Carbohydrate Metabolism PDF

CARBOHYDRATE Energy is extracted from food via oxidation, resulting in the end products carbon dioxide and water. This process occurs in 4 stages, shown below. 1- Metabolic fuels are hydrolyzed in the gastrointestinal tract 2- The building blocks are degraded by various pathways in tissues to a com...

CARBOHYDRATE Energy is extracted from food via oxidation, resulting in the end products carbon dioxide and water. This process occurs in 4 stages, shown below. 1- Metabolic fuels are hydrolyzed in the gastrointestinal tract 2- The building blocks are degraded by various pathways in tissues to a common metabolic intermediate, acetyl-CoA 3-The citric acid, Krebs, or tricarboxylic acid [TCA] cycle oxidizes acetyl- CoA to CO2 4- Oxidative phosphorylation, in which the energy of NADH and FADH2 is released via the electron transport chain (ETC) and used by an ATP synthase to produce ATP  METABOLIC ENERGY STORAGE ATP is formed in catabolic pathways by phosphorylation of ADP and may provide energy for biosynthesis (anabolic pathways). There is a limited amount of ATP in circulation. Most of the excess energy from the diet is stored as fatty acids and glycogen. Although proteins can be mobilized for energy in a prolonged fast, they are normally more important for other functions.  REGULATION OF FUEL METABOLISM Insulin is an anabolic hormone that promotes fuel storage. Its action is opposed by a number of hormones, including glucagon, epinephrine, cortisol, and growth hormone. The major function of glucagon is to respond rapidly to decreased blood glucose levels by promoting the synthesis and release of glucose into the circulation. Anabolic and catabolic pathways are controlled at three important levels 1- Allosteric inhibitors and activators of rate-limiting enzymes 2- Control of gene expression by insulin and glucagon 3- Phosphorylation (glucagon) and dephosphorylation (insulin) of rate limiting enzymes  Well-Fed State Immediately after a meal, the blood glucose level rises and stimulates the release of insulin. The three major target tissues for insulin are liver, muscle, and adipose tissue. Insulin promotes glycogen synthesis in liver and muscle. After the glycogen stores are filled, the liver converts excess glucose to fatty acids and triglycerides. Insulin promotes triglyceride synthesis in adipose tissue and protein synthesis in muscle, as well as glucose entry into both tissues. After a meal, most of the energy needs of the liver are met by the oxidation of excess amino acids. Two tissues, brain and red blood cells are insensitive to insulin (are insulin independent). The brain and other nerves derive energy from oxidizing glucose to C02 and water in both the well-fed and normal fasting states. Only in prolonged fasting does this situation change. Under all conditions, red blood cells use glucose anaerobically for all their energy needs.  Post absorptive State Glucagon and epinephrine levels rise during an overnight fast. These hormones exert their effects on skeletal muscle, adipose tissue, and liver. In liver, glycogen degradation and the release of glucose into the blood are stimulated. Hepatic gluconeogenesis is also stimulated by glucagon, but the response is slower than that of glycogenolysis. The release of amino acids from skeletal muscle and fatty acids from adipose tissue are both stimulated by the decrease in insulin and by an increase in epinephrine. The amino acids and fatty acids are taken up by the liver, where the amino acids provide the carbon skeletons and the oxidation of fatty acids provides the ATP necessary for gluconeogenesis.  StarvationProlonged Fast Levels of glucagon and epinephrine are markedly elevated during starvation. Lipolysis is rapid, resulting in excess acetyl- CoA that is used for ketone synthesis. Levels of both lipids and ketones are therefore increased in the blood. Muscle uses fatty acids as the major fuel, and the brain adapts to using ketones for some of its energy. After several weeks of fasting, the brain derives approximately two thirds of its energy from ketones and one third from glucose. The shift from glucose to ketones as the major fuel diminishes the amount of protein that must be degraded to support gluconeogenesis. There is no "energy-storage form" for protein because each protein has a specific function in the cell. Therefore, the shift from using glucose to ketones during starvation spares protein, which is essential for these other functions. Red blood cells (and renal medullary