Greetings. So today we want to continue our discussions about fuel and how the body is using fuel and how we move from a fasted state to a fed state. We said that when we had a fed state insulin was the dominant hormone. Today we're going to talk about glucagon which is the dominant hormone during the fasted state. We want to talk about how the blood glucose levels govern the amount of glucagon that's going to be secreted. And secondly we want to identify the major target sites for glucagon and it's effect on these cells. And thirdly we talk about disease states that glucagon plays in. So, as you recall the body can be in a fed state or a fasted state. The fed state is an anabolic state, we're building storage forms of fuel. We are moving materials from the GI tract such as glucose, amino acids and fatty acids. We store the glucose in a very labile storage form called glycogen within liver. Amino acids are stored in muscle mass and fats are stored within the fat. Fatty acids are stored within fat, the fat cells. In the fasted state which is the catabolic state, we reverse these reactions. We degrade fat to free fatty acids and glycerol. These products are deliver to the liver. The liver produces a rise in plasma glucose as well as ketone bodies. We will also degrade muscle under conditions of starvation. We will liberate amino acids. This is an expensive fuel to degrade for the body. The amino acids can be converted by the liver into glucose. Then of course our labile form of carbohydrate storage which is glycogen will be degraded within the liver. Again we produce glucose. The brain can use both the glucose as well as the ketones which are generated and secreted into the blood by the liver. All the other tissue can use these fuel sources as well. So what are the reflex loops that are involved? We said that insulin is in an opposing action to glucagon. The reflex loop is described here. When we've had low plasma glucose levels, then we activate the secretion of glucagon from the alpha cell of the pancreas. By releasing the glucagon from the alpha cell of the pancreas, then glucagon targets the liver. In the liver it will cause a breakdown of glycogen and a release of glucose and also of ketonic bodies into the blood plasma. This obviously raises blood plasma. That is a simple feedback then, a negative feedback, which will turn off the production of glucagon. Glucagon is very tightly regulated by the presence of insulin. Under conditions where we have low plasma glucose, that is less than 80 mg per deciliter then we have domination of glucagon. Insulin is not present. But if the plasma glucose levels rises to higher than 100 mg per deciliter then under those conditions it will feed back and turn on our beta cells. The beta cells then secrete insulin. The beta cell inhibit the actions of the alpha cell and inhibit the secretion of glucagon. That's a direct inhibition of neighboring cells. So when do see a change in glucagon? Glucagon will occur during the day, but the change in glucagon is very small. What happens is that when we eat breakfast there is a spike in insulin. Then between breakfast and lunch there is a dip in insulin because plasma glucose levels are falling. We will have a very small rise in glucagon. The same thing will happen at lunch and then again at dinner. When insulin is high, glucagon is low. Insulin falls because blood glucose levels are falling. With feeding, insulin will then rise. The fluctuation in glucagon is not very large. We can see glucagon rising in a larger manner when we have intense exercise. That's what shown here. Here we have sufficient levels of glucose in the early part of our intense exercise, in the first hour. Then as the plasma glucose levels start to decline, you can see that insulin levels are declining and glucagon levels are rising. So, with a very intense exercise, we can form hypoglycemia. And emia means it's in your blood. Glyco means a process, the sugar. hypo means it's a low. Hypoglycemia is low glucose level within the blood, a low plasma glucose level. This rise in glucagon will mobilize glucose from our storage fuels but the other thing that you should notice is that we have a drop in insulin. As insulin is dropping then and we have a rise in plasma glucose. How is it that the blood glucose then can enter into the cells and actually be used as fuel if the insulin is not present? What happens is that under these conditions, gucose moves into the skeletal muscle. But it's not through mobilization of the GLUT4 transporters by activation of the insulin receptors. Instead it is the working of the skeletal muscle itself which changes the intercellular signaling pathways. That is muscle contraction move those GLUT4 transporters up to the cell surface. Glucose can enter into the muscle, the skeletal muscle, the working muscle at a very rapid rate. It's one of the reasons why people who have diabetes are told to exercise. Glucagon is a hormone that is part of of our reaction to stress. And as you recall, when we were talking about the hypothalamus-pituitary-adrenal axis, we said that we had two hormones which were released by the adrenal glands. These two hormones are released in response to stress. That's what diagramed here. So we have a drop in plasma glucose levels or we have an activation of the sympathetic nervous system. Under these conditions then the lowering of blood plasma glucose triggers