DEFINITIONS OF TERMS Fasting A state of abstinence from all food or drinks that provide calories. For a complete list of defined terms, see the Glossary. LESSON 2.4 WORKBOOK Part two: Glucose homeostasis in the blood Un-Storing energy In the previous lesson we learned about the metabolic pathways the liver uses to shuttle energy from glucose into storage as glycogen, fat, and amino acids. In this lesson, we will focus on the reverse: metabolism of glycogen, fats and amino acids to generate glucose. We will also discuss the different stages your body undergoes during fasting. Low blood sugar: Causes and consequences Figure 1: The symptoms of low blood sugar. Why is low blood glucose a problem? Even with all of the built in mechanisms we have to maintain glucose homeostasis there is still a normal range in which glucose rises and falls in the blood. After we eat, the extra energy from food is stored as glycogen in the muscles and the liver, and as triglycerides in the adipose tissue. Between meals, these stores of energy are broken down, providing energy until you eat again. It is normal for blood glucose concentrations to slowly decline a bit between meals, but severe drops in glucose are rare in healthy individuals. Some symptoms of low blood sugar are hunger, feeling jittery, nauseous, confused or light headed. More symptoms are shown in Figure 1. Some health conditions can lead to dangerously low levels of glucose, including diabetes and excessive alcohol intake. Because the brain relies on glucose for energy, not having adequate blood glucose levels will stress the brain. Having excessively low glucose concentrations in the blood for long periods of time can lead to seizures, fainting, coma or even death. 1. What happens to the blood glucose concentrations of a healthy individual between meals? a. It rises slightly. b. It drops to a dangerously low level. c. It slowly drops, but is not dangerous. d. It remains constant. 90
DEFINITIONS OF TERMS Glucagon A hormone formed in the pancreas that promotes the breakdown of glycogen to glucose. Gluconeogenesis A metabolic pathway that results in the generation of glucose from other carbon substrates, such as glycerol and amino acids. For a complete list of defined terms, see the Glossary. The pancreas senses low blood glucose Specific hormones are released from your digestive system when energy stores are full or are dropping. Recall from Lesson 2.3 that when glucose levels increase the pancreas releases insulin. Similarly, the pancreas will sense when the blood glucose levels are low and send the message to storage organs that more glucose is needed in the Low$Blood$Glucose$ Promotes$Glucagon$Release$ Pancreas( blood. The pancreas sends this signal in the form of glucagon, a hormone made out of amino acids. Glucagon opposes the actions of insulin, and stimulates the production and release of glucose. Therefore, the result of glucagon being released from the pancreas is an increase in glucose concentrations in the blood. In addition to insulin and glucagon, hormones are released from other parts of your digestive system that send signals to the brain regarding the state of energy storage. This is an intricate process involving several organs and signaling systems. We will learn a lot more about these hormones, and how your body tells your brain that it is time to start and stop eating in Unit 3. The liver is the master regulator of blood glucose Insulin$ Glucagon$Signals$the$Liver$ $to$un;store$glucose$$ Liver( Figure 2: Low levels of glucose stimulate the pancreas to make glucagon that signals the liver to un-store glucose. We learned in Lesson 2.3 that the liver is the master regulator in determining how glucose will be stored. The liver is also the organ that delivers glucose to the blood when blood glucose concentrations get too low. The liver will break down its glycogen stores and release them into the blood. Remember that the muscle cannot export its glucose, so even if the muscle has leftover glycogen to break down into the glucose, that glucose can only be used in the muscle. 2. What is the pancreas' response when more glucose is needed in the blood? a. It releases glucagon. b. It releases insulin. c. It releases glucose. d. It releases fatty acids. 91
The conundrum: How does the energy from fat and amino acids reach the brain? If every organ in our body could use fat or amino acids for energy then we would not need to maintain a steady concentration of blood glucose. We know that this isn t the case, because both the brain and the red blood cells rely on glucose as their energy source. To get around this problem, the liver can make new glucose to release into the blood from the carbon in amino acids and triglycerides, a process called gluconeogenesis ( gluco = glucose, neo = new, genesis = generation). Converting stored energy into glucose Figure 4: Un-storing energy: triglycerides from adipose cells and amino acids from muscle cells are the batteries. Gluconeogenesis Amino Acids Glucose (Blood) Triglycerides Figure 3: Only