March, 2013

CAUTION: HORMONES AT WORK: PART I: ENERGY


By Dr. Howard Glicksman

We live in a world made from matter. Matter is made up of atoms and molecules that follow the laws of nature. All life is made up of atoms and molecules that are organized into cells. Our body has trillions of them. Each cell needs to have enough energy to live, grow and work properly. A car uses oxygen to release the energy in gasoline for it to move. So too, the cells in our body use oxygen to release the energy in a sugar molecule called glucose so they can do what they need to do. The laws of nature demand that the faster a car goes the more energy it uses. We know that to do this the car has to be given more gas and must use up more oxygen. Similarly, we know that the faster we move and the harder we work the more energy we use. To do this we have to breathe faster and harder to provide our muscles with more oxygen. And by feeling hungry afterward we know that we have used up more glucose as well. In summary, the cells in our body need to have enough energy to live, grow and work properly and therefore must have enough oxygen and glucose to survive within the laws of nature.

We get oxygen, by breathing in air, and glucose, by mainly eating food. Most people know that itís their lungs that bring in oxygen and their digestive system that takes in glucose. And many people know that oxygen and glucose are put into the blood where they are sent to the tissues by the cardiovascular system which consists of the heart and the blood vessels. There are even some who know that it is hemoglobin, a complex protein made in the red blood cells, which is needed to carry oxygen to the tissues, and that the liver is the most important organ for supplying glucose to the brain. However, what most people donít know and appreciate is how the body controls the production of red blood cells so it can transport enough oxygen to its tissues, and the storage and release of glucose by the liver to make sure the brain always has enough for its energy needs. Having the right amounts of oxygen and glucose in the tissues is not as simple as just breathing in air and eating food. Nor is it as simple as just having lungs, a digestive and cardiovascular system, red blood cells and a liver. Without the body being able to control how much oxygen and glucose it sends to the cells in its tissues, life as we know it would be impossible. The proof of this is that when our body is no longer able to provide enough oxygen, or glucose, to our cells, particularly the ones in the brain, we die. In other words, control is the key to life. But how does the body do it? One of the most important sets of molecules which work to give the body control are the hormones. Letís first look at what is needed to control something and then weíll see where the hormones fit into the scheme to keep us alive.

To be able to control something requires having at least three different parts all working together in harmony. The first thing you need is a sensor to detect what needs to be controlled. If you have no way of being aware of what needs to be controlled how can you control it? The sensor is like the reconnaissance team that an army sends out to check on the whereabouts and activities of its enemy. Without this information the army would be working in the dark. The second thing you need to control something is an integrator which interprets the information from the sensors, makes decisions about what needs to be done, and then sends out orders. If you donít understand the information from the sensors and canít make decisions about what should be done then what use are the sensors in the first place and how can you control something? The integrator is like army headquarters where the information from the reconnaissance team is analyzed, decisions are made about what needs to be done and orders are sent out. Without army headquarters there would be no coordinated action in the field. The third thing you need to control something is an effector which receives the orders from the integrator and does something. If you have a sensor to detect what needs to be controlled and an integrator to know what needs to be done, but not an effector to do it, then whatís the use of having the first two and how can anything be controlled? The effector is like the soldiers, who at the orders received from headquarters go and do what needs to be done. Without soldiers there is no army and the battle is already lost.

Hormones are protein molecules that are sent out by special gland cells into the blood to help regulate specific functions of the body. The hormones are chemical messengers sent out by gland cells just like the orders sent out by army headquarters. The gland cells have sensors on their surface that can detect how much of a specific chemical (like oxygen or glucose) is present in the blood. So, the gland cells have their own reconnaissance team that can detect a specific chemical which the body must control to survive. The gland cells take the information from their sensors, analyze it, and then send out the right amount of a specific hormone into the blood. The gland cells act as the integrator, just like army headquarters, to send out orders to direct activities in the field. These actions, done at a distance from the gland cells, are designed to achieve a specific goal; the control of a specific chemical (like oxygen or glucose) so the body can stay alive. The hormones from the different gland cells travel in the blood to specific target organs to pass on their orders. The cells in these organs act as the effector, which, like the soldiers in the field, receive the orders and perform a specific action. This effect, done at the direction of the integrator, helps to control the specific chemical (like oxygen or glucose) that was sensed by the gland cells which sent out the hormone in the first place.

