makes them a much more compact form of energy storage than hydrophilic carbohydrates. However, animals, including humans, lack the necessary enzymatic machinery and so do not synthesize glucose from lipids, though glycerol can be converted to glucose.[8]

All carbohydrates share a general formula of approximately CnH2nOn; glucose is C6H12O6. Monosaccharides may be chemically bonded together to form disaccharides such assucrose and longer polysaccharides such as starch and cellulose.

Glycogen, a storage form of glucose in vertebrates, is synthesized by glycogenesis when glucose levels are high and degraded by glycogenolysis when glucose is in short supply. Glucose can also be synthesized from noncarbohydrate precursors by reactions referred to as gluconeogenesis. The pentose phosphate pathway enables cells to convert glucose-6-phosphate, a derivative of glucose, to ribose- 5-phosphate (the sugar used to synthesize nucleotides and nucleic acids) and other types of monosaccharides. NADPH, an important cellular reducing agent, is also produced by this pathway. In Chapter 9, the glyoxylate cycle, used by some organisms (primarily plants) to manufacture carbohydrate from fatty acids, is considered. Photosynthesis, a process in which light energy is captured to drive carbohydrate synthesis, is described in Chapter 13. Any discussion of carbohydrate metabolism focuses on the synthesis and usage of glucose, a major fuel for most organisms. In vertebrates, glucose is transported throughout the body in the blood. If cellular energy reserves are low, glucose is degraded by the glycolytic pathway. Glucose molecules not required for immediate energy production are stored as glycogen in liver and muscle. The energy requirements of many tissues (e.g., brain, red blood cells, and exercising skeletal muscle cells) depend on an uninterrupted flow of glucose. Depending on a cell’s metabolic requirements, glucose can also be used to synthesize, for example, other monosaccharides, fatty acids, and certain amino acids. Figure 8.2 summarizes the major pathways of carbohydrate metabolism in animals.

See: Carbohydrate Metabolism¹

Reference

1. http://en.wikipedia.org/wiki/Carbohydrate_metabolism

2. http://global.oup.com/us/companion.websites/fdscontent/uscompanion/us/static/companion.websites/9780199730841/

McKee_Chapter8_Sample.pdf