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 and 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 are going to be governing 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 a storage forms of fuel. So, we are moving materials from the GI tract such as glucose, amino acids and fatty acids and 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 fatty, fatty acids are stored within fats, the fat cells. In the fasted state which is going to be the catabolic state, we're going to be reverse these reactions, and we're going to degrade fat to free fatty acids and glycerol. And this is deliver to the liver which then gives us a rise in plasma glucose as well as ketone bodies. We will also degrade muscle under conditions of starvation where we will then liberate amino acids, this is an expensive fuel to be degrading for the body. But the amino acids can be converted by the liver into glucose. And then of course our labile form of carbohydrate storage which is glucagon will be degraded within the liver and we release then glucose. The brain can use both the glucose as well as the ketones which are being liberated and secreted into the blood by the liver and all the other tissue can use these sources as well. So what are the reflex loops that we're talking about then? So we said that we had insulin is an opposing action to glucagon and the reflex loop is described here. When we've had low plasma glucose levels, then we will activate the secretion of glucagon from the alpha cell of the pancreas. By releasing the glucagon from the alpha cell of the pancreas, we will under these conditions, then have glucagon target to the liver and 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 and that's a feedback then, a negative feedback, which is going to turn off the production of glucagon. Glucagon is very tightly regulated by the presence of insulin and under conditions where we have low plasma glucose, that is less than 80 mg per deciliter then we have a domination of glucagon and 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 and the beta cells then secrete insulin. And the beta cell will inhibit the actions of the alpha cell and inhibit the secretion of glucagon and 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. So what happens is that when we eat breakfast we'll have a spike in insulin and then between breakfast and lunch then there will be a dip in insulin because plasma glucose levels are falling and will have a very small rise in glucagon. And then the same thing will happen at lunch and then again at dinner so that when insulin is high, glucagon is low. And then when insulin falls because blood glucose levels are falling, insulin will then will rise. But the fluctuation in glucagon is not very large. We can see glucagon rising in a larger manner when we have intense exercise so that's what shown here. And so here we have levels of glucose in the early part of our intense exercise so in the first hour. And then as the plasma glucose levels start to decline now, you can see that insulin levels are declining and that glucagon levels are rising. So, with a very intense exercise, we can form hypoglycemia. And glycemia is simply emia means it's in your blood. Glyco meaning process the sugar and hypo meaning it's a low blood glucose level within a blood, a low glucose level. This rise in glucagon is going to mobilize glucose from our storage fuels but the other thing that you should notice is that we have a drop in insulin. And 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. So what happens is that under these conditions, we can get insulin to move into the skeletal muscle. But it's not through mobilization of the GLUT4 transporters by activation of the insulin receptors, but instead it's the working of the skeletal muscle itself which changes the intercellular signaling pathways. And that in turn will move those GLUT4 transporters up to the cell surface, and so 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. So 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 coming from the adrenal glands. And that these two hormones are released in response to stress and that's what diagramed here. So we have a drop in plasma glucose levels or we have an activation of the sympathetic nervous system. So under these conditions then the lowering of blood plasma glucose is triggering 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, and it in turn is working on the cortex of the adrenal to secrete Cortisol. So Cortisol is our first hormone. The sympathetic nervous system directly innervates the medulla of the adrenal and that's activation the sympathetic nervous system will cause secretion of epinephrine. Epinephrine is their second hormone. Cortisol and epinephrine both work on fats, the stored forms of fuel and they will cause lipolysis. So they're going to change the metabolism of the fat cells so that it starts to degrade fat. And in doing so then, we're going to release free fatty acids and glycerol. And these are delivered to the liver to raise plasma glucose levels. The sympathetic nervous system coordinately is going to effect the pancreas and the beta cells of the pancreas and it's going to inhibit the secretion of insulin from the pancreatic beta cells. And by removing the activation of the beta cell, that is removing the insulin, we will automatically activate the alpha cell to secrete glucagon and that's our third hormone. The drop in plasma glucose itself below 80 ml per desiliter 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. And these three hormones are working in concert to affect the metabolism of the liver to raise the plasma glucose levels. Each individual hormone will raise plasma glucose level in the isolation of the others but not as much as when all three of them are together and 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 then are present. And 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 the diabetic patient or diabetic individual who has insulin deficiency and that is 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. So we have much higher secretion of glucagon into the bloodstream. As the individual is eating and there's an increase in blood plasma glucose the blood plasma glucose is not met by insulin and instead, the blood plasma glucose rises. In addition, the glucagon is active and the glucagon will work on the liver to cause a secretion of glucose into the bloodstream. There's nothing that dampens the activity of the glucagon. So we have not only the glucose coming in from the diet but we have this additional amount of glucose which is being made by the liver. So we have very high circulating levels of plasma glucose, such as in that individual's son, who 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, so that a lot of the glucose will stay in the presumptive urine and because it's osmotically active, it holds water. And so we have then an increase of glucose in the urine, an increase in urine output, and consequently, a loss of electrolytes and this leads to dehydration. The glucagon itself is working in the liver and as I said, it increases the secretion of glucose, but it also is causing a lipolysis to occur so that we are shifting metabolism so that we have ketones. 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. And so, that means that we are creating metabolic acidosis. And under these conditions with dehydration plus metabolic acidosis, the individual can go into a coma and 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 become a very serious condition when it's unopposed by insulin. What are key concepts? So, 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. And we have high insulin to glucagon ratio, we have fuel storage and this is an anabolic condition. When we have low insulin to glucagon ratio, this promotes mobilization of the fuel stores, and that's a catabolic condition. Third, glucagon acts in concert with cortisone and epinephrine, which are being secreted from the adrenal glands in response to stress. And these three hormones glucagon, cortisol and epinephrine are changing 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 and this is then called synergy. And fourth, the type one diabetic are prone to metabolic acidosis and dehydration because insulin is absent or insufficient and that the glucagon dominates. And when glucagon dominates, it causes the liver to add more glucose to the plasma so that the glucose is 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.