cells) that have few, if any, mitochondria continue to be dependent on glucose for their energy. PATTERNS OF FUEL METABOLISM IN TISSUES  Liver Two major roles of liver in glucose metabolism 1- maintain a constant level of blood glucose 2- synthesize ketones when excess fatty acids are oxidized. After a meal, the glucose concentration in the portal blood is elevated. The liver extracts excess glucose and uses it to replenish its glycogen stores. Any glucose remaining in the liver is then converted to acetyl CoA and used for fatty acid synthesis. The increase in insulin after a meal stimulates both glycogen synthesis and fatty acid synthesis in liver. The fatty acids are converted to triglycerides and released into the blood as very low density lipoproteins (VLDLs). In the well-fed state, the liver derives most of its energy from the oxidation of excess amino acids. Between meals and during prolonged fasts, the liver releases glucose into the blood. The increase in glucagon during fasting promotes both glycogen degradation and gluconeogenesis. Lactate, glycerol, and amino acids provide carbon skeletons for glucose synthesis.  Adipose Tissue After a meal, the elevated insulin stimulates glucose uptake by adipose tissue. Insulin also stimulates fatty acid release from VLDL and chylomicron triglyceride. Lipoprotein lipase, an enzyme found in the capillary bed of adipose tissue, is induced by insulin. The fatty acids that are released from lipoproteins are taken up by adipose tissue and re-esterified to triglyceride for storage. Insulin is also very effective in suppressing the release of fatty acids from adipose tissue. During the fasting state, the decrease in insulin and the increase in epinephrine activate hormone-sensitive lipase in fat cells, allowing fatty acids to be released into the circulation.  Skeletal Muscle Resting muscle The major fuels of skeletal muscle are glucose and fatty acids. Because of the enormous bulk, skeletal muscle is the body's major consumer of fuel. After a meal, under the influence of insulin, skeletal muscle takes up glucose to replenish glycogen stores and amino acids that are used for protein synthesis. Both excess glucose and amino acids can also be oxidized for energy. In the fasting state, resting muscle uses fatty acids derived from free fatty acids in the blood. Ketones may be used if the fasting state is prolonged. Active muscle The primary fuel used to support muscle contraction depends on the magnitude and duration of exercise as well as the major fibers involved. Skeletal muscle has stores of both glycogen and some triglycerides. Fast-twitch muscle fibers have a high capacity for anaerobic glycolysis but are quick to fatigue. They are involved primarily in short-term, high-intensity exercise. Slow-twitch muscle fibers in arm and leg muscles are well vascularized and primarily oxidative. They are used during prolonged, low-to-moderate intensity exercise and resist fatigue. Slow-twitch fibers and the number of their mitochondria increase dramatically in trained endurance athletes. Short bursts of high-intensity exercise are supported by anaerobic glycolysis drawing on stored muscle glycogen. During moderately high, continuous exercise, oxidation of glucose and fatty acids are both important, but after 1 to 3 hours of continuous exercise at this level, muscle glycogen stores become depleted, and the intensity of exercise declines to a rate that can be supported by oxidation of fatty acids.  Cardiac Muscle During fetal life cardiac muscle primarily uses glucose as an energy source, but in the postnatal period there is a major switch to β-oxidation of fatty acids. Thus, ketones are present during prolonged fasting, they are also used. Thus, not surprisingly, cardiac myocytes most closely parallel the skeletal muscle during extended periods of exercise. In patients with cardiac hypertrophy, this situation reverses to some extent. In the failing heart, glucose oxidation increases, and β- oxidation falls.  Brain Although the brain represents 2% of total body weight, it obtains 15 % of the cardiac output, uses 20% of total 02, and consumes 25% of the total glucose. Therefore, glucose is the primary fuel for the brain. Blood glucose levels are tightly regulated to maintain the concentration levels that enable sufficient glucose uptake into the brain via GLUT 1 and GLUT 3 transporters. Because glycogen levels in the brain are minor, normal function depends upon continuous glucose supply from the bloodstream. In hypoglycemic conditions (