Homeostatic Control of Blood Glucose
Homeostasis
The body keeps several physiological parameters within a defined range, including body temperature, blood pressure, and the concentration of serum glucose. The defined ranges of these parameters are maintained to optimize the health of the organism within the environment it is living.
Homeostasis is the ability of a system to keep a certain parameter within a defined range or near set point. Often environmental factors or changes around the system cause the parameter to move outside its normal range. A homeostatic system senses the change in the parameter and then triggers effectors to return the parameter to its normal range.
Occasionally, the homeostatic systems in an organism breakdown or environmental conditions become so extreme that the homeostatic system cannot keep the parameters within their normal ranges. This can often lead to damage to tissues and organs and eventually disease. Many of the drugs we have developed were designed to return parameters to their normal ranges and restore health.
Homeostatic systems have at least three essential components: sensors, controllers and effectors. Sensors measure the current value of the parameter (e.g. blood pressure, blood glucose, body temperature). Controllers compare the measured value of the parameter with its set point. If the controller measure a significant different between the measured value and set point, it will activate effectors that return the parameter to the set point. The set point of the parameter is usually determined by the current physiological needs of the organism.
If you have driven a relatively new car, you have likely used a homeostatic system: cruise control. Cruise control is designed to keep the car’s speed at set point. The driver enters the set point, say 65 MPH. A sensor in the car detects the car’s current speed. The sensors sends that information to the controller which compares the current speed with the speed set by the driver. If the car’s current speed falls below the set point (e.g. car is going up a hill), the controller activates an effector, the accelerator, to increase the speed of the car. Biological homeostatic systems use similar components, but because those components have arise through evolution rather than design, the components can be more difficult to identify.
Homeostasis of Blood Glucose
The human body tries to keep serum glucose concentration within a narrow range of 4 mM to about 6 mM. We define this range as normal because when concentrations remain outside this range for prolonged periods, illness and disease can result.
Another illustration of how important serum glucose concentration is to the body comes from research done a patients who were under severe caloric restriction. The patients’ blood was drawn over time and the amount of different metabolites was measured. What is remarkable is that even after days of caloric restriction, serum glucose is held at a constant concentration, despite the near complete exhaustion of glycogen stores in less than a day.
Why does the body try to maintain serum glucose concentrations even under extreme circumstances? One reason is to maintain a ready supply of energy for the brain. The brain accounts for about 2% of the body’s weight but consumes about 20% of its energy. As alternative, the brain can use ketone bodies derived from fatty acids, but glucose is the preferred energy source. One consequence to an organism of a low concentration of serum glucose (hypoglycemia) is loss of brain function which can be catastrophic to the health of the organism.
Given the importance of glucose as an energy source for the brain, why not keep serum glucose concentrations high to ensure a consistent and adequate supply of glucose for the brain? Glucose reacts with proteins in a process called glycation. The reaction does not depend on any specific enzyme but the rate increass as the concentration of glucose increases. Glycation results in the covalent attachment of glucose to proteins which can alter the structure and function of proteins causing damage to tissues or changes in cell behavior. Many of the pathologic conditions associated with diabetes are likely due to tissue damage resulting from glycation of proteins.
To keep glucose within a narrow range, we need sensors that detect serum glucose concentrations, a controller that can compare the current concentration to the set point, and effectors that can increase or decrease the serum concentration of glucose.
Hormonal control of serum glucose
Two hormones are primarily responsible for controlling the concentration of serum glucose: insulin and glucagon. Insulin levels increase when serum glucose levels are high and causes a decrease in serum glucose concentration. Glucagon levels increase at low serum glucose concentrations and cause the serum glucose levels to rise. Remarkably, the production of both hormones are very sensitive to changes in concentration near the set point of serum glucose concentration. So, to a large extent we can understand how the body controls serum glucose concentration by understanding how glucose concentrations regulate the production of insulin and glucagon.
Insulin
Beta-cells in the pancreas sense blood glucose concentrations and release insulin when glucose concentrations rise above a certain point. Beta-cells store insulin in secretory granules which fuse with the cell membrane to release insulin in bursts.
This graph shows a time course of insulin release after an increase in blood glucose. The first phase comprises a burst of insulin that is released from secretory granules that have fused with the cell membrane. The second phase represents the synthesis of new insulin and its release via secretory granule. If blood glucose levels remain high after the initial release of insulin, beta-cells will continue to synthesize and release insulin .
The response of beta-cells to blood glucose levels is usually sufficient to rapidly return serum glucose concentrations to the normal range. After eating a meal, the intestines absorbs much of the glucose in the food and release it into the circulatory system. This can raise serum glucose levels above the maximum threshold of the normal range, but within a few hours, insulin has returned serum glucose concentrations to the normal range.
How insulin reduces serum glucose concentrations
Insulin affects cells in many different tissues and organs but skeletal muscle and adipose tissue are the primary tissues that take up glucose in response to insulin. In addition, insulin also inhibits lipolysis in adipocyte to lower lipid levels in the blood and it inhibits glycogenolysis in the liver to further reduce glucose in the blood. Thus, insulin regulates the distribution of energy throughout the body.
Glucagon
How does the body respond when the concentration of blood glucose falls below its normal level to avoid hypoglycemia? Alpha-cells in the pancreas, which reside next to beta-cells, sense low glucose levels and release glucagon. Glucagon is a short polypeptide that binds receptors in cells in the liver. The signaling pathway triggered by these receptors increases the rate of glycogenolysis and to a lesser extent gluconeogenesis to increase glucose release from the liver and raise the concentration of glucose in plasma.
Thus, the body has two mechanisms that keep blood glucose concentrations within a narrow range. Insulin is produced when blood glucose concentration becomes too high and causes skeletal muscle to take up more glucose. Glucagon is produced when blood glucose concentration is too low and causes the liver to produce and release more glucose.
Adjusting the set point
Homeostatic systems function to keep parameter near a set point or within a narrow range, but they’re a certain conditions under which the body physiologically benefits from changing the set point of parameter. For example, the set point for blood pressure changes during the day and is lowest at night when the organism is asleep.
Some conditions also demand an increase in serum glucose concentrations. For example, during exercise the body elevates serum glucose to increase energy supplies to skeletal muscle. How does the body change the homeostatic system to allow it to temporarily reset serum glucose concentrations above the normal range?
The pancreas is innervated by many nerve fibers, some of which are part of the sympathetic nervous system. The sympathetic nervous system is activated under condition in which the body has an increased demand for energy. To decrease insulin release, sympathetic nerve fibers release neurotransmitters onto beta-cells and alpha-cells. One neurotransmitter binds a G-protein coupled receptor on beta-cells and activates a pathway that decreases insulin secretion. A different neurotransmitter binds a G-protein coupled receptor on alpha-cells and activates a pathway that increases glucagon secretion. The exact events in this pathway are not clear, but the net result is an increase in serum glucose.