However, army headquarters must send out different orders to different soldiers telling them to do different things. So too, the bodyís different gland cells must send out different messages to different target cells to get different things done. And just as the soldiers canít take just any message or do whatever they want, the target cells must respond to the right message and do the right thing, otherwise the body wouldnít be able to control anything. The way the body ensures that the right target cells receive the right orders so they can do the right thing is for them to have specific receptors. The receptors in the target cells are proteins with a special shape that allow them to attach to specific molecules when they come in contact with them. Think of it like a key fitting into a lock, or tuning your radio or television to a specific station. When the hormone attaches to its specific receptor this signals the target cell to do something. And what the target cell does directly affects the specific chemical (like oxygen or glucose) that the gland cell which sent out the hormone detected in the first place. Now weíll look at why the body must control its content of oxygen and glucose and how it actually does it. Be prepared to exercise your wonder as you never have before!


Oxygen
All the cells in the body need energy to live, grow and work properly. They get most of this by releasing some of the energy that is stored in glucose. If there isnít enough oxygen around to help our cells get as much energy as possible out of glucose, they die, and so do we. We get oxygen by breathing in air through our lungs. The reason why we have to breathe several times a minute is because our body has no way of storing oxygen, like it can for glucose. We can go hours and even days without eating, but our need for oxygen is so acute that if we stop breathing we die in just four minutes. The amount of oxygen we need is directly related to how much energy we need. And the amount of energy we need is directly related to how much we weigh and what we are doing. Experience tells us that lifting a heavy bowling ball up against gravity requires a lot more energy than lifting up a golf ball. And throwing either one of them as far as possible requires even more energy. Remember, our body is made from atoms and molecules that must follow the laws of nature with respect to work and energy. Therefore our body must be able to provide its cells with enough oxygen to do what it needs to do to survive in the world.

At total rest, a 70 kg (154 lbs) male needs about 250 mL/min (milliliters per minute) of oxygen to maintain his body function. This means that, when most of his muscles are totally relaxed, his organs and tissues (e.g. brain, heart, liver, kidneys) use 250 mL/min of oxygen to do what they need to do to keep him alive. When walking slowly his body uses 500 mL/min of oxygen, quickly 1,000 mL/min of oxygen, and while jogging his body uses 2,000 mL/min of oxygen. And with maximum physical exertion, the type of effort that our ancestors would have needed to run as fast as possible to catch something to eat or avoid being eaten, he uses over 3,500 mL/min of oxygen. The way the body tells us to breathe in enough oxygen is through the respiratory center in the brain. It receives information on the level of oxygen in the blood and how much muscle activity is taking place. Based on this information it sends out orders to the muscles of respiration to make the lungs breathe fast and hard enough to bring enough oxygen in to allow us to do what we want to do.

However, the laws of nature present the body with a problem when it comes to trying to send enough oxygen to the tissues. The lungs are very good at taking oxygen from the air and putting it into the blood. The problem is that, unlike sugar and salt, oxygen does not dissolve well in water. Since blood is mostly made of water (and the blood cells that float within it) this means that oxygen does not dissolve well in blood as well. In fact, without a better way to transport oxygen the body would only be able to provide itself with about 5% of the energy it needs at rest and only 2% of the energy it needs to be active enough to win the battle for survival. In other words, without some other way of transporting oxygen in the blood it would be impossible for human life to exist in the world.

The solution to the bodyís problem with oxygen transport is a large and complex protein called hemoglobin. Hemoglobin is made in the red blood cells which travel throughout the body in the circulation. The hemoglobin molecule contains iron which is able to pick up oxygen in the lungs, carry it in the blood, and release it to the cells in the tissues. Medical scientists know the maximum amount of oxygen each gram of hemoglobin can carry and drop off to the tissues. They also know how much blood is pumped by the heart when the body is at rest or is exerting maximum effort. By using these numbers it is possible to figure out the minimum amount of hemoglobin per liter of blood the average male must have to survive when he is at total rest (4.5 gm/dL) and when he is active enough to win the battle for survival (14-16 gm/dL). The normal range of hemoglobin in an adult male is indeed 14-16 gm/dL and for an adult female it is 12-14 gm/dL. Clinical experience teaches that people are not able to survive very long with a hemoglobin below 4.5 gm/dL.

