Metabolism in fasting and starvation.docx

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Biomedical Sciences
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Prof.Christina Mitchell

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Metabolism in fasting and starvation Explain how metabolic processes are divided among specialised tissues and organs. In the average adult male there are both circulating energy as well as stored fuel reserves. Usually there is circulating 20g of glucose, 0.3g of free fatty acids and 3g of triacylglycerols. Stored fuel is located in three areas, the liver, the muscle and in adipose tissue. Within the liver there is 75g of stored glycogen. This can undergo a metabolic process called glycolysis that restores aa falling bold glucose level. Within the muscle there is 250g of stored glycogen, though this is not accessible for blood glucose, instead glycogen in the muscle is aids in generation of ATP to aid in muscle contraction. The muscle also contains 6kg of muscle that can also be used to produce energy. Adipose tissue contains 15kg of fat to use as an energy source. These measurements of course are based on an average male. These tissues and organs are specialised in terms of metabolic function. The brain is an organs for which glucose is essential. On average the brain requires 115g of glucose per day, which oxidises in the brain almost completely to CO2 and H2O. 36g of glucose are required by the rbc, bone marrow, renal medual and peripheral nerevs. These produce pyruvic and lactic acid. These glucose stores are obtained from the diet, the liver and via gluconeogenesis. Discuss how metabolism shifts during fasting and starvation. In the well fed state, insulin is released by the pancreas, which signals the liver and other tissues that glucose level in the body are high and to increase the intake of glucose into these tissues. This this promotes glycogen synthesis and to storage of glucose. In the well fed state, ATP is produced at levels that are more than adequate in providing energy for normal biochemical reactions. In this case energy such as protiens, triglycerides and more so glucose are converted into molecules that are stored in the body and able to be re-converted when needed by the body. This is the storage of glucose as glycogen, within the liver and muscle. In the fasting state and in starvation, metabolism shifts to re-convert these energy stores to glucose to provide energy for the body, most importantly the brain. After six days of starvation the concentrations of energy-contributing molecules drastically change, glucose drops greatly from~6mM to ~4mM, while keytone bodies rise signisicantly from 0mM to ~6mM. When blood glucose levels fall, the body is led into a ‘fasting state’. In this state, glucagon is released by the pancreas and acts on the liver to initiate glycogenolysis, this is the conversion of stored glycogen back into glucose. This glucose is released into the blood and used primarily by the brain for energy. This results in a cascade of reactions and initiated by the binding of glucagon (one molecule) on a hepatocyte. This activates a g-coupled protein receptor, which activates protein adenylyl cyclase a producing cyclic AMP (20x molecules) from ATP. This cAMP is a secondary messenger that phosphorylates protein kinase a, switching it from inactive to active (10x molecules). This acts to activate protein kinase b (100x molecules) which then activates glycogen phosphorylase a (1000x molecules). This enzyme is the first in the glycogenolysis which results in the formation of 10,000 glucose molecules that is released into the blood. During early fasting or high activity, amino acids degrade to pyruvate, which is transaminated to alanine. Alanine circulates the liver and can be converted back to pyruvate and enter gluconeogenesis. Another adaptation is the cori cycle, this involves the formation of lactate, which moves to the liver and can also enter the gluconeogenic cycle. This can contribute to raising blood glucose levels, though this is fuel of last resort in the fasting of exhausted organism. The stores of glycogen within a human last typically 24 hours. After the glycogen stores have been exhausted the body moves into a starvation state where during the first 24 hours of starvation the main source of energy is derived from triglycerides. The average male has over 400,000kj of triglycerides stored in the adipose tissue. During starvation these triglycerides are broken down into fatty acids via lipolysis. This biochemical pathway is initiated by epinephrine, which binds to receptors on the adipose tissue, activating protein kinase a, this phosphorylates hormone sensitive lipase (HSL) and perilipin. These enzymes along with CGI-58 and adipose triglyceride lipase (ATGL), forms a complex that liberates the fatty acids, and he remaining glycerol can enter gluconeogenesis. The liberated fatty acids cannot be used directly as a fuel source. They enter the mitochondria where they undergo beta oxidation. ATP converts the fatty acid into acyl adenylate. Acyl-Coa Synthase changes the adenylate group for a Coa-A, creating Acyl- CoA. This occurs in the skeletal muscle, cardiac muscle and the liver. Though a number of biochemical changes, this Acyl-CoA enters the mitochondria and enters the TCA cycle. ATP generated in this cycle enters gluconeogenesis to produce more glucose. Glucose stores are important for brain function, though during fasting most of the glucose stores as allocated to the muscles and red blood cells. Therefore in low levels, the brain requires an alternate source of energy. Fatty acids can be used, though not as a direct source. Oxaloacetate stores are eventually depleted which results in a build-up of acetyl-coA. Accumulation of acetyl-coA favours ketone body synthesis. The liver converts the fatty acids into ketones via ketogenesis, which are transported to the brain, are broken down into acetyl-coA and can be used in the TCA cycle. Prolonged fasting then requires the body to begin using muscle proteins as a source of energy. The skeletal muscle begins to degrade with yield glucogenic amino acids, this also produces urea, which is exported to the kidney and exerted in urine. The CAC intermediates derived from protein degradation are diverted into gluconeogenesis and glucose is exported to the brain via the bloodstream. Diabetes mellitus Diabetes mellitus is a metabolic disease characterised by elevated fasting blood glucose levels (hyperglycaemia). This can result from either the inability to produce insulin, or the inability to respond to it. Chronic hyperglycaemia leads to the damage of most body
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