[MUSIC] As we have seen a major target for both insulin and is the glucose metabolism. How are these opposite actions integrated in the intact organism? We can start by analyzing what happens if we momentarily eliminate all glucagon from the body. This can be done in animals by injecting large amounts of high affinity neutralizing antibody against glucagon here, in a conscious rabbit. During the experiment, plasma glucose concentrations were kept rather constant by variable infusions of glucose, so called glucose clamping. The figure shows that almost immediately after antibody administration it was necessary to infuse large amounts of glucose corresponding to about half of the animals normal glucose turnover, to maintain constant levels of glucose and plasma. The conclusion is that the amount of glucagon normally secreted is essential for the maintenance of at least half of the hepatic glucose production. A similar experiment but performed in humans, is seen in the next figure. Here both insulin and glucagon secretion is blocked by infusion of somatostatin resulting in very low concentrations of glucagon but, insulin concentrations are kept up by exerting this infusion, resulting in a selective glucagon deficiency. The immediate effect of this is that hepatic glucose production is almost completely halted so that a large amount of glucose has to be infused to maintain normal plasma levels. What, then, is the role of insulin? This can be studied in similar experiments with somatostatin in which glucagon levels are substituted by infusions. In these experiments hepatic glucose production, there's a rapidly increase resulting in hyperglycemia. In other words, hepatic glucose production is tightly and simultaneously regulated by both glucagon and insulin, the two being equally important. Even the slightest changes of either hormone level or in the ratio between the two hormones in the portal plasma, will result in changes in hepatic glucose production, and thereby in principle, in plasma glucose levels. What we have discussed here, delineates the regulation in post absorptive fasting state. What happens if one challenges the system with glucose? In the next figure we can see what happens. Glucose concentrations are elevated by the glucose infusion. But along with that we see that the plasma concentration of insulin rises while the concentration of glucagon falls. As a consequence, hepatic glucose production is shut down while peripheral glucose uptake increases. Now let us see what happens if we eliminate these changes in insulin and glucagon secretion. Again this can be done by infusing somatostatin to keep the andoginious production at a minimum and then substituting the basal concentrations of the two hormones by exerting this infusion. Now there are no changes in insulin and glucagon concentrations in response to the glucose administration. This means that there is no inhibition of hepatic glucose production and as a result plasma glucose concentrations rise inappropriately. This is exactly what happens in type two diabetes and probably explains the hypoglycemia of this disease. Because of the role of glucagon in appropriate hepatic glucose production and diabetes, there has been considerable interest in developing glucagon receptor antagonist for the therapy of diabetes. It was feared by many that glucagon antagonism might be dangerous, increasing the risk of serious hypoglycemia. However, extreme glucagon deficiency as observed during complete immuno neutralization, or in glucagon receptor knock out of mice, does not result in hypoglycemia, not even in response to fasting. The explanation is that it is not the actions of glucagon that are limiting for maintaining blood glucose in the fasting state when all glycogen depots are exhausted and glucose production is completely dependent on gluconeogenesis. It is the supply of substrates for gluconeogenesis and the hormone responsible for this is cortisol. Therefore, cortisol, rather than glucagon, is indispensable for survival during fasting. This explains that glucagon antagonism does not cause hypoglycemia unless inappropriately large amounts of insulin are also present. In fact, glucagon antagonism is highly effective against the hyperglycemia of type two diabetes in agreement with the mechanisms outlined above. However, several unexpected adverse effects of glucagon antagonists developed so far, have haltered their further development. Finally, it may be instructive to look at glucose regulation during muscular exercise. Since this illustrates the interplay between all the important glucose regulating mechanisms of the body. As we outlined in the beginning, muscular work is highly demanding in terms of fuel needs. During initial contractions, the muscles will utilize ATP already present. But these supplies are exhausted within seconds. Phosphocreatine next helps rephosphorylate ADP, but within 30 to 60 seconds anaerobic and then aerobic glycolysis starts up and provides ATP for contraction. Substrate for glycolysis is the glycogen stores of the muscles. However, concurrently, mechanisms involving the central and autonomic nervous systems are engaged to ensure continuous fuel supplies. In fact, the muscular work, itself, was initiated as the result of a central cerebral command. In addition, sensory afferent neurons from muscles, tendons and joints also signal to the brain that work is ongoing. The irradiating central command engages the sympathetic nervous system. Thus primary neurons to the adrenal medulla are activated resulting in a release of adrenaline which is graded according to the intensity of the work. Also sympathetic fibers to adipose tissue and muscles release noradrenaline that activates glycolysis and glycogenolysis. Fatty acids released from triglycerides are transported, bound to albumin, to the working muscles for combustion. And glycerol released in the same process is transported to the liver to serve as substrate for gluconeogenesis. Sympathetic nerve fibers to the pancreas will strongly inhibit insulin secretion. This is actually one of the most conspicuous endocrine changes in response to exercise. And stimulate glucagon secretion. This in turn, will stimulate hepatic glucose production, involving both glycogenolysis and gluconeogenesis. The gluconeogenesis is supported by the supply of lactate from the muscles and glycerol from the adipose tissue. Noradrenaline released from the sympathetic neurons innovating the liver will stimulate glycogenolysis further. In this way, muscular work can be sustained for hours without hypoglycemia. At moderate exercise, glucose may fall slightly adding to the stimulation of glucagon secretion. But at higher intensities, glucose concentrations actually rise. But how can glucose uptake in the muscles proceed in the absence of insulin? It turns out that muscular contractions result in an insulin-independent translocation of glucose transporters to the cell membranes allowing the necessary transport of glucose. It follows that if a person with diabetes was treated with a dose of insulin that is just sufficient to keep the plasma glucose at five millimoles per liter, if he starts to exercise, then the insulin independent glucose uptake in the muscles may be sufficient to cause even severe hypoglycemia. Thank you very much for listening. [MUSIC]