When a personís level of hemoglobin is lower than normal they are said to have anemia. With worsening anemia they experience increasing fatigue, weakness and shortness of breath with activity. This happens because, although their lungs may be bringing in enough oxygen, their tissues canít get enough of it. This occurs because their blood is unable to transport enough oxygen due to it not having enough hemoglobin. However, the body must also be sure not to make too much hemoglobin as well. After all, hemoglobin is made by the red blood cells which are particles that float in the blood. Therefore the laws of nature that govern the flow of liquids must be kept in mind as well. Just as having too many food particles in the kitchen sink can clog up the drain, so too, having too many red blood cells in the circulation can slow the flow of blood, especially in very small blood vessels. This sludging of blood can lead to tissue damage and, depending on the organs involved, even death. In other words, not just any number of red blood cells making just any amount of hemoglobin is sufficient for life. It is important for the body to take control of how many red blood cells and how much hemoglobin it makes so it can survive within the laws of nature. Letís take a look at how it does it.

Recall, the first thing you need to take control is to have a sensor that can detect what needs to be controlled. Special cells in the kidneys seem to monitor the oxygen content of the blood. Since the hemoglobin in the red blood cells carries oxygen, the oxygen content of the blood is a reflection of the amount of hemoglobin and the number of red blood cells. Recall, the second thing you need to take control is something to integrate the information from the sensors and make decisions about what must be done. These special cells in the kidneys also act as the integrators. Based on the level of oxygen they send out the right amount of a hormone called erythropoietin. Red blood cells usually live about 90-120 days, so, these kidney cells always send out a certain amount of erythropoietin so the body can replace the ones it loses. If the oxygen level starts to drop, as it can for people with chronic lung disease, then these cells send out more erythropoietin. Recall, the third thing you need to take control is an effector that can do something about the situation. Once it is released from the kidneys erythropoietin travels to the bone marrow. Here it attaches to specific receptors on special cells and tells them to mature into red blood cells that can make hemoglobin. This is how the body controls its production of red blood cells and hemoglobin so it can transport enough oxygen to the tissues. Clinical experience shows that people with chronic lung disease tend to have higher levels of hemoglobin due to their tendency to have lower oxygen levels in the blood. In addition, people with chronic kidney disease tend to have lower levels of hemoglobin because they have fewer kidney cells to produce erythropoietin.

Glucose
As noted above, just as a car needs the energy that is in gasoline to run properly, so too, the body needs the energy that is in glucose to survive. Experience teaches that when we havenít eaten for a while, our blood glucose level drops and our stomach is empty, then the hunger center in our brain tells us to eat something. The complex molecules that are in what we eat and drink enter the digestive system where they are broken down into simpler atoms and molecules so they can be brought into the body. In particular, carbohydrates are broken down into simple sugars, like glucose, which are then absorbed into the blood. Some of this glucose is rapidly taken up by tissues, like the brain and other organs, to be used for their immediate energy needs. However, the amount of glucose absorbed after a typical meal is usually much more than what the tissues of the body can use right away and so an excess remains. The body is able to chemically link these excess glucose molecules together to form a carbohydrate called glycogen. Most of the glycogen in the body is made and stored in the liver, with smaller amounts in the muscles, kidneys and other tissues. These tissues can then use this stored glucose in between meals and overnight when there arenít any new supplies of glucose coming into the body. However, the brain is unable to store glucose and is therefore mostly dependent on the glucose present in the blood for all of its energy needs. Once the liver and other tissues have filled up their glycogen stores any excess glucose is then stored as fat, apparently without limit.