the liver can make glucose from fat and protein through gluconeogenesis. Because the brain normally relies on glucose for energy, there must be a constant supply of glucose into the blood stream even when other tissues are using fatty acids or amino acids as their energy source. When glycogen stores are not enough, the liver will make new glucose to export into the blood through gluconeogenesis. Counting carbons: from Acetyl CoA to glucose Gluconeogenesis makes glucose by starting with an intermediate in the citric acid cycle and undergoing several reactions to yield glucose. Another way to think of gluconeogenesis is as the reverse of glycolysis. The two carbons in acetyl CoA can be added to other intermediates in the citric acid cycle that contain four carbons, resulting in a six-carbon molecule of glucose. 3. Which of the following substrates can be used for gluconeogenesis? a. Amino acids. b. Glycerol. c. Acetyl CoA. d. All of the above. 4. How are triglycerides used as energy in the body? a. Fatty acids are used in the citric acid cycle in every cell of the body. b. Fatty acids are used for energy in most cells, glycerol is used for gluconeogenesis in the liver. c. The fatty acids must first be converted to glucose. d. Only the adipose tissue uses triglycerides for energy. 92
DEFINITIONS OF TERMS Lipolysis The metabolic breakdown of lipids to release energy. Urea A nitrogen-containing compound mostly made from degraded proteins. For a complete list of defined terms, see the Glossary. Glucose is created from amino acids The intermediates in the citric acid cycle that are added to acetyl CoA to make glucose are made from amino acids. Remember that amino acids are made from the carbon chain and an amino group; the nitrogen-containing amino group of the amino acid is broken off, leaving the carbon skeleton. This results in free nitrogen, which can be harmful to our cells if left floating in the blood. The liver will package this nitrogen up as urea, which is excreted in urine. Physicians can determine if a patient is breaking down excesses amino acids because they will have high urea concentrations in their urine. The carbons of amino acids are required for the synthesis of new glucose, and amino acids used to build muscles are the first to be broken down when dietary amino acids run out. Because of this, whenever your body is in a state of needing to undergo gluconeogenesis, your muscles are most likely being broken down to provide amino acids. Amino acids Glucose Acetyl CoA Citric acid cycle Triglyceride Lipolysis Adipose Figure 6: Triglycerides stored in the adipose tissue are broken down to acetyl CoA by lipolysis. Amino acids are used as intermediates in the citric acid cycle. Muscle Amino acids Urea Glucose Acetyl CoA Citric acid cycle Figure 5: The liver can make glucose from acetyl CoA and the carbon skeletons of amino acids, in a process called gluconeogenesis. This creates extra urea, which is excreted in the urine. Energy is released from Fat As triglycerides are metabolized in a process called lipolysis ( lipo = lipid, lysis = to break) they produce one molecule of glycerol that can be used to make glucose, and three fatty acids that are used to generate ATP. The process of producing ATP from fatty acids was discussed in Lesson 2.2. The carbons of the fatty acids chains are broken off, two at a time, and converted into acetyl CoA. This acetyl CoA is used in the citric acid cycle to generate NADH and FADH 2 for the electron transport chain. The three carbons of glycerol are then used directly in the synthesis of new glucose. 93
The type of energy store you use depends on how long you have been fasting The body s response to fasting is largely a function of how long one has gone without eating. For this reason we will discuss fasting in three stages: The first hours of fasting, 1-7 days of fasting, and more than a week of fasting. We can use these stages as a guideline, however each person s metabolism and body is unique, therefore the times listed here may vary for each individual. 0-12 hours after eating 1-7 days after eating One week after eating Components to be broken down: Liver and muscle glycogen stores. Triglyceride stores in adipose Broken down into: Glucose Fatty acids and glycerol Used for: Energy for the brain, red blood cells and other cells Fatty acids: energy for cells other than the brain and red blood cells; Glycerol: gluconeogenesis Body protein Amino acids Intermediates in citric acid cycle; carbons of some amino acids used for gluconeogenesis Triglyceride stores in adipose Fatty acids and glycerol; ketone bodies Fatty acids: energy for cells other than the brain and red blood cells; Glycerol: gluconeogenesis (as long as amino acids are available) Ketone bodies: energy for the brain Body protein Amino acids Gluconeogenesis until there is no spare protein to break down Triglyceride stores in adipose Fatty acids and glycerol; ketone bodies Fatty acids and glycerol: energy for cells other than the brain and red blood cells; Ketone bodies: energy for the brain Figure 7: This table outlines the different source of energy throughout the stages of fasting and starvation. 94