a stress response. From the hypothalamus, we will secrete CRH or Corticotropin-Releasing Hormone, which works on the pituitary on the corticotrophs to release ACTH. In turn ACTH works on the cortex of the adrenal to secrete Cortisol. Cortisol is our first hormone. The sympathetic nervous system directly innervates the medulla of the adrenal. With activation of the sympathetic nervous system, the medulla secretes epinephrine. Epinephrine is the second hormone. Cortisol and epinephrine both work on fat, the stored form of fuel in adipose Tissue. They cause lipolysis to occur. They change the metabolism of the fat cells so that it starts to degrade fat. In doing so then, we are releasing free fatty acids and glycerol. These are delivered to the liver to raise plasma glucose levels. The sympathetic nervous system coordinately alters secretion of the pancreas. The beta cells of the pancreas will be inhibited which decreases secretion of insulin from the pancreatic beta cells. By removing the activity of the beta cell, that is removing insulin, we will automatically activate the alpha cell to secrete glucagon. This is our third hormone. The drop in plasma glucose itself below 80 ml per deciliter can also activate the release of glucagon from the alpha cells. So we have three hormones then present within the plasma. We have cortisol, we have epinephrine, and we have glucagon. These three hormones work in concert to affect the metabolism of the liver to raise the plasma glucose level. Each individual hormone will raise plasma glucose level in isolation of the others, but not as much as when all three of them are together. With all three of them are together, we get a bigger bang for the buck. This is called synergy. So we get a very large rise in plasma glucose levels when all three hormones are present. Note that all three hormones are coordinately released from their glands by the sympathetic nervous system. Now I just want to talk a little bit about diabetes and the pathology of diabetes. When we have insulin dependent diabetes that is not well controlled, and this is a diabetic patient or diabetic individual who has insulin deficiency, then there's no insulin being made from the beta cell, because the beta cells are missing. Under these conditions, these individuals will have glucagon excess. There is a much higher secretion of glucagon into the bloodstream. As the individual eats, there's an increase in blood plasma glucose. This increase in plasma glucose is not met by insulin. Instead, blood plasma glucose rises. In addition, glucagon is active. Glucagon acts in the liver to make more glucose. This increases the secretion of glucose into the bloodstream. There's nothing to dampen the activity of glucagon. So we have not only the glucose coming in from the diet but this additional amount of glucose which is being made by the liver. Consequently there is a very high circulating level of plasma glucose. This we observed in my friend's son. He had 350 milligrams per deciliter as a fasting plasma glucose level. This increase in blood glucose will overwhelm the transporters that are in the kidney. A lot of the glucose stays in the presumptive urine. Because it's osmotically active, it holds water. So the increase of glucose in the urine causes an increase in urine output. Consequently, there is a loss of electrolytes. This may lead to dehydration. The glucagon itself is working in the liver. As I said, it increases the secretion of glucose, but it also is causing a lipolysis to occur. We are shifting metabolism so that we have ketones generated. And ketones are acids, they are ketonic acids. Ketotic acids simply means that as we generate these substances, they can be used by the brain, and by tissues as fuel, but that they are dropping the pH of the plasma, because they are in fact acids. That means that we are creating metabolic acidosis. Under these conditions of dehydration plus metabolic acidosis, the individual can go into a coma. It actually can be life threatening. So the glucagon in a diabetic type one, the activity of the glucagon in the diabetic type one can lead to a very serious condition when it's unopposed by insulin. What are key concepts? First of all we have energy from the diet that can be used immediately or stored in fat and glycogen. Secondly, we have insulin to glucagon ratio which regulates our minute to minute metabolism. When we have high insulin to glucagon ratio, we have fuel storage. This is an anabolic condition. When we have low insulin to glucagon ratio, this promotes mobilization of the fuel stores. This is a catabolic condition. Third, glucagon acts in concert with cortisol and epinephrine, which are being secreted from the adrenal glands in response to stress. These three hormones glucagon, cortisol and epinephrine change the phenotype of the individual so that they can address a fight or flight situation. Their net effect is going to be greater than each alone. This is called synergy. And fourth, the type one diabetic is prone to metabolic acidosis and dehydration because insulin is absent or insufficient and glucagon dominates. When glucagon dominates, it causes the liver to add more glucose to the plasma. Such that glucose coming in from the diet is added to by that which is produced by the liver. And under these conditions, you can have very high circulating levels of plasma glucose. Okay, so see you next time.