One way the body makes sure that the brain receives enough glucose between meals, during exercise and while fasting, is to have the liver release glucose from its glycogen stores into the circulation. In fact, the liver has the capacity to store enough glucose to meet the bodyís energy needs for about 24 hours. In addition, when necessary, the liver can take some proteins and fats and convert them into glucose and other molecules that the brain can use for energy as well. So, it is the liver that is able to store and provide enough glucose for the energy needs of the brain and the rest of the body as well. This is part of the reason why we donít have to eat food as often as we have to breathe in air. But clinical experience teaches that not just any blood level of glucose will do for human survival. The brain always needs a certain amount of glucose because even though the body may be physically at rest the brain is always working very hard. It must keep us awake, monitor whatís going on inside and around us, and control vital functions like breathing and the circulation. Between meals the blood glucose level usually runs between 70-90 mg/dL (milligrams per deciliter). In between meals or while fasting, when the blood glucose level starts to drop under 70 mg/dL, our hunger center warns us to eat something and we may feel nervous. Clinical experience with diabetics shows that if the blood glucose drops below 50 mg/dL, then symptoms of brain malfunction, like weakness, dizziness and problems with concentration taking place. If the blood glucose drops below 40 mg/dL, then problems with speaking and increased confusion and drowsiness occur. If it goes below 30 mg/dL, seizures and coma result. And when the blood glucose drops under 20 mg/dL brain death is certain to take place. So, being able to control the blood glucose is very important for human survival and it doesnít just happen because we eat and drink things that have sugar in them. It requires the body to know when to store glucose and when to release it so that the brain is always receiving what it needs. Letís see how it does it.

Recall, the first thing you need to take control is to have a sensor that can detect what needs to be controlled. The pancreas is not only an exocrine gland that sends fluid containing proteins into the intestine to help digest food, but also an endocrine gland that sends hormones into the blood to help control the blood glucose. Scattered throughout the pancreas are small clumps of cells called the islets of Langerhans which perform its endocrine function. These cells have glucosensors that allow them to detect the blood level of glucose.

Recall, the second thing you need to take control is something to integrate the data and then decide what needs to be done. There are two different types of gland cells in the islets of Langerhans that together control the blood glucose. One type is the beta cell which sends out an hormone called insulin. After a meal the more the blood glucose rises above 70 mg/dL, the more insulin the beta cells release into the blood. However, after an overnight fast, during exercise, or in between meals, the more the blood glucose drops toward 70 mg/dL, the less insulin the beta cells send out. The other type of cell is the alpha cell which sends out an hormone called glucagon. After an overnight fast, during exercise, or in between meals, the more the blood glucose drops to 70 mg/dL and below, the more glucagon the alpha cells send out into the blood. And, after a meal, the more the blood glucose rises above 70 mg/dL, the less glucagon the alpha cells send out.

As you can see, both the beta and alpha cells have glucosensors but they respond to changes in blood glucose in opposite ways. The higher the blood glucose rises above 70 mg/dL, the more insulin the beta cells send out and the less glucagon the alpha cells send out. And when the blood glucose drops to 70 mg/dL and below, the less insulin the beta cells send out and the more glucagon the alpha cells send out.

Recall, the third thing you need to take control is an effector that can do something about the situation. After a meal, the blood glucose rises because the amount of glucose brought into the blood is more than what the body can use right away. As noted above, the beta cells react to this rise in blood glucose and send out more insulin. Insulin travels in the blood where it locks onto specific receptors within target organs, like the liver, and tells these cells to use glucose for energy and store what is left over. In general, insulin is an anabolic hormone which promotes the formation of more complex molecules from simpler ones. Not only does insulin promote the formation of glycogen from glucose in the liver and muscles, it also tells some cells to take in amino acids to form proteins and others to take in fatty acids to form fat. In other words, insulin tells the body “we've just been fed and weíve got more than we need right now so let's store up the excess for later use”.

In contrast, while fasting overnight, exercising, or in between meals, the blood glucose falls because the body is taking glucose out of the blood and using it for its energy needs without new supplies coming in through the digestive system. As noted above, the alpha cells react to this drop in blood glucose by sending out more glucagon. The glucagon travels in the blood where it locks onto specific receptors on cells, mainly in the liver, and tells them to release the stored glucose that is in glycogen. In general, glucagon is a catabolic hormone which promotes the breakdown of more complex molecules into simpler ones. Not only does glucagon cause glucose to be released from the glycogen stores, it also tells cells to breakdown certain proteins and fats so they can be used for energy as well. In other words, glucagon tells the body “we haven't been fed for awhile so release the energy we stored up from before”.

Once again, you can see that insulin and glucagon order the liver and other cells to do things that are opposed to each other. Insulin signals the body that it is in the “fed state” and must take glucose out of the blood and store it in the liver and fat cells for later use, while glucagon signals the body that it is in “starvation mode” and must release glucose from the liver into the blood so the brain will have enough energy.