Figure 8: In short term fasting the glycogen and proteins go first. 1-7 Days after eating 0-12 Hours after eating If a person is mostly sedentary, their glycogen stores will last about 2 days. The amount of glycogen you can store is related to how muscular you are. A more muscular person can store more glycogen, but the higher lean muscle mass also means that more glucose will be used to maintain those muscles. Therefore even a body builder can t last a week on their glycogen! After the glycogen stores have been exhausted new glucose still needs to enter the blood stream for the brain and the red blood cells. The liver will begin to rely more on amino acids for gluconeogenesis. Glycerol from triglycerides can be used to make new glucose, but this can only occur as long as there is enough spare amino acids that can be used alongside the glycerol In the first few hours after eating the body will use its shortterm energy stores, which include glucose from glycogen and stores of triglycerides. As the fast progresses, the liver will exhaust its stores of glycogen and rely on gluconeogenesis. The body will begin to breakdown lean muscle mass to free up amino acids that can be used to make new glucose for the brain and the red blood cells. At the same time gluconeogenesis is occurring, triglycerides will be released from adipose stores to provide energy to tissues other than the brain and the red blood cells. Figure 9: In long-term fasting proteins and fats are used. for gluconeogenesis. Unfortunately, only a limited amount of amino acids can be broken down for energy purposes because amino acids are used to build important structural elements in our cells. If we were to use all of our amino acids up for energy, we would be digesting our own tissues which is not beneficial! After the expendable amino acids are used up, the body turns to our fat stores as the primary energy source. If triglycerides become the only energy source available, the brain will start to use a metabolite of lipolysis called ketone bodies. Ketone bodies will pass into the brain to be used in the citric acid cycle. One of the waste products of ketone bodies will be excreted in the urine and the breath, and smells sweet. Because of this, if someone s body is breaking down fatty acids into ketone bodies for energy, their breath will smell sweet, a phenomenon called 'ketone breath'. The brain will start using ketone bodies for energy after only about 3 days of fasting, and the amount of ketone bodies that the brain relies on increases as the fast continues. 95
By the end of the first week of fasting metabolism begins to slow down, and a person will start to feel extremely fatigued. By slowing down the metabolism, cells will use less energy and the lifespan is prolonged. After one week without eating At this point in fasting, the only energy source available is the triglycerides stored in adipose tissue. The amount of time a person can live without eating depends on the amount of their adipose tissue stores. Typically, the body can survive about three weeks before breaking down vital proteins in the muscles and organs to use as energy. Once this process begins, fatality is near. Figure 10: Each of the organ s roles during fasting. A quick review of today s material Using the figure to the left (Figure 10) we can locate the organ or tissue in which each metabolic process we ve discussed today is occurring. The pancreas senses low blood glucose and secretes glucagon, which sends a message to the liver, telling it to export more glucose into the blood. The liver will export glucose from its own glycogen stores into the blood. The muscles break down glycogen into glucose to use for their own energy needs, and secrete amino acids into the blood from broken down proteins. The adipose tissue releases fatty acids and glycerol. The liver will then take up amino acids and triglycerides and secretes new glucose into the blood from gluconeogenesis. As always, the brain uses glucose, while the kidneys are busy excreting the extra urea that is being produced from the breakdown of amino acids. 96
STUDENT RESPONSES We have now discussed the body s response to fasting. What might the body s reaction be if you were to stop eating carbohydrates completely, and no glucose was coming into the blood from the diet? How might this response differ from fasting? Remember to identify your sources 97
TERMS For a complete list of defined terms, see the Glossary. TERM Fasting Glucagon Gluconeogenesis Lipolysis Urea DEFINITION A state of abstinence from all food or drinks that provide calories. A hormone formed in the pancreas that promotes the breakdown of glycogen to glucose. A metabolic pathway that results in the generation of glucose from other carbon substrates, such as glycerol and amino acids. The metabolic breakdown of lipids to release energy. A nitrogen-containing compound mostly made from degraded proteins. 98