In the early winter of 1922 the parents of Leonard Thompson, a 14 year-old boy suffering from the incurable “sugar disease”, brought him to the University of Toronto in the hope of him receiving an experimental treatment. For the prior several months the previously healthy teenager had been urinating very frequently, was always thirsty, had lost a lot of weight and was very weak. The doctors had said that he had diabetes mellitus, a condition that derives its name from the frequent passing of large amounts of sweet smelling urine due to high blood levels of glucose. Dr. Frederick Banting, and his assistant Charles Best, had isolated the pancreatic hormone that they had named “isletin” (later changed to insulin) and had used it to successfully treat dogs with the same condition. Banting and Best knew that it was a deficiency of insulin that caused this disorder in glucose metabolism. It naturally led to exhaustion and dehydration, soon to be followed by coma and death. Leonard Thompson was the first human to receive insulin and the resulting dramatic improvement in his condition changed the hopes of every diabetic forever.

Since the time of Banting and Best medical science has learned that the blood glucose level is controlled on a moment to moment basis by the relationship between insulin and glucagon. As noted above, insulin tells the body that it is in the “fed state” and tells the tissues to take glucose out of the blood and store it for future use as glycogen and fat. In contrast, glucagon tells the body that it is in “starvation mode” and tells the tissues to not only convert glycogen to glucose but also proteins and fat to glucose as well. When there is very little or no insulin in the blood (type I diabetes), or it isnít as effective as it should be in the tissues (type II diabetes), this allows glucagon to take over. When glucagon takes over, not only do the tissues not take in glucose to store it, they continue to produce more glucose from protein and fat even though the blood glucose level is already high. In the setting when a diabetic accidentally takes too much insulin this allows insulin to take over. When insulin takes over the tissues continue to take glucose out of the blood and put it into storage even though the blood glucose level is dangerously low. So, by using insulin and glucagon the body is able to take control of its blood glucose by storing it when it has an excess amount and releasing it when it is needed by the tissues, especially the brain. Although a person can live for a few months without insulin, the absence of glucagon is incompatible with life.

Points to Ponder
The way our body makes sure it has enough oxygen and glucose for its cells is not just as simple as breathing in air and eating food. Neither is it just as simple as having lungs, a liver and kidneys, and a digestive and cardiovascular system. To control the transport of oxygen to the tissues the body must also have (1) special kidney cells that can (2) sense oxygen and (3) make erythropoietin, and (4) bone marrow cells with (5) erythropoietin receptors that can turn into red blood cells and (6) produce hemoglobin. If any one of these six parts is missing the whole system fails and the body dies because it canít produce hemoglobin and transport enough oxygen to the tissues. To control its blood glucose level the body must also have (1) beta and (2) alpha cells in the pancreas, that have (3) glucosensors and (4) produce insulin and (5) glucagon respectively, and (6) liver cells with (7) insulin and (8) glucagon receptors that can (9) store glucose as glycogen or release it at the right time. If any one these nine parts is missing the whole system fails and the body dies because it canít control its blood glucose. Each part that contributes to the sensor, the integrator, and the effector is needed to perform its vital function for body survival. Dr. Michael Behe calls a system where the absence of any one part renders it useless as being irreducibly complex. The systems our body uses to transport enough oxygen to the tissues and control its blood glucose demonstrate irreducible complexity.

One must then wonder how an irreducibly complex system with so many vital parts could have come into existence? Does it make sense that each of these systems could have come about one step at a time? First the sensor, with no integrator or effector, or the integrator with no sensor or effector, or the effector with no sensor or integrator? The idea is totally absurd. They must have all come together as a system to perform a function to keep the body alive. And which system came first? The one controlling oxygen transport or the one for blood glucose control? Remember, without either one the body dies. In addition to these there are many other irreducibly complex systems each of which is absolutely vital for life. There are control systems in the body for water, sodium, potassium, calcium, blood pressure and temperature just to name a few. Each of these systems has its own sensor(s), integrator(s) and effector(s). And if just one of these parts is missing the whole system fails and the body dies. But if a system is irreducibly complex does that make it automatically capable of supporting life? If you think about it youíll realize that there is one more piece of the puzzle thatís needed, a piece thatís beyond irreducible complexity, to enable these systems to keep us alive within the laws of nature.

If you built a car to race in the Daytona 500 and put in an engine that gave it the power to only go 10 m.p.h. do you think it would win? Real numbers have real consequences when it comes to dealing with the laws of nature. A car with a certain weight requires a large enough engine with the right type of fuel to provide enough energy to make it go fast enough to win the race. As noted above, our ancestors would have needed 3,500 mL/min of oxygen going to their tissues to give them enough energy to win the battle for survival. This means that not just any amount of red blood cells and hemoglobin would have been enough for our ancestors to go on living and reproducing. Based on what we know about how the body actually works, they would have had to have had a hemoglobin of about 15 gm/dL of blood to do this. But what if the system that uses erythropoietin to produce red blood cells were set instead to make hemoglobin at a level of 1.5 gm/dL? Not only would they have not been able to exert enough effort to get food to eat or avoid being eaten, they could not have even survived at rest (need 4.5 gm/dL). And what if it were set instead to make hemoglobin at a level of 150 gm/dL? They certainly would have had the capacity to transport enough oxygen to the tissues. But they also would have had too many red blood cells which would have clogged up their small blood vessels and resulted in severe organ damage and death. And we know that if the blood glucose drops below 50 mg/dL the brain malfunctions and below 20mg/dL it dies. This means that not just any level of blood glucose would have been enough for our ancestors to go on living and reproducing. Based on what we know about how the body actually works, they would have had to have had enough insulin to tell their body to store glucose when their blood level rose above 70 mg/dL and enough glucagon to tell the liver to release it when it dropped below 70 mg/dL. But what if the system that uses insulin and glucagon to control the blood glucose were set differently? What would have happened if the beta cells released more insulin when the blood glucose rose above 20 mg/dL and the alpha cells didnít send out glucagon until it dropped below 20 mg/dL? Clinical experience tells us that their brains would never have had enough glucose to function properly and they wouldnít have been able to survive and reproduce.

Real numbers have real consequences when it comes to dealing with the laws of nature. Just because a system is irreducibly complex does not automatically mean that it will be able to function well enough to allow for life. Besides being irreducibly complex, systems that allow for life must also have a “natural survival capacity”. By this I mean that each system must give the organism the capacity to survive by taking into account the laws of nature. This usually involves having a knowledge of what is needed to keep the organism alive and then being able to do what needs to be done. The blood must carry enough oxygen to the tissues to allow the body to have enough energy to win the battle for survival. The system that uses erythropoietin seems to inherently know that the hemoglobin must be about 15 gm/dL of blood to get the job done and it does it naturally. The body must have enough glucose in the blood so the brain, and its other organs and tissues, have enough energy to work properly so it can stay alive. The system that uses insulin and glucagon seems to inherently know that the blood glucose needs to stay above 60 mg/dL to get the job done and it does it naturally. The same can be said for each of the other control systems that manage water, sodium, potassium, calcium, blood pressure and temperature as well. Not only are each of these systems irreducibly complex with a natural survival capacity, but without any one of them the body dies.

The laws of nature have put up many obstacles to prevent life from existing. Just as a car can die from not having enough gas for energy, or oil for seizing parts, or anti-freeze for engine overheating, so too, all physicians know that there are many different ways for us to die. If you really want to begin to understand how life came into existence, you first have to understand how easily it can become nonexistent. Did life really come about by random chemicals coming together to form cells, then simple organisms, and then complex ones like us? Do you think a tornado hitting a junk yard could produce a fully functioning Boeing 747? Science still has a lot of explaining to do.

Dr. G.
drhglicksman@yahoo.com

Howard Glicksman M. D. graduated from the University of Toronto in 1978. He practiced primary care medicine for almost 25 yrs in Oakville, Ontario and Spring Hill, Florida. He now practices palliative medicine for a Hospice organization in his community. He has a special interest in how the ethos of our culture has been influenced by modern science’s understanding and promotion of what it means to be a human being. Comments and questions about this column or any of the previous ones are welcome at drhglicksman@yahoo.com

Copyright 2013 Dr. Howard Glicksman. All rights reserved. International copyright secured.